Split (2)

train · 1.7k rows

problem string	solution string	n_hop int64	dataset string	split string	__index_level_0__ int64
Title: Advanced glycation end products cause increased CCN family and extracellular matrix gene expression in the diabetic rodent retina. Abstract: AIMS/HYPOTHESIS: Referred to as CCN, the family of growth factors consisting of cystein-rich protein 61 (CYR61, also known as CCN1), connective tissue growth factor (CTGF, also known as CCN2), nephroblastoma overexpressed gene (NOV, also known as CCN3) and WNT1-inducible signalling pathway proteins 1, 2 and 3 (WISP1, -2 and -3; also known as CCN4, -5 and -6) affects cellular growth, differentiation, adhesion and locomotion in wound repair, fibrotic disorders, inflammation and angiogenesis. AGEs formed in the diabetic milieu affect the same processes, leading to diabetic complications including diabetic retinopathy. We hypothesised that pathological effects of AGEs in the diabetic retina are a consequence of AGE-induced alterations in CCN family expression. MATERIALS AND METHODS: CCN gene expression levels were studied at the mRNA and protein level in retinas of control and diabetic rats using real-time quantitative PCR, western blotting and immunohistochemistry at 6 and 12 weeks of streptozotocin-induced diabetes in the presence or absence of aminoguanidine, an AGE inhibitor. In addition, C57BL/6 mice were repeatedly injected with exogenously formed AGE to establish whether AGE modulate retinal CCN growth factors in vivo. RESULTS: After 6 weeks of diabetes, Cyr61 expression levels were increased more than threefold. At 12 weeks of diabetes, Ctgf expression levels were increased twofold. Treatment with aminoguanidine inhibited Cyr61 and Ctgf expression in diabetic rats, with reductions of 31 and 36%, respectively, compared with untreated animals. Western blotting showed a twofold increase in CTGF production, which was prevented by aminoguanidine treatment. In mice infused with exogenous AGE, Cyr61 expression increased fourfold and Ctgf expression increased twofold in the retina. CONCLUSIONS/INTERPRETATION: CTGF and CYR61 are downstream effectors of AGE in the diabetic retina, implicating them as possible targets for future intervention strategies against the development of diabetic retinopathy. 1-hop neighbor's text information:Title: Global and societal implications of the diabetes epidemic. Abstract: Changes in human behaviour and lifestyle over the last century have resulted in a dramatic increase in the incidence of diabetes worldwide. The epidemic is chiefly of type 2 diabetes and also the associated conditions known as 'diabesity' and 'metabolic syndrome'. In conjunction with genetic susceptibility, particularly in certain ethnic groups, type 2 diabetes is brought on by environmental and behavioural factors such as a sedentary lifestyle, overly rich nutrition and obesity. The prevention of diabetes and control of its micro- and macrovascular complications will require an integrated, international approach if we are to see significant reduction in the huge premature morbidity and mortality it causes. 1-hop neighbor's text information:Title: Role of connective tissue growth factor in the pathogenesis of diabetic nephropathy. Abstract: We characterized a rabbit polyclonal antibody raised against human recombinant connective tissue growth factor (CTGF). The antibody recognised a higher molecular mass form (approx. 56 kDa) of CTGF in mesangial cell lysates as well as the monomeric (36-38 kDa) and lower molecular mass forms (<30 kDa) reported previously. Immunohistochemistry detected CTGF protein in glomeruli of kidneys of non-obese diabetic mice 14 days after the onset of diabetes, and this was prominent by 70 days. CTGF protein is also present in glomeruli of human patients with diabetic nephropathy. No CTGF was detected in either normal murine or human glomeruli. Transient transfection of a transformed human mesangial cell line with a CTGF-V5 epitope fusion protein markedly increased fibronectin and plasminogen activator inhibitor-1 synthesis in cultures maintained in normal glucose (4 mM) conditions; a CTGF-antisense construct reduced the elevated synthesis of these proteins in high glucose (30 mM) cultures. Culture of primary human mesangial cells for 14 days in high glucose, or in low glucose supplemented with recombinant CTGF or transforming growth factor beta1, markedly increased CTGF mRNA levels and fibronectin synthesis. However, whilst co-culture with a CTGF-antisense oligonucleotide reduced the CTGF mRNA pool by greater than 90% in high glucose, it only partially reduced fibronectin mRNA levels and synthesis. A chick anti-CTGF neutralizing antibody had a similar effect on fibronectin synthesis. Thus both CTGF and CTGF-independent pathways mediate increased fibronectin synthesis in high glucose. Nevertheless CTGF expression in diabetic kidneys is likely to be a key event in the development of glomerulosclerosis by affecting both matrix synthesis and, potentially through plasminogen activator inhibitor-1, its turnover. 1-hop neighbor's text information:Title: Early and intermediate Amadori glycosylation adducts, oxidative stress, and endothelial dysfunction in the streptozotocin-induced diabetic rats vasculature. Abstract: AIMS/HYPOTHESIS: In a model of streptozotocin-induced Type 1 diabetes mellitus in rats of 9 weeks duration, we analysed time associations between the development of hyperglycaemia, early and intermediate glycosylation Amadori adducts, or AGE compared with enhancement of oxidative stress and endothelial dysfunction. METHODS: Endothelial function was tested at several stages of streptozotocin-induced diabetes and after treatment with insulin, resulting in different concentrations of blood glucose, glycosylated haemoglobin (an Amadori adduct), and AGE. Other animals were studied antagonising the formation of AGE with aminoguanidine. RESULTS: Relaxation in response to acetylcholine (1 nmol/l to 10 micro mol/l) was tested in isolated segments from aorta or mesenteric microvessels. Impairment of endothelium-dependent relaxations occurred after 2 weeks of untreated diabetes. Preincubation of vessels affected with 100 U/ml superoxide dismutase improved the relaxations to acetylcholine, along the time-course of the endothelial impairment. This indicates the participation of reactive oxygen species on diabetic endothelial dysfunction. The impairment of endothelium-dependent relaxations was recovered after 3 more weeks of insulin treatment. Aminoguanidine treatment did not modify this pattern of development. The time course of the rise and disappearance of endothelial dysfunction showed a higher correlation with glycosylated haemoglobin concentrations than with blood glucose or serum AGE. CONCLUSION/INTERPRETATION: Enhancement of early and intermediate Amadori adducts of protein glycosylation was the factor showing a better relation with the development of endothelium impairment. These results are consistent with a role for these products in the development of diabetic vasculopathy. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2 0 0,0	1	pubmed	train	0
Title: Accelerated diabetes in non-obese diabetic (NOD) mice differing in incidence of spontaneous disease. Abstract: The NOD mouse is an established model of autoimmune diabetes mellitus. Various lines of NOD mice differ in their incidence of spontaneous diabetes, e.g. 93% of female NOD/Lt mice compared with 46% of female NOD/Wehi mice develop diabetes by 250 days. These two lines were studied under conditions which greatly accelerate the onset of hyperglycaemia. It was hoped that their responses to these manipulations would reveal characteristic differences which would increase our understanding of diabetes resistance in the low incidence NOD/Wehi line. One dose of 300 mg/kg of cyclophosphamide (CP) produced hyperglycaemia in 50% of NOD mice within 2 weeks in both lines. They were also equally susceptible to diabetes induced by splenocyte transfer at 21 days of age from prediabetic 150-day-old NOD/Lt or NOD/Wehi females. Five daily 40 mg/kg doses of streptozotocin (STZ) resulted in a severity of diabetes in the NOD mice greater than in C57BL or SJL/mice. While the incidence and severity of diabetes induced in the two NOD lines were similar, this appeared to be principally due to sensitivity to the toxic effects of STZ rather than its ability to exacerbate autoimmune beta cell destruction. It has previously been shown that it is possible to prevent diabetes in susceptible NOD mice with simple, relatively benign therapies and here we show that it is possible to induce diabetes in resistant animals at a rate indistinguishable from fully predisposed individuals. It therefore appears that the prediabetic NOD mouse is poised in an immunologically precarious state with the onset of disease being highly dependent on factors which exacerbate or moderate autoimmune destruction. 1-hop neighbor's text information:Title: Association of beta-cell-specific expression of endogenous retrovirus with development of insulitis and diabetes in NOD mouse. Abstract: The administration of cyclophosphamide to nonobese diabetic (NOD) male mice produces a rapid progression to overt diabetes (greater than 70%) with severe insulitis in 2-3 wk, whereas none of the untreated control NOD male mice became diabetic. When the thin sections of islets from the NOD male mice, which received silica for the preservation of islets and subsequently cyclophosphamide, were examined under the electron microscope, clusters of endogenous retrovirus-like particles (type A) were frequently found in the beta-cells. In contrast, retrovirus-like particles were rarely found in the beta-cells from NOD male mice that received only silica. Other endocrine cells, including alpha-, delta-, pancreatic polypeptide-producing, and exocrine acinar cells, did not contain such viruslike particles. These viruslike particles were also not found in spleen, liver, or kidney in either cyclophosphamide-treated or untreated NOD male mice. There was a clear correlation between the presence of retrovirus-like particles in the beta-cells and insulitis lesions in the cyclophosphamide-treated mice. On the basis of these observations, we conclude that the beta-cell-specific expression of endogenous retrovirus (like particles) is associated with the development of insulitis and diabetes in NOD mice. 1-hop neighbor's text information:Title: High and low diabetes incidence nonobese diabetic (NOD) mice: origins and characterisation. Abstract: The Nonobese Diabetic mouse (NOD mouse) is an established model of autoimmune diabetes mellitus. While all colonies of NOD mice are derived from a single diabetic female detected during the breeding of a cataract-prone strain of mice, some of the dispersed colonies have been separated for many generations and express varying levels of diabetes. It is unclear to what extent this is due to environmental factors such as diet factor or a result of the varied origins of the colonies. Here we compare the incidence of diabetes and severity of insulitis in two divergent lines of NOD mice that differ in incidence of disease, but are maintained in the same environment. F1 crosses were performed and the progeny found to express the disease incidence of the low incidence line. This finding is consistent with either a dominant resistance gene(s) being responsible for reduced penetrance of disease or a transmissible environmental agent reducing the severity of the autoimmune process. 1-hop neighbor's text information:Title: Anti-suppressor effect of cyclophosphamide on the development of spontaneous diabetes in NOD mice. Abstract: In the NOD mouse, an autoimmune process beginning by 5 weeks of age with lymphocyte infiltration and destruction of insulin-secreting beta cells leads to overt diabetes which begins to appear by 11 weeks of age. Although there is a high incidence of insulitis by 10 weeks of age (greater than 80%) in both males and females, by 30 weeks of age diabetic symptoms have occurred in 53-80% of females and in 12-40% of males. Intraperitoneal injection of a high dose (200 mg/kg) of cyclophosphamide (CY) consistently induces the onset of diabetes in male and female NOD mice at an age when spontaneous diabetes rarely occurs. Spleen T cells from CY-induced diabetic mice are capable of transferring the disease into irradiated nondiabetic syngeneic recipients. This indicates that the diabetogenic effect of CY is not mediated by direct toxicity on pancreatic beta cells but is mediated by abrogation of a suppressor mechanism which may prevent activation of T cells responsible for the development of diabetes in the NOD mouse. Additionally, CY is only effective in NOD mice and not in F1 hybrids between NOD and other strains of mice. Thus, the potential beta cell aggressor mechanism is not present in these hybrids as it is in homozygous mice, which indicates that it is not under the control of dominant genes. 2-hop neighbor's text information:Title: The pathogenicity of islet-infiltrating lymphocytes in the non-obese diabetic (NOD) mouse. Abstract: The aim of the present study was to investigate the pathogenic properties of islet-infiltrating lymphocytes related to the severity of the autoimmune destruction of islet beta-cells in the NOD mouse. We analysed the development of insulin-dependent diabetes mellitus (IDDM) produced by adoptive transfer of islet lymphocytes from NOD into NOD.scid mice. Here we show that the transfer was most effective when both CD4+ and CD8+ T cells were present in the infiltrate, but CD4+ T cells alone were sufficient to cause the disease. Islet lymphocytes from both females and males transferred diabetes effectively, but the severity of IDDM was higher when female islet lymphocytes were used. Unexpectedly, the sensitivity of male islets to beta-cell damage was greater than that of female islets. Treatment of NOD females with a peptide of heat shock protein (hsp)60, p277, known to protect NOD mice from IDDM, reduced the pathogenicity of the islet lymphocytes. In contrast, administration of cyclophosphamide to males, a treatment that accelerates the disease, rendered the islet lymphocytes more pathogenic. More severe disease in the recipient NOD.scid mice was associated with more interferon-gamma (IFN-gamma)-secreting islet T cells of the NOD donor. The disease induced by islet lymphocytes was strongly inhibited by co-transfer of spleen cells from prediabetic mice, emphasizing the regulatory role of peripheral lymphocytes. Thus, the cellular characteristics of the islet infiltrate and the pathogenicity of the cells are subject to complex regulation. 2-hop neighbor's text information:Title: In vivo activity and in vitro specificity of CD4+ Th1 and Th2 cells derived from the spleens of diabetic NOD mice. Abstract: CD4+ T cell lines were generated from the spleens of diabetic NOD mice against crude membrane preparations derived from a rat insulinoma. Adoptive transfer of these lines into neonatal mice confirms that overt diabetes is induced by gamma-IFN-secreting Th1 cells, whereas transfer of IL-4-secreting Th2 cells resulted in a nondestructive peri-islet insulitis. Analysis of the antigens recognized by individual T cell clones from the Th1 line included reactivity against an insulinoma membrane fraction enriched in proteins of approximately 38 kD. Immune responses to the same antigen preparation have been associated with T cell clones derived from human insulin-dependent diabetes mellitus. The specificity of Th2 cells includes reactivity to a fraction enriched in proteins of 30 kD. The data suggest that in insulin-dependent diabetes mellitus the balance between beta cell destruction, associated with intra-islet infiltration, and nondestructive (potential protective) peri-islet insulitis may depend on both the antigens recognized, and the prevailing cytokine environment. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	0 0 0 1 1,0	2	pubmed	train	5
Title: Prevalence and risk factors for urinary incontinence in women with type 2 diabetes and impaired fasting glucose: findings from the National Health and Nutrition Examination Survey (NHANES) 2001-2002. Abstract: OBJECTIVE: Diabetes is associated with increased risk of urinary incontinence. It is unknown whether women with pre-diabetes, or impaired fasting glucose (IFG), have increased prevalence of incontinence. We determined the prevalence of, and risk factors for, incontinence among U.S. women with diabetes and IFG. RESEARCH DESIGN AND METHODS: The 2001-2002 National Health and Nutrition Examination Survey measured fasting plasma glucose and obtained information about diabetes and urinary incontinence among 1,461 nonpregnant adult women. Self-reported weekly or more frequent incontinence, both overall and by type (urge and stress), was our outcome. RESULTS: Of the 1,461 women, 17% had diabetes and 11% met criteria for IFG. Prevalence of weekly incontinence was similar among women in these two groups (35.4 and 33.4%, respectively) and significantly higher than among women with normal fasting glucose (16.8%); both urge and stress incontinence were increased. In addition to well-recognized risk factors including age, weight, and oral estrogen use, two microvascular complications caused by diabetes, specifically macroalbuminuria and peripheral neuropathic pain, were associated with incontinence. CONCLUSIONS: Physicians should be alert for incontinence, an often unrecognized and therefore undertreated disorder, among women with diabetes and IFG, in particular those with microvascular complications. The additional prospect of improvements in their incontinence may help motivate some high-risk women to undertake difficult lifestyle changes to reduce their more serious risk of diabetes and its sequelae. 1-hop neighbor's text information:Title: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Abstract: BACKGROUND: Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial. METHODS: 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48-60 years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6.1-15.0 mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. In the conventional group, the aim was the best achievable FPG with diet alone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy. FINDINGS: Over 10 years, haemoglobin A1c (HbA1c) was 7.0% (6.2-8.2) in the intensive group compared with 7.9% (6.9-8.8) in the conventional group--an 11% reduction. There was no difference in HbA1c among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-related endpoint; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40, p=0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints between the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p<0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg). INTERPRETATION: Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes.(ABSTRACT TRUNCATED) 1-hop neighbor's text information:Title: Type 2 diabetes mellitus and risk of developing urinary incontinence. Abstract: OBJECTIVES: To evaluate the association between type 2 diabetes mellitus (DM) and development of urinary incontinence in women. DESIGN: Prospective, observational study. SETTING: The Nurses' Health Study cohort. PARTICIPANTS: Eighty-one thousand eight hundred forty-five women who reported information on urinary function in 1996. MEASUREMENTS: Self-reported, physician-diagnosed DM was ascertained using questionnaire from 1976 to 1996 and confirmed using standard criteria. Self-reported urinary incontinence, defined as leakage at least weekly, was ascertained in 1996 and 2000. Logistic regression models were used to calculate multivariate-adjusted relative risks (RRs) and 95% confidence intervals (CIs) for the relationship between DM (as of 1996) and prevalent and incident incontinence. RESULTS: The risk of prevalent incontinence (multivariate RR=1.28, 95% CI=1.18-1.39) and incident incontinence (multivariate RR=1.21, 95% CI=1.02-1.43) was significantly greater in women with DM than women without. Using a validated severity index, risk of developing severe incontinence was even more substantial in women with DM than in those without (multivariate RR=1.40, 95% CI=1.15-1.71 for leakage enough to wet the underwear; RR=1.97, 95% CI=1.24-3.12 for leakage enough to wet the outer clothing). In addition, risk of incontinence increased with duration of DM (P-trend=.03 for prevalent incontinence; P=.001 for incident incontinence). CONCLUSION: DM independently increases risk of urinary incontinence in women. Because risk of incontinence appeared associated with longer duration of DM, even delaying the onset of DM could have important public health implications. 1-hop neighbor's text information:Title: Urinary incontinence among women with type 1 diabetes--how common is it? Abstract: PURPOSE: We compared the prevalence, level of bother and effect on daily activities of urinary incontinence among women with type 1 diabetes enrolled in the Epidemiology of Diabetes Interventions and Complications study to a population based sample of women with normal glucose. MATERIALS AND METHODS: We performed a cross-sectional analysis of women with type 1 diabetes and normal glucose tolerance using 2 study populations. The Diabetes Control and Complications Trial cohort followup, Epidemiology of Diabetes Interventions and Complications, began in 1994. In 2004 women participants (550) completed a self-administered questionnaire on urinary incontinence. Our primary outcome was weekly or greater incontinence, overall and by type. Prevalence of urinary incontinence was compared to a subgroup of women with normal glucose in the 2001 to 2002 National Health and Nutrition Examination Survey (NHANES). RESULTS: Overall 65% of women with type 1 diabetes reported any urinary incontinence (17% reported weekly incontinence). Nearly 40% of these women were greatly bothered by their incontinence and 9% believed it affected their day-to-day activities. Women with type 1 diabetes had a nearly 2-fold greater prevalence of weekly urge incontinence compared to those without diabetes in the NHANES cohort (8.8% vs 4.5%, p = 0.01). CONCLUSIONS: Urinary incontinence is common in women with type 1 diabetes and the prevalence of weekly urge incontinence is far greater compared to that in women with normal glucose levels. Moreover, the prevalence of urinary incontinence in women with type 1 diabetes was greater than that of neuropathy, retinopathy and nephropathy. These findings highlight the importance of screening for urinary incontinence among women with type 1 diabetes. Studies examining factors associated with urinary incontinence in women with type 1 diabetes are warranted. 2-hop neighbor's text information:Title: Blood glucose monitoring is associated with better glycemic control in type 2 diabetes: a database study. Abstract: BACKGROUND: The value of self-monitoring blood glucose (SMBG) in type 2 diabetes is controversial. OBJECTIVE: To determine SMBG testing rates are positively associated with glycemic control in veterans on oral hypoglycemic agents (OHA). DESIGN: Observational database study. SUBJECTS: Southwestern Healthcare Network veterans taking OHA in 2002 and followed through the end of 2004. MEASUREMENTS: OHA and glucose test strip (GTS) prescriptions were derived from pharmacy files. Subjects were categorized into five groups according to their end-of-study treatment status: group 1 (no medication changes), group 2 (increased doses of initial OHA), group 3 (started new OHA), group 4 (both OHA interventions), and group 5 (initiated insulin). We then used multiple linear regression analyses to examine the relationship between the SMBG testing rate and hemoglobin A1c (HbA1c) within each group. RESULTS: We evaluated 5,862 patients with a mean follow-up duration of 798 +/- 94 days. Overall, 44.2% received GTS. Ultimately, 47% of subjects ended up in group 1, 21% in group 2, 9% in group 3, 8% in group 4, and 16% in group 5. A univariate analysis showed no association between the SMBG testing rate and HbA1c. However, after stratifying by group and adjusting for initial OHA dose, we found that more frequent testing was associated with a significantly lower HbA1c in groups 1, 4, and 5. The effect ranged from -0.22% to -0.94% for every ten GTS/week. CONCLUSIONS: Higher SMBG testing rates were associated with lower HbA1c, but only when stratifying the analyses to control for treatment intensification. 2-hop neighbor's text information:Title: Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. Abstract: OBJECTIVE: To determine the relation between systolic blood pressure over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes. DESIGN: Prospective observational study. SETTING: 23 hospital based clinics in England, Scotland, and Northern Ireland. PARTICIPANTS: 4801 white, Asian Indian, and Afro-Caribbean UKPDS patients, whether randomised or not to treatment, were included in analyses of incidence; of these, 3642 were included in analyses of relative risk. OUTCOME MEASURES: Primary predefined aggregate clinical outcomes: any complications or deaths related to diabetes and all cause mortality. Secondary aggregate outcomes: myocardial infarction, stroke, lower extremity amputation (including death from peripheral vascular disease), and microvascular disease (predominantly retinal photocoagulation). Single end points: non-fatal heart failure and cataract extraction. Risk reduction associated with a 10 mm Hg decrease in updated mean systolic blood pressure adjusted for specific confounders. RESULTS: The incidence of clinical complications was significantly associated with systolic blood pressure, except for cataract extraction. Each 10 mm Hg decrease in updated mean systolic blood pressure was associated with reductions in risk of 12% for any complication related to diabetes (95% confidence interval 10% to 14%, P<0.0001), 15% for deaths related to diabetes (12% to 18%, P<0.0001), 11% for myocardial infarction (7% to 14%, P<0.0001), and 13% for microvascular complications (10% to 16%, P<0.0001). No threshold of risk was observed for any end point. CONCLUSIONS: In patients with type 2 diabetes the risk of diabetic complications was strongly associated with raised blood pressure. Any reduction in blood pressure is likely to reduce the risk of complications, with the lowest risk being in those with systolic blood pressure less than 120 mm Hg. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2 2 1 2 2,2	2	pubmed	train	7
Title: Prevalence and risk factors for urinary incontinence in women with type 2 diabetes and impaired fasting glucose: findings from the National Health and Nutrition Examination Survey (NHANES) 2001-2002. Abstract: OBJECTIVE: Diabetes is associated with increased risk of urinary incontinence. It is unknown whether women with pre-diabetes, or impaired fasting glucose (IFG), have increased prevalence of incontinence. We determined the prevalence of, and risk factors for, incontinence among U.S. women with diabetes and IFG. RESEARCH DESIGN AND METHODS: The 2001-2002 National Health and Nutrition Examination Survey measured fasting plasma glucose and obtained information about diabetes and urinary incontinence among 1,461 nonpregnant adult women. Self-reported weekly or more frequent incontinence, both overall and by type (urge and stress), was our outcome. RESULTS: Of the 1,461 women, 17% had diabetes and 11% met criteria for IFG. Prevalence of weekly incontinence was similar among women in these two groups (35.4 and 33.4%, respectively) and significantly higher than among women with normal fasting glucose (16.8%); both urge and stress incontinence were increased. In addition to well-recognized risk factors including age, weight, and oral estrogen use, two microvascular complications caused by diabetes, specifically macroalbuminuria and peripheral neuropathic pain, were associated with incontinence. CONCLUSIONS: Physicians should be alert for incontinence, an often unrecognized and therefore undertreated disorder, among women with diabetes and IFG, in particular those with microvascular complications. The additional prospect of improvements in their incontinence may help motivate some high-risk women to undertake difficult lifestyle changes to reduce their more serious risk of diabetes and its sequelae. 1-hop neighbor's text information:Title: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. Abstract: OBJECTIVE: To determine whether tight control of blood pressure prevents macrovascular and microvascular complications in patients with type 2 diabetes. DESIGN: Randomised controlled trial comparing tight control of blood pressure aiming at a blood pressure of <150/85 mm Hg (with the use of an angiotensin converting enzyme inhibitor captopril or a beta blocker atenolol as main treatment) with less tight control aiming at a blood pressure of <180/105 mm Hg. SETTING: 20 hospital based clinics in England, Scotland, and Northern Ireland. SUBJECTS: 1148 hypertensive patients with type 2 diabetes (mean age 56, mean blood pressure at entry 160/94 mm Hg); 758 patients were allocated to tight control of blood pressure and 390 patients to less tight control with a median follow up of 8.4 years. MAIN OUTCOME MEASURES: Predefined clinical end points, fatal and non-fatal, related to diabetes, deaths related to diabetes, and all cause mortality. Surrogate measures of microvascular disease included urinary albumin excretion and retinal photography. RESULTS: Mean blood pressure during follow up was significantly reduced in the group assigned tight blood pressure control (144/82 mm Hg) compared with the group assigned to less tight control (154/87 mm Hg) (P<0.0001). Reductions in risk in the group assigned to tight control compared with that assigned to less tight control were 24% in diabetes related end points (95% confidence interval 8% to 38%) (P=0.0046), 32% in deaths related to diabetes (6% to 51%) (P=0.019), 44% in strokes (11% to 65%) (P=0.013), and 37% in microvascular end points (11% to 56%) (P=0.0092), predominantly owing to a reduced risk of retinal photocoagulation. There was a non-significant reduction in all cause mortality. After nine years of follow up the group assigned to tight blood pressure control also had a 34% reduction in risk in the proportion of patients with deterioration of retinopathy by two steps (99% confidence interval 11% to 50%) (P=0.0004) and a 47% reduced risk (7% to 70%) (P=0.004) of deterioration in visual acuity by three lines of the early treatment of diabetic retinopathy study (ETDRS) chart. After nine years of follow up 29% of patients in the group assigned to tight control required three or more treatments to lower blood pressure to achieve target blood pressures. CONCLUSION: Tight blood pressure control in patients with hypertension and type 2 diabetes achieves a clinically important reduction in the risk of deaths related to diabetes, complications related to diabetes, progression of diabetic retinopathy, and deterioration in visual acuity. 1-hop neighbor's text information:Title: Cardiovascular risk factors in confirmed prediabetic individuals. Does the clock for coronary heart disease start ticking before the onset of clinical diabetes? Abstract: Although type II diabetes is associated with both microvascular and macrovascular complications, duration of diabetes and severity of glycemia are strongly associated only with the former. Since prediabetic individuals are hyperinsulinemia, and since hyperinsulinemia may be a cardiovascular risk factor, we hypothesized that prediabetic individuals might have an atherogenic pattern of risk factors even before the onset of clinical diabetes, thereby explaining the relative lack of an association of macrovascular complications with either glycemic severity or disease duration. We documented the cardiovascular risk factor status of 614 initially nondiabetic Mexican Americans who later participated in an 8-year follow-up of the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease. Individuals who were nondiabetic at the time of baseline examination, but who subsequently developed type II diabetes (ie, confirmed prediabetic subjects, n = 43), had higher levels of total and low-density lipoprotein cholesterol, triglyceride, fasting glucose and insulin, 2-hour glucose, body mass index, and blood pressure, and lower levels of high-density lipoprotein cholesterol than subjects who remained nondiabetic (n = 571). Most of these differences persisted after adjustment for obesity and/or level of glycemia, but were abolished after adjustment for fasting insulin concentration. When subjects with impaired glucose tolerance at baseline (n = 106) were eliminated, the more atherogenic pattern of cardiovascular risk factors was still evident (and statistically significant) among initially normoglycemic prediabetic subjects. These results indicate that prediabetic subjects have an atherogenic pattern of risk factors (possibly caused by obesity, hyperglycemia, and especially hyperinsulinemia), which may be present for many years and may contribute to the risk of macrovascular disease as much as the duration of clinical diabetes itself. 1-hop neighbor's text information:Title: Diabetes and the risk of multi-system aging phenotypes: a systematic review and meta-analysis. Abstract: BACKGROUND: Observational studies suggested an association between diabetes and the risk of various geriatric conditions (i.e., cognitive impairment, dementia, depression, mobility impairment, disability, falls, and urinary incontinence). However, the magnitude and impact of diabetes on older adults have not been reviewed. METHODOLOGY/PRINCIPAL FINDINGS: MEDLINE and PSYCINFO databases were searched through November 2007 for published studies, supplemented by manual searches of bibliographies of key articles. Population-based, prospective cohort studies that reported risk of geriatric outcomes in relation to diabetes status at baseline were selected. Two authors independently extracted the data, including study population and follow-up duration, ascertainment of diabetes status at baseline, outcomes of interest and their ascertainment, adjusted covariates, measures of association, and brief results. Fifteen studies examined the association of DM with cognitive dysfunction. DM was associated with a faster decline in cognitive function among older adults. The pooled adjusted risk ratio (RR) for all dementia when persons with DM were compared to those without was 1.47 (95% CI, 1.25 to 1.73). Summary RRs for Alzheimer's disease and vascular dementia comparing persons with DM to those without were 1.39 (CI, 1.16 to 1.66) and 2.38 (CI, 1.79 to 3.18), respectively. Four of 5 studies found significant association of DM with faster mobility decline and incident disability. Two studies examined the association of diabetes with falls in older women. Both found statistically significant associations. Insulin users had higher RR for recurrent falls. One study for urinary incontinence in older women found statistically significant associations. Two studies for depression did not suggest that DM was an independent predictor of incident depression. CONCLUSIONS/SIGNIFICANCE: Current evidence supports that DM is associated with increased risk for selected geriatric conditions. Clinicians should increase their awareness and provide appropriate care. Future research is required to elucidate the underlying pathological pathway. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2 2 2,2	1	pubmed	train	8
Title: HLA and insulin gene associations with IDDM. Abstract: The HLA DR genotype frequencies in insulin-dependent diabetes mellitus (IDDM) patients and the frequencies of DR alleles transmitted from affected parent to affected child both indicate that the DR3-associated predisposition is more "recessive" and the DR4-associated predisposition more "dominant" in inheritance after allowing for the DR3/DR4 synergistic effect. B locus distributions on patient haplotypes indicate that only subsets of both DR3 and DR4 are predisposing. Heterogeneity is detected for both the DR3 and DR4 predisposing haplotypes based on DR genotypic class. With appropriate use of the family structure of the data a control population of "unaffected" alleles can be defined. Application of this method confirms the predisposing effect associated with the class 1 allele of the polymorphic region 5' to the insulin gene. 1-hop neighbor's text information:Title: Evidence of a non-MHC susceptibility locus in type I diabetes linked to HLA on chromosome 6. Abstract: Linkage studies have led to the identification of several chromosome regions that may contain susceptibility loci to type I diabetes (IDDM), in addition to the HLA and INS loci. These include two on chromosome 6q, denoted IDDM5 and IDDM8, that are not linked to HLA. In a previous study, we noticed that the evidence for linkage to IDDM susceptibility around the HLA locus extended over a total distance of 100 cM, which suggested to us that another susceptibility locus could reside near HLA. We developed a statistical method to test this hypothesis in a panel of 523 multiplex families from France, the United States, and Denmark (a total of 667 affected sib pairs, 536 with both parents genotyped), and here present evidence (P = .00003) of a susceptibility locus for IDDM located 32 cM from HLA in males but not linked to HLA in females and distinct from IDDM5 and IDDM8. A new statistical method to test for the presence of a second susceptibility locus linked to a known first susceptibility locus (here HLA) is presented. In addition, we analyzed our current family panel with markers for IDDM5 and IDDM8 on chromosome 6 and found suggestions of linkage for both of these loci (P = .002 and .004, respectively, on the complete family panel). When cumulated with previously published results, with overlapping families removed, the affected-sib-pair tests had a significance of P = .0001 for IDDM5 and P = .00004 for IDDM8. 1-hop neighbor's text information:Title: Genetic analysis of type 1 diabetes using whole genome approaches. Abstract: Whole genome linkage analysis of type 1 diabetes using affected sib pair families and semi-automated genotyping and data capture procedures has shown how type 1 diabetes is inherited. A major proportion of clustering of the disease in families can be accounted for by sharing of alleles at susceptibility loci in the major histocompatibility complex on chromosome 6 (IDDM1) and at a minimum of 11 other loci on nine chromosomes. Primary etiological components of IDDM1, the HLA-DQB1 and -DRB1 class II immune response genes, and of IDDM2, the minisatellite repeat sequence in the 5' regulatory region of the insulin gene on chromosome 11p15, have been identified. Identification of the other loci will involve linkage disequilibrium mapping and sequencing of candidate genes in regions of linkage. 1-hop neighbor's text information:Title: Testing parental imprinting in insulin-dependent diabetes mellitus by the marker-association-segregation-chi 2 method. Abstract: Among patients with insulin-dependent diabetes mellitus (IDDM), an excess of DR3 and DR4 alleles is classically described when compared with the general population. In addition, an excess of maternal DR3 and paternal DR4 alleles among patients (DR3DR4) is observed. In order to explain these observations, two alternative hypotheses can be tested: maternal effect and parental imprinting. Maternal effect has been tested and not rejected on a sample of 416 caucasians affected with IDDM. Under this hypothesis, the children of a DR3 mother are expected to have an earlier exposure and, hence, an earlier age at onset. However, we did not observe such a difference in age at onset in this data set. Using the marker-association-segregation-chi 2 method, we have tested four hypotheses with different parental effects of two susceptibility alleles, alpha 0 and beta 0, at two different closely linked loci. Under the hypothesis that best fitted the data, the probability of being affected depended on the parental inheritance of the susceptibility alleles, suggesting parental imprinting (i.e., differential role of maternal and paternal allele), without evidence for a cis-trans effect. We conclude that parental imprinting on a specific allelic combination may explain the observations on the HLA genotypes of the patients and their relatives. 2-hop neighbor's text information:Title: Insulin immunization of nonobese diabetic mice induces a protective insulitis characterized by diminished intraislet interferon-gamma transcription. Abstract: We reported previously that daily injections of isophane insulin prevented both hyperglycemia and insulitis in nonobese diabetic (NOD) mice (Atkinson, M., N. Maclaren; and R. Luchetta. 1990. Diabetes. 39:933-937). The possible mechanisms responsible include reduced immunogenicity of pancreatic beta-cells from "beta-cell rest" and induced active immunoregulation to insulin (Aaen, IK., J. Rygaard, K. Josefsen, H. Petersen, C. H. Brogren, T. Horn, and K. Buschard. 1990. Diabetes. 39:697-701). We report here that intermittent immunizations with insulin or its metabolically inactive B-chain in incomplete Freund's adjuvant also prevent diabetes in NOD mice, whereas immunizations with A-chain insulin or with BSA do not. Adoptive transfer of splenocytes from B-chain insulin-immunized mice prevented diabetes in recipients co-infused with diabetogenic spleen cells, an effect that was abolished by prior in vivo elimination of either CD4+ or CD8+ cells. Insulin immunization did not reduce the extent of intraislet inflammation (insulitis); however, it did abolish expression of IFN-gamma mRNA within the insulitis lesions. Immunizations with insulin thus induce an active suppressive response to determinants on the B-chain that converts the insulitis lesion from one that is destructive to one that is protective. 2-hop neighbor's text information:Title: Susceptibility to insulin dependent diabetes mellitus maps to a 4.1 kb segment of DNA spanning the insulin gene and associated VNTR. Abstract: Recent studies have demonstrated that a locus at 11p15.5 confers susceptibility to insulin dependent diabetes mellitus (IDDM). This locus has been shown to lie within a 19 kb region. We present a detailed sequence comparison of the predominant haplotypes found in this region in a population of French Caucasian IDDM patients and controls. Identification of polymorphisms both associated and unassociated with IDDM has allowed us to define further the region of association to 4.1 kb. Ten polymorphisms within this region are in strong linkage disequilibrium with each other and extend across the insulin gene locus and the variable number tandem repeat (VNTR) situated immediately 5' to the insulin gene. These represent a set of candidate disease polymorphisms one or more of which may account for the susceptibility to IDDM. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1 1 1 1,1	2	pubmed	train	9
Title: Prevalence and risk factors for urinary incontinence in women with type 2 diabetes and impaired fasting glucose: findings from the National Health and Nutrition Examination Survey (NHANES) 2001-2002. Abstract: OBJECTIVE: Diabetes is associated with increased risk of urinary incontinence. It is unknown whether women with pre-diabetes, or impaired fasting glucose (IFG), have increased prevalence of incontinence. We determined the prevalence of, and risk factors for, incontinence among U.S. women with diabetes and IFG. RESEARCH DESIGN AND METHODS: The 2001-2002 National Health and Nutrition Examination Survey measured fasting plasma glucose and obtained information about diabetes and urinary incontinence among 1,461 nonpregnant adult women. Self-reported weekly or more frequent incontinence, both overall and by type (urge and stress), was our outcome. RESULTS: Of the 1,461 women, 17% had diabetes and 11% met criteria for IFG. Prevalence of weekly incontinence was similar among women in these two groups (35.4 and 33.4%, respectively) and significantly higher than among women with normal fasting glucose (16.8%); both urge and stress incontinence were increased. In addition to well-recognized risk factors including age, weight, and oral estrogen use, two microvascular complications caused by diabetes, specifically macroalbuminuria and peripheral neuropathic pain, were associated with incontinence. CONCLUSIONS: Physicians should be alert for incontinence, an often unrecognized and therefore undertreated disorder, among women with diabetes and IFG, in particular those with microvascular complications. The additional prospect of improvements in their incontinence may help motivate some high-risk women to undertake difficult lifestyle changes to reduce their more serious risk of diabetes and its sequelae. 1-hop neighbor's text information:Title: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Abstract: BACKGROUND: Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial. METHODS: 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48-60 years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6.1-15.0 mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. In the conventional group, the aim was the best achievable FPG with diet alone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy. FINDINGS: Over 10 years, haemoglobin A1c (HbA1c) was 7.0% (6.2-8.2) in the intensive group compared with 7.9% (6.9-8.8) in the conventional group--an 11% reduction. There was no difference in HbA1c among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-related endpoint; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40, p=0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints between the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p<0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg). INTERPRETATION: Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes.(ABSTRACT TRUNCATED) 1-hop neighbor's text information:Title: Type 2 diabetes mellitus and risk of developing urinary incontinence. Abstract: OBJECTIVES: To evaluate the association between type 2 diabetes mellitus (DM) and development of urinary incontinence in women. DESIGN: Prospective, observational study. SETTING: The Nurses' Health Study cohort. PARTICIPANTS: Eighty-one thousand eight hundred forty-five women who reported information on urinary function in 1996. MEASUREMENTS: Self-reported, physician-diagnosed DM was ascertained using questionnaire from 1976 to 1996 and confirmed using standard criteria. Self-reported urinary incontinence, defined as leakage at least weekly, was ascertained in 1996 and 2000. Logistic regression models were used to calculate multivariate-adjusted relative risks (RRs) and 95% confidence intervals (CIs) for the relationship between DM (as of 1996) and prevalent and incident incontinence. RESULTS: The risk of prevalent incontinence (multivariate RR=1.28, 95% CI=1.18-1.39) and incident incontinence (multivariate RR=1.21, 95% CI=1.02-1.43) was significantly greater in women with DM than women without. Using a validated severity index, risk of developing severe incontinence was even more substantial in women with DM than in those without (multivariate RR=1.40, 95% CI=1.15-1.71 for leakage enough to wet the underwear; RR=1.97, 95% CI=1.24-3.12 for leakage enough to wet the outer clothing). In addition, risk of incontinence increased with duration of DM (P-trend=.03 for prevalent incontinence; P=.001 for incident incontinence). CONCLUSION: DM independently increases risk of urinary incontinence in women. Because risk of incontinence appeared associated with longer duration of DM, even delaying the onset of DM could have important public health implications. 1-hop neighbor's text information:Title: Urinary incontinence among women with type 1 diabetes--how common is it? Abstract: PURPOSE: We compared the prevalence, level of bother and effect on daily activities of urinary incontinence among women with type 1 diabetes enrolled in the Epidemiology of Diabetes Interventions and Complications study to a population based sample of women with normal glucose. MATERIALS AND METHODS: We performed a cross-sectional analysis of women with type 1 diabetes and normal glucose tolerance using 2 study populations. The Diabetes Control and Complications Trial cohort followup, Epidemiology of Diabetes Interventions and Complications, began in 1994. In 2004 women participants (550) completed a self-administered questionnaire on urinary incontinence. Our primary outcome was weekly or greater incontinence, overall and by type. Prevalence of urinary incontinence was compared to a subgroup of women with normal glucose in the 2001 to 2002 National Health and Nutrition Examination Survey (NHANES). RESULTS: Overall 65% of women with type 1 diabetes reported any urinary incontinence (17% reported weekly incontinence). Nearly 40% of these women were greatly bothered by their incontinence and 9% believed it affected their day-to-day activities. Women with type 1 diabetes had a nearly 2-fold greater prevalence of weekly urge incontinence compared to those without diabetes in the NHANES cohort (8.8% vs 4.5%, p = 0.01). CONCLUSIONS: Urinary incontinence is common in women with type 1 diabetes and the prevalence of weekly urge incontinence is far greater compared to that in women with normal glucose levels. Moreover, the prevalence of urinary incontinence in women with type 1 diabetes was greater than that of neuropathy, retinopathy and nephropathy. These findings highlight the importance of screening for urinary incontinence among women with type 1 diabetes. Studies examining factors associated with urinary incontinence in women with type 1 diabetes are warranted. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2 2 1,2	1	pubmed	train	10
Title: IL-1alpha, IL-1beta, and IFN-gamma mark beta cells for Fas-dependent destruction by diabetogenic CD4(+) T lymphocytes. Abstract: Cytokines such as IL-1alpha, IL-1beta, and IFN-gamma have long been implicated in the pathogenesis of autoimmune diabetes, but the mechanisms through which they promote diabetogenesis remain unclear. Here we show that CD4(+) T lymphocytes propagated from transgenic nonobese diabetic (NOD) mice expressing the highly diabetogenic, beta cell-specific 4.1-T-cell receptor (4.1-TCR) can kill IL-1alpha-, IL-1beta-, and IFN-gamma-treated beta cells from NOD mice. Untreated NOD beta cells and cytokine-treated beta cells from Fas-deficient NOD.lpr mice are not targeted by these T cells. Killing of islet cells in vitro was associated with cytokine-induced upregulation of Fas on islet cells and was independent of MHC class II expression. Abrogation of Fas expression in 4.1-TCR-transgenic NOD mice afforded nearly complete protection from diabetes and did not interfere with the development of the transgenic CD4(+) T cells or with their ability to cause insulitis. In contrast, abrogation of perforin expression did not affect beta cell-specific cytotoxicity or the diabetogenic potential of these T cells. These data demonstrate a novel mechanism of action of IL-1alpha, IL-1beta, and IFN-gamma in autoimmune diabetes, whereby these cytokines mark beta cells for Fas-dependent lysis by autoreactive CD4(+) T cells. 1-hop neighbor's text information:Title: Perforin-independent beta-cell destruction by diabetogenic CD8(+) T lymphocytes in transgenic nonobese diabetic mice. Abstract: Autoimmune diabetes in nonobese diabetic (NOD) mice results from destruction of pancreatic beta cells by T lymphocytes. It is believed that CD8(+) cytotoxic T lymphocytes (CTLs) effect the initial beta-cell insult in diabetes, but the mechanisms remain unclear. Studies of NOD.lpr mice have suggested that disease initiation is a Fas-dependent process, yet perforin-deficient NOD mice rarely develop diabetes despite expressing Fas. Here, we have investigated the role of perforin and Fas in the ability of beta cell-reactive CD8(+) T cells bearing a T-cell receptor (8.3-TCR) that is representative of TCRs used by CD8(+) CTLs propagated from the earliest insulitic lesions of NOD mice, and that targets an immunodominant peptide/H-2Kd complex on beta cells, to effect beta-cell damage in vitro and in vivo. In vitro, 8.3-CTLs killed antigenic peptide-pulsed non-beta-cell targets via both perforin and Fas, but they killed NOD beta cells via Fas exclusively. Perforin-deficient 8.3-TCR-transgenic NOD mice expressing an oligoclonal or monoclonal T-cell repertoire developed diabetes even more frequently than their perforin-competent littermates. These results demonstrate that diabetogenic CD8(+) CTLs representative of CTLs putatively involved in the initiation of autoimmune diabetes kill beta cells in a Fas-dependent and perforin-independent manner. 1-hop neighbor's text information:Title: Antigen-presenting cells in adoptively transferred and spontaneous autoimmune diabetes. Abstract: Histological techniques were used to identify antigen-presenting cells (APC) in adoptively transferred diabetes in NOD mice and Ins-HA transgenic mice, and in spontaneously diabetic NOD mice. In adoptively transferred disease, CD4+ T cells and F4/80+ macrophages dominated early infiltrates. By contrast, in spontaneously developing diabetes in NOD mice, lymphocytic infiltrates appeared to be well organized around a network of VCAM-1+ NLDC-145+ ICAM-1+ dendritic cells. Thus, the primary APC spontaneous autoimmune disease appears to be the strongly stimulatory dendritic cell rather than the normally resident macrophage. Next, we used chimeric animals to demonstrate that insulitis and diabetes could occur even when responding T cells were unable to recognize islet-specific antigen directly on beta cells. Altogether, the results demonstrate that immune-mediated damage does not require direct contact between CD4+ T cells and beta cells. Moreover, despite the induction of ICAM-1, VCAM-1, and class II on vascular endothelium near islet infiltrates, these experiments show that recruitment of lymphocytes occurs even when antigen presentation is not possible on vascular endothelium. 1-hop neighbor's text information:Title: Beta 2-microglobulin-deficient NOD mice do not develop insulitis or diabetes. Abstract: The role of CD8+ T-cells in the development of diabetes in the nonobese diabetic (NOD) mouse remains controversial. Although it is widely agreed that class II-restricted CD4+ T-cells are essential for the development of diabetes in the NOD model, some studies have suggested that CD8+ T-cells are not required for beta-cell destruction. To assess the contribution of CD8+ T-cells to diabetes, we have developed a class of NOD mouse that lacks expression of beta 2-microglobulin (NOD-B2mnull). NOD-B2mnull mice, which lack both class I expression and CD8+ T-cells in the periphery, not only failed to develop diabetes but were completely devoid of insulitis. These results demonstrate an essential role for CD8+ T-cells in the initiation of the autoimmune response to beta-cells in the NOD mouse. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 0 1,1	1	pubmed	train	12
Title: [Association of vitamin D receptor gene polymorphism with type 1 diabetes mellitus in two Spanish populations]. Abstract: BACKGROUND AND OBJECTIVE: In order to assess whether vitamin D receptor gene polymorphisms are involved in the genetic regulation of type 1 diabetes susceptibility, a case-control study was conducted in two Spanish populations with different genetic backgrounds. PATIENTS AND METHOD: 155 patients with childhood-onset type 1 diabetes and 280 healthy controls from Barcelona, and 89 patients and 116 controls from Navarre were studied for vitamin D receptor gene polymorphisms in peripheral blood DNA. Intron 8 (BsmI) and exon 2 (FokI) segments were amplified by PCR and sequenced to determine each corresponding genotype. Differences for allele, genotype and combined haplotype and genotype distribution between patients and controls within each population and between the two populations were analyzed. RESULTS: BsmI genotype and allele frequencies showed a tendency towards increased bb genotype and b allele frequencies in Barcelona patients and the tendency was inverse in Navarre. FokI polymorphism distribution analysis showed a significant decrease in ff genotype (p = 0.016) in patients versus controls from Navarre. Combined genotypes showed homozygous bb/FF genotype to be increased in Barcelona patients (p = 0.04) whereas homozygous bb/ff genotype was decreased in Navarre patients (p = 0.02) versus their corresponding controls. BF haplotype frequency distribution between patients and controls was inverse and significantly different between Barcelona and Navarre (p = 0.04). CONCLUSIONS: Combined genotypes for vitamin D receptor gene polymorphisms at intron 8 and exon 2 suggest that the more active form of vitamin D receptor gene (FF genotype) can be increased in Mediterranean diabetic patients whereas the less active form (ff genotype) can be decreased in those from Navarre. Our results suggest that, in both groups, the F allele of exon 2 VDR gene polymorphism may increase type 1 diabetes susceptibility. 1-hop neighbor's text information:Title: FokI polymorphism, vitamin D receptor, and interleukin-1 receptor haplotypes are associated with type 1 diabetes in the Dalmatian population. Abstract: Vitamin D and interleukin (IL)-1 have been suggested to function in the pathogenesis of type 1 diabetes mellitus (T1DM). Therefore, we examined the influence of gene polymorphisms in vitamin D receptor (VDR) and interleukin-1 receptor type I (IL-1-R1) on susceptibility to T1DM in the Dalmatian population of South Croatia. We genotyped 134 children with T1DM and 132 controls; for FokI polymorphism studies, we extended the control group to an additional 102 patients. The VDR gene polymorphism FokI displayed unequal distribution (P = 0.0049) between T1DM and control groups, with the ff genotype occurring more frequently in T1DM individuals whereas the VDR gene polymorphism Tru9I did not differ in frequency between studied groups. All tested polymorphisms of the IL-1-R1 gene [PstI, HinfI, and AluI (promoter region) and PstI-e (exon 1B region)] displayed no differences between cases and controls. Haplotype analysis of the VDR gene (FokI, BsmI, ApaI, TaqI, Tru9I) and of the IL-1-R1 gene (PstI, HinfI, AluI, PstI-e) found haplotypes VDR FbATu (P = 0.0388) and IL-1-R1 phap' (P = 0.0419) to be more frequent in T1DM patients whereas the BatU haplotype occurred more often in controls (P = 0.0064). Our findings indicate that the VDR FokI polymorphism and several VDR and IL-1-R1 haplotypes are associated with susceptibility to T1DM in the Dalmatian population. 2-hop neighbor's text information:Title: HLA complex genes in type 1 diabetes and other autoimmune diseases. Which genes are involved? Abstract: The predisposition to develop a majority of autoimmune diseases is associated with specific genes within the human leukocyte antigen (HLA) complex. However, it is frequently difficult to determine which of the many genes of the HLA complex are directly involved in the disease process. The main reasons for these difficulties are the complexity of associations where several HLA complex genes might be involved, and the strong linkage disequilibrium that exists between the genes in this complex. The latter phenomenon leads to secondary disease associations, or what has been called 'hitchhiking polymorphisms'. Here, we give an overview of the complexity of HLA associations in autoimmune disease, focusing on type 1 diabetes and trying to answer the question: how many and which HLA genes are directly involved? 2-hop neighbor's text information:Title: An association between type 1 diabetes and the interleukin-1 receptor type 1 gene. The DiMe Study Group. Childhood Diabetes in Finland. Abstract: The polygenic susceptibility to type 1 diabetes is well established and recent studies have demonstrated linkage of a further locus on chromosome 2q to disease. We have studied a polymorphism of the interleukin-1 receptor type 1 gene (IL1R1) on chromosome 2q in type 1 diabetic and control subjects from Finland, the United Kingdom, South India: three populations in which the risk of disease varies from very high to very low. In the medium-risk U.K. population we find a very strong association of IL1R1 with type 1 diabetes (p = 0.0002) but we find no overall association in either the high-risk Finnish or low-risk South-Indian populations. However, we do find heterogeneity of risk at IL1R1 amongst Finnish diabetic subjects according to the possession of HLA-DR associated susceptibility (p = 0.0001); there is an association with IL1R1 in only those Finnish diabetic subjects who do not possess high-risk HLA-DR4 or DR3 haplotypes (p = 0.006), as recently demonstrated for the insulin gene region in this population. We find no such heterogeneity of risk in either the U.K. or South-Indian populations. This study further demonstrates the genetic heterogeneity of disease susceptibility between and within populations and also supports the hypothesis of an interaction of the IL1R1 locus with genes within the HLA and insulin gene regions in the susceptibility to type 1 diabetes. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1 1,1	2	pubmed	train	13
Title: Nocturnal electroencephalogram registrations in type 1 (insulin-dependent) diabetic patients with hypoglycaemia. Abstract: Eight Type 1 (insulin-dependent) diabetic patients with no diabetic complications were studied overnight for two consecutive and one subsequent night with continuous monitoring of electroencephalogram and serial hormone measurements. The aims were: 1) to evaluate the influence of spontaneous and insulin-induced hypoglycaemia on nocturnal electroencephalogram sleep-patterns and, 2) to evaluate counter-regulatory hormone responses. Spontaneous hypoglycaemia occurred on six nights (38%) with blood glucose concentrations less than 3.0 mmol/l and on four nights less than 2.0 mmol/l. All the patients experienced insulin-induced hypoglycaemia with a blood glucose nadir of 1.6 (range 1.4-1.9) mmol/l. The electroencephalogram was analysed by a new method developed for this purpose in contrast to the traditional definition of delta-, theta-, alpha- and beta-activity. The blood glucose concentration could be correlated to the rank of individual electroencephalogram-patterns during the whole night, and specific hypoglycaemic amplitude-frequency patterns could be assigned. Three of the eight patients showed electroencephalogram changes at blood glucose levels below 2.0 (1.6-2.0) mmol/l. The electroencephalogram classes representing hypoglycaemic activity had peak frequencies at 4 and 6 Hz, respectively, clearly different from the patients' delta- and theta-activity. The changes were not identical in each patient, however, they were reproducible in each patient. The changes were found equally in all regions of the brain. The three patients with electroencephalogram changes during nocturnal hypoglycaemia could only be separated from the other five patients by their impaired glucagon responses. Against this background the possibility of protection by glucagon, against neurophysiologic changes in the brain during hypoglycaemia may be considered. 1-hop neighbor's text information:Title: Defective awakening response to nocturnal hypoglycemia in patients with type 1 diabetes mellitus. Abstract: BACKGROUND: Nocturnal hypoglycemia frequently occurs in patients with type 1 diabetes mellitus (T1DM). It can be fatal and is believed to promote the development of the hypoglycemia-unawareness syndrome. Whether hypoglycemia normally provokes awakening from sleep in individuals who do not have diabetes, and whether this awakening response is impaired in T1DM patients, is unknown. METHODS AND FINDINGS: We tested two groups of 16 T1DM patients and 16 healthy control participants, respectively, with comparable distributions of gender, age, and body mass index. In one night, a linear fall in plasma glucose to nadir levels of 2.2 mmol/l was induced by infusing insulin over a 1-h period starting as soon as polysomnographic recordings indicated that stage 2 sleep had been reached. In another night (control), euglycemia was maintained. Only one of the 16 T1DM patients, as compared to ten healthy control participants, awakened upon hypoglycemia (p = 0.001). In the control nights, none of the study participants in either of the two groups awakened during the corresponding time. Awakening during hypoglycemia was associated with increased hormonal counterregulation. In all the study participants (from both groups) who woke up, and in five of the study participants who did not awaken (three T1DM patients and two healthy control participants), plasma epinephrine concentration increased with hypoglycemia by at least 100% (p < 0.001). A temporal pattern was revealed such that increases in epinephrine in all participants who awakened started always before polysomnographic signs of wakefulness (mean +/- standard error of the mean: 7.5 +/- 1.6 min). CONCLUSIONS: A fall in plasma glucose to 2.2 mmol/l provokes an awakening response in most healthy control participants, but this response is impaired in T1DM patients. The counterregulatory increase in plasma epinephrine that we observed to precede awakening suggests that awakening forms part of a central nervous system response launched in parallel with hormonal counterregulation. Failure to awaken increases the risk for T1DM patients to suffer prolonged and potentially fatal hypoglycemia. 1-hop neighbor's text information:Title: Nocturnal hypoglycaemia and sleep disturbances in young teenagers with insulin dependent diabetes mellitus. Abstract: OBJECTIVE: To determine the effect of nocturnal hypoglycaemia on sleep architecture in adolescents with insulin dependent diabetes mellitus (IDDM). DESIGN: 20 adolescents with IDDM (mean age 12.8 years, mean glycated haemoglobin (HbA1c) 8.9%) were studied on one night. Plasma glucose was measured every 30 minutes and cortisol and growth hormone levels every 60 minutes. Sleep was recorded using standard polysomnographic montages, and sleep architecture was analysed for total sleep time, stages 1-4, rapid eye movement, fragmentation, and arousals. RESULTS: Six subjects (30%) became hypoglycaemic (five subjects < 2.5 mmol/l), with one being symptomatic. There were no differences in age, HbA1c, duration of diabetes, or insulin regimen between hypoglycaemic and non-hypoglycaemic subjects. Hypoglycaemia was not predicted by glucose measurements before bed. There was no detectable rise in plasma cortisol or growth hormone concentrations during hypoglycaemia. Sleep architecture was not disturbed by nocturnal hypoglycaemia with no differences found in sleep stages, fragmentation, or arousals. CONCLUSIONS: Nocturnal hypoglycaemia is a common and usually asymptomatic complication of treatment in adolescents with IDDM. Moderate hypoglycaemia has not been shown to affect sleep architecture adversely. These findings are consistent with, and may explain, the observation that severe hypoglycaemia, with consequent seizure activity, is more common at night than during the day. Counterregulatory hormone responses to nocturnal hypoglycaemia may be less marked than with similar degrees of diurnal hypoglycaemia. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1,1	1	pubmed	train	20
Title: IL-1alpha, IL-1beta, and IFN-gamma mark beta cells for Fas-dependent destruction by diabetogenic CD4(+) T lymphocytes. Abstract: Cytokines such as IL-1alpha, IL-1beta, and IFN-gamma have long been implicated in the pathogenesis of autoimmune diabetes, but the mechanisms through which they promote diabetogenesis remain unclear. Here we show that CD4(+) T lymphocytes propagated from transgenic nonobese diabetic (NOD) mice expressing the highly diabetogenic, beta cell-specific 4.1-T-cell receptor (4.1-TCR) can kill IL-1alpha-, IL-1beta-, and IFN-gamma-treated beta cells from NOD mice. Untreated NOD beta cells and cytokine-treated beta cells from Fas-deficient NOD.lpr mice are not targeted by these T cells. Killing of islet cells in vitro was associated with cytokine-induced upregulation of Fas on islet cells and was independent of MHC class II expression. Abrogation of Fas expression in 4.1-TCR-transgenic NOD mice afforded nearly complete protection from diabetes and did not interfere with the development of the transgenic CD4(+) T cells or with their ability to cause insulitis. In contrast, abrogation of perforin expression did not affect beta cell-specific cytotoxicity or the diabetogenic potential of these T cells. These data demonstrate a novel mechanism of action of IL-1alpha, IL-1beta, and IFN-gamma in autoimmune diabetes, whereby these cytokines mark beta cells for Fas-dependent lysis by autoreactive CD4(+) T cells. 1-hop neighbor's text information:Title: Mechanisms of beta cell death in diabetes: a minor role for CD95. Abstract: Insulin-dependent diabetes mellitus is an autoimmune disease, under polygenic control, manifested only when >90% of the insulin-producing beta cells are destroyed. Although the disease is T cell mediated, the demise of the beta cell results from a number of different insults from the immune system. It has been proposed that foremost amongst these effector mechanisms is CD95 ligand-induced beta cell death. Using the nonobese diabetic lpr mouse as a model system, we have found, to the contrary, that CD95 plays only a minor role in the death of beta cells. Islet grafts from nonobese diabetic mice that carry the lpr mutation and therefore lack CD95 were protected only marginally from immune attack when grafted into diabetic mice. An explanation to reconcile these differing results is provided. 1-hop neighbor's text information:Title: Beta cell MHC class I is a late requirement for diabetes. Abstract: Type 1 diabetes occurs as a result of an autoimmune attack on the insulin-producing beta cells. Although CD8 T cells have been implicated both early and late in this process, the requirement for direct interaction between these cells and MHC class I on the beta cells has not been demonstrated. By using nonobese diabetic mice lacking beta cell class I expression, we show that both initiation and progression of insulitis proceeds unperturbed. However, without beta cell class I expression, the vast majority of these mice do not develop hyperglycemia. These findings demonstrate that a direct interaction between CD8 T cells and beta cells is not required for initiation or early disease progression. The requirement for class I on beta cells is a relatively late checkpoint in the development of diabetes. 1-hop neighbor's text information:Title: Major histocompatibility complex class I-deficient NOD-B2mnull mice are diabetes and insulitis resistant. Abstract: Specific allelic combinations within the class II region of the major histocompatibility complex (MHC) represent a major genetic component for susceptibility to autoimmune insulin-dependent diabetes mellitus (IDDM) in humans. We produced and used a stock of NOD/Lt mice congenic for a functionally inactivated beta 2-microglobulin (B2mnull) locus to assess whether there was an absolute requirement for MHC class I expression and/or CD8+ T-cells in diabetogenesis. These NOD-B2mnull mice do not express cell surface MHC class I molecules or produce detectable levels of CD8+ T-cells and are diabetes and insulitis resistant. Previous results from transgenic mouse models indicated that intracellular accumulation of MHC class I molecules negatively affects pancreatic beta-cell function and can result in the development of nonautoimmune insulin-dependent diabetes mellitus (IDDM). MHC class I molecules have been shown to accumulate intracellularly in the presence of a disrupted B2m locus, but this mutation does not negatively affect plasma insulin levels in either NOD/Lt mice or in those of a mixed 129 and C57BL/6 genetic background. Interestingly, 14% of the male mice in this mixed background did develop hyperinsulinemia (> 1,500 pM) independent of the disrupted B2m locus, suggesting that these mice could conceivably develop insulin-resistant diabetes. However, none of these mice became diabetic at up to 22 months of age. Thus, elimination of cell surface MHC class I expression with a disrupted B2m gene blocks autoimmune diabetes in NOD/Lt mice, without engendering a separate, distinct form of glucose intolerance. 2-hop neighbor's text information:Title: Widespread expression of an autoantigen-GAD65 transgene does not tolerize non-obese diabetic mice and can exacerbate disease. Abstract: Glutamic acid decarboxylase (GAD)65 is a pancreatic beta cell autoantigen implicated as a target of T cells that initiate and sustain insulin-dependent diabetes mellitus (IDDM) in humans and in non-obese diabetic (NOD) mice. In an attempt to establish immunological tolerance toward GAD65 in NOD mice, and thereby to test the importance of GAD in IDDM, we generated three lines transgenic for murine GAD65 driven by a major histocompatibility complex class I promoter. However, despite widespread transgene expression in both newborn and adult mice, T cell tolerance was not induced. Mononuclear cell infiltration of the islets (insulitis) and diabetes were at least as bad in transgenic mice as in nontransgenic NOD mice, and in mice with the highest level of GAD65 expression, disease was exacerbated. In contrast, the same transgene introduced into mouse strain, FvB, induced neither insulitis nor diabetes, and T cells were tolerant to GAD. Thus, the failure of NOD mice to develop tolerance toward GAD65 reflects at minimum a basic defect in central tolerance, not seen in animals not predisposed to IDDM. Hence, it may not be possible experimentally to induce full tolerance toward GAD65 in prediabetic individuals. Additionally, the fact that autoimmune infiltration in GAD65 transgenic NOD mice remained largely restricted to the pancreas, indicates that the organ-specificity of autoimmune disease is dictated by tissue-specific factors in addition to those directing autoantigen expression. 2-hop neighbor's text information:Title: CD8 T cell clones from young nonobese diabetic (NOD) islets can transfer rapid onset of diabetes in NOD mice in the absence of CD4 cells. Abstract: T cells play an important role in the pathogenesis of diabetes in the nonobese diabetic (NOD) mouse. CD8 cytotoxic T cell lines and clones were generated from the lymphocytic infiltrate in the islets of Langerhans of young (7-wk-old). NOD mice by growing them on (NOD x B6-RIP-B7-1)F1 islets. These cells proliferate specifically to NOD islets and kill NOD islets in vitro. The cells are restricted by H-2Kd, and all bear T cell antigen receptor encoded by V beta 6. When these CD8 T cell lines and clones are adoptively transferred to irradiated female NOD, young NOD-SCID, and CB17-SCID mice, diabetes occurs very rapidly, within 10 d of transfer and without CD4 T cells. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1 1 1 2,1	2	pubmed	train	22
Title: Prevalence and risk factors for urinary incontinence in women with type 2 diabetes and impaired fasting glucose: findings from the National Health and Nutrition Examination Survey (NHANES) 2001-2002. Abstract: OBJECTIVE: Diabetes is associated with increased risk of urinary incontinence. It is unknown whether women with pre-diabetes, or impaired fasting glucose (IFG), have increased prevalence of incontinence. We determined the prevalence of, and risk factors for, incontinence among U.S. women with diabetes and IFG. RESEARCH DESIGN AND METHODS: The 2001-2002 National Health and Nutrition Examination Survey measured fasting plasma glucose and obtained information about diabetes and urinary incontinence among 1,461 nonpregnant adult women. Self-reported weekly or more frequent incontinence, both overall and by type (urge and stress), was our outcome. RESULTS: Of the 1,461 women, 17% had diabetes and 11% met criteria for IFG. Prevalence of weekly incontinence was similar among women in these two groups (35.4 and 33.4%, respectively) and significantly higher than among women with normal fasting glucose (16.8%); both urge and stress incontinence were increased. In addition to well-recognized risk factors including age, weight, and oral estrogen use, two microvascular complications caused by diabetes, specifically macroalbuminuria and peripheral neuropathic pain, were associated with incontinence. CONCLUSIONS: Physicians should be alert for incontinence, an often unrecognized and therefore undertreated disorder, among women with diabetes and IFG, in particular those with microvascular complications. The additional prospect of improvements in their incontinence may help motivate some high-risk women to undertake difficult lifestyle changes to reduce their more serious risk of diabetes and its sequelae. 1-hop neighbor's text information:Title: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. Abstract: BACKGROUND: Type 2 diabetes affects approximately 8 percent of adults in the United States. Some risk factors--elevated plasma glucose concentrations in the fasting state and after an oral glucose load, overweight, and a sedentary lifestyle--are potentially reversible. We hypothesized that modifying these factors with a lifestyle-intervention program or the administration of metformin would prevent or delay the development of diabetes. METHODS: We randomly assigned 3234 nondiabetic persons with elevated fasting and post-load plasma glucose concentrations to placebo, metformin (850 mg twice daily), or a lifestyle-modification program with the goals of at least a 7 percent weight loss and at least 150 minutes of physical activity per week. The mean age of the participants was 51 years, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 34.0; 68 percent were women, and 45 percent were members of minority groups. RESULTS: The average follow-up was 2.8 years. The incidence of diabetes was 11.0, 7.8, and 4.8 cases per 100 person-years in the placebo, metformin, and lifestyle groups, respectively. The lifestyle intervention reduced the incidence by 58 percent (95 percent confidence interval, 48 to 66 percent) and metformin by 31 percent (95 percent confidence interval, 17 to 43 percent), as compared with placebo; the lifestyle intervention was significantly more effective than metformin. To prevent one case of diabetes during a period of three years, 6.9 persons would have to participate in the lifestyle-intervention program, and 13.9 would have to receive metformin. CONCLUSIONS: Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk. The lifestyle intervention was more effective than metformin. 1-hop neighbor's text information:Title: Lifestyle intervention is associated with lower prevalence of urinary incontinence: the Diabetes Prevention Program. Abstract: OBJECTIVE: Diabetes is associated with increased urinary incontinence risk. Weight loss improves incontinence, but exercise may worsen this condition. We examined whether an intensive lifestyle intervention or metformin therapy among overweight pre-diabetic women was associated with a lower prevalence of incontinence. RESEARCH DESIGN AND METHODS: We analyzed data from the Diabetes Prevention Program, a randomized controlled trial in 27 U.S. centers. Of the 1,957 women included in this analysis, 660 (34%) were randomized to intensive lifestyle therapy, 636 (32%) to metformin, and 661 (34%) to placebo with standard lifestyle advice. The main outcome measure was incontinence symptoms by frequency and type by a validated questionnaire completed at the end-of-trial visit (mean 2.9 years). RESULTS: The prevalence of total (stress or urge) weekly incontinence was lower among women in the intensive lifestyle group (38.3%) than those randomized to metformin (48.1%) or placebo (45.7%). This difference was most apparent among women with stress incontinence (31.3% for intensive lifestyle group vs. 39.7% for metformin vs. 36.7% for placebo, P = 0.006). Changes in weight accounted for most of the protective effect of the intensive lifestyle intervention on stress incontinence. CONCLUSIONS: Less-frequent urinary incontinence may be a powerful motivator for women to choose lifestyle modification to prevent diabetes. 1-hop neighbor's text information:Title: Look AHEAD (Action for Health in Diabetes): design and methods for a clinical trial of weight loss for the prevention of cardiovascular disease in type 2 diabetes. Abstract: Overweight and obesity are major contributors to both type 2 diabetes and cardiovascular disease (CVD). Moreover, individuals with type 2 diabetes who are overweight or obese are at particularly high risk for CVD morbidity and mortality. Although short-term weight loss has been shown to ameliorate obesity-related metabolic abnormalities and CVD risk factors, the long-term consequences of intentional weight loss in overweight or obese individuals with type 2 diabetes have not been adequately examined. The primary objective of the Look AHEAD clinical trial is to assess the long-term effects (up to 11.5 years) of an intensive weight loss program delivered over 4 years in overweight and obese individuals with type 2 diabetes. Approximately 5000 male and female participants who have type 2 diabetes, are 45-74 years of age, and have a body mass index >or=25 kg/m(2) will be randomized to one of the two groups. The intensive lifestyle intervention is designed to achieve and maintain weight loss through decreased caloric intake and increased physical activity. This program is compared to a control condition given diabetes support and education. The primary study outcome is time to incidence of a major CVD event. The study is designed to provide a 0.90 probability of detecting an 18% difference in major CVD event rates between the two groups. Other outcomes include components of CVD risk, cost and cost-effectiveness, diabetes control and complications, hospitalizations, intervention processes, and quality of life. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2 2 2,2	1	pubmed	train	25
Title: Accelerated diabetes in non-obese diabetic (NOD) mice differing in incidence of spontaneous disease. Abstract: The NOD mouse is an established model of autoimmune diabetes mellitus. Various lines of NOD mice differ in their incidence of spontaneous diabetes, e.g. 93% of female NOD/Lt mice compared with 46% of female NOD/Wehi mice develop diabetes by 250 days. These two lines were studied under conditions which greatly accelerate the onset of hyperglycaemia. It was hoped that their responses to these manipulations would reveal characteristic differences which would increase our understanding of diabetes resistance in the low incidence NOD/Wehi line. One dose of 300 mg/kg of cyclophosphamide (CP) produced hyperglycaemia in 50% of NOD mice within 2 weeks in both lines. They were also equally susceptible to diabetes induced by splenocyte transfer at 21 days of age from prediabetic 150-day-old NOD/Lt or NOD/Wehi females. Five daily 40 mg/kg doses of streptozotocin (STZ) resulted in a severity of diabetes in the NOD mice greater than in C57BL or SJL/mice. While the incidence and severity of diabetes induced in the two NOD lines were similar, this appeared to be principally due to sensitivity to the toxic effects of STZ rather than its ability to exacerbate autoimmune beta cell destruction. It has previously been shown that it is possible to prevent diabetes in susceptible NOD mice with simple, relatively benign therapies and here we show that it is possible to induce diabetes in resistant animals at a rate indistinguishable from fully predisposed individuals. It therefore appears that the prediabetic NOD mouse is poised in an immunologically precarious state with the onset of disease being highly dependent on factors which exacerbate or moderate autoimmune destruction. 1-hop neighbor's text information:Title: Association of beta-cell-specific expression of endogenous retrovirus with development of insulitis and diabetes in NOD mouse. Abstract: The administration of cyclophosphamide to nonobese diabetic (NOD) male mice produces a rapid progression to overt diabetes (greater than 70%) with severe insulitis in 2-3 wk, whereas none of the untreated control NOD male mice became diabetic. When the thin sections of islets from the NOD male mice, which received silica for the preservation of islets and subsequently cyclophosphamide, were examined under the electron microscope, clusters of endogenous retrovirus-like particles (type A) were frequently found in the beta-cells. In contrast, retrovirus-like particles were rarely found in the beta-cells from NOD male mice that received only silica. Other endocrine cells, including alpha-, delta-, pancreatic polypeptide-producing, and exocrine acinar cells, did not contain such viruslike particles. These viruslike particles were also not found in spleen, liver, or kidney in either cyclophosphamide-treated or untreated NOD male mice. There was a clear correlation between the presence of retrovirus-like particles in the beta-cells and insulitis lesions in the cyclophosphamide-treated mice. On the basis of these observations, we conclude that the beta-cell-specific expression of endogenous retrovirus (like particles) is associated with the development of insulitis and diabetes in NOD mice. 1-hop neighbor's text information:Title: High and low diabetes incidence nonobese diabetic (NOD) mice: origins and characterisation. Abstract: The Nonobese Diabetic mouse (NOD mouse) is an established model of autoimmune diabetes mellitus. While all colonies of NOD mice are derived from a single diabetic female detected during the breeding of a cataract-prone strain of mice, some of the dispersed colonies have been separated for many generations and express varying levels of diabetes. It is unclear to what extent this is due to environmental factors such as diet factor or a result of the varied origins of the colonies. Here we compare the incidence of diabetes and severity of insulitis in two divergent lines of NOD mice that differ in incidence of disease, but are maintained in the same environment. F1 crosses were performed and the progeny found to express the disease incidence of the low incidence line. This finding is consistent with either a dominant resistance gene(s) being responsible for reduced penetrance of disease or a transmissible environmental agent reducing the severity of the autoimmune process. 1-hop neighbor's text information:Title: Anti-suppressor effect of cyclophosphamide on the development of spontaneous diabetes in NOD mice. Abstract: In the NOD mouse, an autoimmune process beginning by 5 weeks of age with lymphocyte infiltration and destruction of insulin-secreting beta cells leads to overt diabetes which begins to appear by 11 weeks of age. Although there is a high incidence of insulitis by 10 weeks of age (greater than 80%) in both males and females, by 30 weeks of age diabetic symptoms have occurred in 53-80% of females and in 12-40% of males. Intraperitoneal injection of a high dose (200 mg/kg) of cyclophosphamide (CY) consistently induces the onset of diabetes in male and female NOD mice at an age when spontaneous diabetes rarely occurs. Spleen T cells from CY-induced diabetic mice are capable of transferring the disease into irradiated nondiabetic syngeneic recipients. This indicates that the diabetogenic effect of CY is not mediated by direct toxicity on pancreatic beta cells but is mediated by abrogation of a suppressor mechanism which may prevent activation of T cells responsible for the development of diabetes in the NOD mouse. Additionally, CY is only effective in NOD mice and not in F1 hybrids between NOD and other strains of mice. Thus, the potential beta cell aggressor mechanism is not present in these hybrids as it is in homozygous mice, which indicates that it is not under the control of dominant genes. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	0 0 0,0	1	pubmed	train	26
Title: Accelerated diabetes in non-obese diabetic (NOD) mice differing in incidence of spontaneous disease. Abstract: The NOD mouse is an established model of autoimmune diabetes mellitus. Various lines of NOD mice differ in their incidence of spontaneous diabetes, e.g. 93% of female NOD/Lt mice compared with 46% of female NOD/Wehi mice develop diabetes by 250 days. These two lines were studied under conditions which greatly accelerate the onset of hyperglycaemia. It was hoped that their responses to these manipulations would reveal characteristic differences which would increase our understanding of diabetes resistance in the low incidence NOD/Wehi line. One dose of 300 mg/kg of cyclophosphamide (CP) produced hyperglycaemia in 50% of NOD mice within 2 weeks in both lines. They were also equally susceptible to diabetes induced by splenocyte transfer at 21 days of age from prediabetic 150-day-old NOD/Lt or NOD/Wehi females. Five daily 40 mg/kg doses of streptozotocin (STZ) resulted in a severity of diabetes in the NOD mice greater than in C57BL or SJL/mice. While the incidence and severity of diabetes induced in the two NOD lines were similar, this appeared to be principally due to sensitivity to the toxic effects of STZ rather than its ability to exacerbate autoimmune beta cell destruction. It has previously been shown that it is possible to prevent diabetes in susceptible NOD mice with simple, relatively benign therapies and here we show that it is possible to induce diabetes in resistant animals at a rate indistinguishable from fully predisposed individuals. It therefore appears that the prediabetic NOD mouse is poised in an immunologically precarious state with the onset of disease being highly dependent on factors which exacerbate or moderate autoimmune destruction. 1-hop neighbor's text information:Title: Transfer of autoimmune diabetes mellitus with splenocytes from nonobese diabetic (NOD) mice. Abstract: The nonobese diabetic (NOD) mouse, a model of human type I diabetes, develops insulitis beginning at 4-6 wk of age. By 30 wk of age, 72% of females and 39% of males develop spontaneous diabetes, apparently because of an overwhelming autoimmune response to the insulin-producing beta-cells within the islets. To identify the immune mechanism responsible for destruction of beta-cells in the NOD mouse, we developed an adoptive transfer protocol that induces diabetes in NOD mice at an age when spontaneous diabetes is rarely observed. Splenocytes from overtly diabetic NOD mice were unable to transfer diabetes to very young (less than or equal to 6 wk) irradiated NOD mice but effectively transferred diabetes to irradiated NOD mice greater than 6 wk of age. In such transfers, overt diabetes was induced within 12-22 days in greater than 95% (79/82) of the recipients. Thus, transfer of splenocytes to young mice induces them to become diabetic at a higher frequency and at a younger age than their untreated littermates. Equally successful transfers with as few as 5 X 10(6) spleen cells have been performed in male and female NOD mice, even though males display a lower spontaneous incidence of diabetes than females. Splenocytes obtained from diabetic mice maintained on insulin for up to 2 mo also transferred diabetes. Because NOD mice display increasing levels of insulitis with age, spleen cells obtained from nondiabetic NOD mice of different ages were tested for their ability to transfer diabetes.(ABSTRACT TRUNCATED AT 250 WORDS) 1-hop neighbor's text information:Title: Raised temperature reduces the incidence of diabetes in the NOD mouse. Abstract: An association between the incidence of childhood Type 1 (insulin-dependent) diabetes mellitus and the average yearly temperature in different countries has been reported, the incidence being higher in countries with a lower mean temperature. We have studied the effect of environmental temperature on the incidence of diabetes in an animal model of Type 1 diabetes, the non-obese diabetic (NOD) mouse. Female NOD mice were divided at weaning, with one group placed at a higher temperature (mean 23.7 +/- 1.7 degrees C) and the other at a lower temperature (21.0 +/- 1.8 degrees C). At 20 weeks of age 6 of 16 mice at lower temperature and 1 of 17 mice at higher temperature had developed diabetes (p less than 0.02); at 30 weeks 10 of 16 and 5 of 17 mice had developed diabetes (p less than 0.05). Non-diabetic animals in the low temperature group had a higher food intake than those in the high temperature group between 13-15 weeks of age (28.0 +/- 1.2 g/week vs 24.8 +/- 0.7 g/week, p less than 0.05). In a parallel experiment, histological examination showed that there were similar degrees of insulitis in the high and low temperature groups at seven weeks of age. We conclude that environmental temperature can affect the incidence of diabetes in the NOD mouse and that this may be related to alterations in food intake. 1-hop neighbor's text information:Title: Syngeneic transfer of autoimmune diabetes from diabetic NOD mice to healthy neonates. Requirement for both L3T4+ and Lyt-2+ T cells. Abstract: We have developed a model of syngeneic adoptive transfer for type I diabetes mellitus of NOD mice. This model consists in injecting spleen cells from diabetic adult mice into newborn NOD recipients. 50% of recipients inoculated with 20 X 10(6) cells develop diabetes within the first 10 wk of life, at a time when none of the control littermates have yet become diabetic. The earliest successful transfers are observed at 3 wk of age, at a time when controls do not even exhibit histological changes in their pancreas. In addition we have shown that: (a) both males and females can be adoptively transferred, despite the fact that males rarely develop spontaneous diabetes in our colony; (b) diabetes transfer is a dose-dependent phenomenon that provides an in vivo assay for comparing the autoimmune potential of spleen cells from mice at various stages of their natural history; (c) the susceptibility of the recipients to the transfer is limited in time and declines after 3 wk; and (d) both L3T4+ and Lyt-2+ T cell subsets are necessary for the successful transfer. The neonatal syngeneic transfer provides an effective model for studies of the cellular events involved at regulatory and effector stages of autoimmune type I diabetes. 2-hop neighbor's text information:Title: Pancreatic lymph nodes are required for priming of beta cell reactive T cells in NOD mice. Abstract: Nonobese diabetic (NOD) mice develop spontaneous autoimmune diabetes that results from the destruction of insulin secreting beta cells by diabetogenic T cells. The time and location of the encounter of autoantigen(s) by naive autoreactive T cells in normal NOD mice are still elusive. To address these issues, we analyzed diabetes development in mice whose spleen or pancreatic lymph nodes (panLNs) had been removed. Excision of panLNs (panLNx) at 3 wk protected mice against insulin autoantibodies (IAAs), insulitis, and diabetes development almost completely, but had no effect when performed at 10 wk. The protection afforded by panLNx at weaning was not due to modifications of the immune system, the absence of autoreactive T cells, or the increase in the potency of regulatory T cells. That panLNs are dispensable during adult life was confirmed by the capacity of 10-wk-old panLNx irradiated recipients to develop diabetes upon transfer of diabetogenic T cells. In contrast, splenectomy had no effect at any age. Partial excision of mesenteric LN at 3 wk did not prevent accelerated diabetes by cyclophosphamide as panLNx did. Thus, in normal NOD mice, autoreactive T cell initial priming occurs in LNs draining the target organ of the disease from 3 wk of age. 2-hop neighbor's text information:Title: WIN 54954 treatment of mice infected with a diabetogenic strain of group B coxsackievirus. Abstract: The therapeutic efficacy of an experimental antiviral agent, WIN 54954, was evaluated in a mouse model in which infection by coxsackievirus B4 (CVB4) strain E2 was followed by diabetes mellitus. Male CD1 mice (age, 5 weeks) were inoculated with 10(4) PFU of CVB4. WIN 54954 was administered orally via gavage tube in a dose of either 5 or 50 mg/kg of body weight per day. Treatment was initiated on the day of inoculation and was continued for 10 days. Control animals received the xanthan gum carrier only. At 3 days postinoculation (p.i.), the mean titer of virus in the pancreas was found to be significantly lower in both the high-dose (P < 0.001) and low-dose (P < 0.05) treatment groups compared with that in the controls. Furthermore, islet histologic abnormalities were significantly less common in the high-dose group (P < 0.02) than in the controls. At 7 weeks p.i., both fasting and 1-h postprandial glucose levels in blood were significantly lower for both the high-dose (P < 0.001) and the low-dose (P < 0.01) treatment groups than in controls. The proportion of mice with persistent viral RNA in the pancreas at this time, as detected by polymerase chain reaction, was significantly reduced in the high-dose treatment group (4 of 11 mice) compared with that in the controls (7 of 8 mice). When mice received 50 mg of WIN 54954 per kg daily beginning at either 48 or 72 h postinoculation, the titers in the pancreas were again significantly reduced at 3 days p.i. compared with those in the controls (P < 0.01 and P < 0.05, respectively). Thus, WIN 54954 effectively reduces virus replication and islet histologic changes acutely and decreases, at 7 weeks, both the metabolic alteration associated with diabetes mellitus and the incidence of detectable viral RNA in the pancreas. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	0 0 0 1 0,0	2	pubmed	train	28
Title: IL-1alpha, IL-1beta, and IFN-gamma mark beta cells for Fas-dependent destruction by diabetogenic CD4(+) T lymphocytes. Abstract: Cytokines such as IL-1alpha, IL-1beta, and IFN-gamma have long been implicated in the pathogenesis of autoimmune diabetes, but the mechanisms through which they promote diabetogenesis remain unclear. Here we show that CD4(+) T lymphocytes propagated from transgenic nonobese diabetic (NOD) mice expressing the highly diabetogenic, beta cell-specific 4.1-T-cell receptor (4.1-TCR) can kill IL-1alpha-, IL-1beta-, and IFN-gamma-treated beta cells from NOD mice. Untreated NOD beta cells and cytokine-treated beta cells from Fas-deficient NOD.lpr mice are not targeted by these T cells. Killing of islet cells in vitro was associated with cytokine-induced upregulation of Fas on islet cells and was independent of MHC class II expression. Abrogation of Fas expression in 4.1-TCR-transgenic NOD mice afforded nearly complete protection from diabetes and did not interfere with the development of the transgenic CD4(+) T cells or with their ability to cause insulitis. In contrast, abrogation of perforin expression did not affect beta cell-specific cytotoxicity or the diabetogenic potential of these T cells. These data demonstrate a novel mechanism of action of IL-1alpha, IL-1beta, and IFN-gamma in autoimmune diabetes, whereby these cytokines mark beta cells for Fas-dependent lysis by autoreactive CD4(+) T cells. 1-hop neighbor's text information:Title: In autoimmune diabetes the transition from benign to pernicious insulitis requires an islet cell response to tumor necrosis factor alpha. Abstract: The islet-infiltrating and disease-causing leukocytes that are a hallmark of insulin-dependent diabetes mellitus produce and respond to a set of cytokine molecules. Of these, interleukin 1beta, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma are perhaps the most important. However, as pleiotropic molecules, they can impact the path leading to beta cell apoptosis and diabetes at multiple points. To understand how these cytokines influence both the formative and effector phases of insulitis, it is critical to determine their effects on the assorted cell types comprising the lesion: the effector T cells, antigen-presenting cells, vascular endothelium, and target islet tissue. Here, we report using nonobese diabetic chimeric mice harboring islets deficient in specific cytokine receptors or cytokine-induced effector molecules to assess how these compartmentalized loss-of-function mutations alter the events leading to diabetes. We found that islets deficient in Fas, IFN-gamma receptor, or inducible nitric oxide synthase had normal diabetes development; however, the specific lack of TNF- alpha receptor 1 (p55) afforded islets a profound protection from disease by altering the ability of islet-reactive, CD4(+) T cells to establish insulitis and subsequently destroy islet beta cells. These results argue that islet cells play a TNF-alpha-dependent role in their own demise. 1-hop neighbor's text information:Title: All-trans retinoic acid inhibits type 1 diabetes by T regulatory (Treg)-dependent suppression of interferon-gamma-producing T-cells without affecting Th17 cells. Abstract: OBJECTIVE: All-trans retinoic acid (ATRA), a potent derivative of vitamin A, can regulate immune responses. However, its role in inducing immune tolerance associated with the prevention of islet inflammation and inhibition of type 1 diabetes remains unclear. RESEARCH DESIGN AND METHODS: We investigated the mechanisms underlying the potential immunoregulatory effect of ATRA on type 1 diabetes using an adoptive transfer animal model of the disease. RESULTS: Our data demonstrated that ATRA treatment inhibited diabetes in NOD mice with established insulitis. In addition, it suppressed interferon (IFN)-gamma-producing CD4(+) and CD8(+) T effector (Teff) cells and expanded T regulatory (Treg) cells in recipient mice transferred with diabetic NOD splenocytes, without affecting either interleukin (IL)-17--or IL-4-producing cells. Consistent with these results, ATRA reduced T-bet and STAT4 expression in T-cells and decreased islet-infiltrating CD8(+) T-cells, suppressing their activation and IFN-gamma/granzyme B expression. Depletion of CD4(+)CD25(+) Treg cells impaired the inhibitory effect of ATRA on islet-infiltrating T-cells and blocked its protective effect on diabetes. Therefore, ATRA treatment induced Treg cell-dependent immune tolerance by suppressing both CD4(+) and CD8(+) Teff cells while promoting Treg cell expansion. CONCLUSIONS: These results demonstrate that ATRA treatment promoted in vivo expansion of Treg cells and induced Treg cell-dependent immune tolerance by suppressing IFN-gamma-producing T-cells, without affecting Th17 cells. Our study also provides novel insights into how ATRA induces immune tolerance in vivo via its effects on Teff and Treg cells. 1-hop neighbor's text information:Title: The role of CD4+ and CD8+ T cells in the destruction of islet grafts by spontaneously diabetic mice. Abstract: Spontaneous development of diabetes in the nonobese diabetic (NOD) mouse is mediated by an immunological process. In disease-transfer experiments, the activation of diabetes has been reported to require participation of both CD4+ and CD8+ T-cell subsets. These findings seem to indicate that the CD4+ cells are the helper cells for the activation of cytotoxic CD8+ cells that directly destroy islet beta cells in type I diabetes. In this report we challenge this interpretation because of two observations: (i) Destruction of syngeneic islet grafts by spontaneously diabetic NOD mice (disease recurrence) is CD4+ and not CD8+ T-cell dependent. (ii) Disease recurrence in islet tissue grafted to diabetic NOD mice is not restricted by islet major histocompatibility complex antigens. From these observations we propose that islet destruction depends on CD4+ effector T cells that are restricted by major histocompatibility complex antigens expressed on NOD antigen-presenting cells. Both of these findings argue against the CD8+ T cell as a mediator of direct islet damage. We postulate that islet damage in the NOD mouse results from a CD4+ T-cell-dependent inflammatory response. 2-hop neighbor's text information:Title: Both CD4+ and CD8+ T-cells in syngeneic islet grafts in NOD mice produce interferon-gamma during beta-cell destruction. Abstract: Syngeneic pancreatic islet grafts in diabetic NOD mice are infiltrated by mononuclear leukocytes, beta-cells are selectively destroyed, and autoimmune diabetes recurs. This model was used to identify islet graft-infiltrating mononuclear leukocytes associated with beta-cell destruction and diabetes recurrence. We compared cell surface antigen and cytokine-producing phenotypes of mononuclear leukocytes in islet grafts from NOD mice that were protected from diabetes recurrence by complete Freund's adjuvant (CFA) administration (beta-cell nondestructive insulitis) and in islet grafts from control phosphate-buffered saline (PBS)-injected NOD mice (beta-cell destructive insulitis). Islet grafts from CFA-injected mice contained fewer CD4+ and CD8+ cells and more B cells; also fewer interferon gamma (IFN-gamma), interleukin-2 (IL-2), and tumor necrosis factor alpha (TNF-alpha)-positive cells and more IL-4 and IL-10 positive cells. By performing two-color immunostaining of cell surface antigens and intracellular IFN-gamma, we found that IFN-gamma positive cells in islet grafts from CFA- and PBS-injected mice were approximately equally divided between CD4+ and CD8+ T-cell subsets. Also, the frequencies of both CD4+ IFN-gamma + and CD8+ IFN-gamma + cells were decreased in islet grafts from CFA-injected mice. These findings suggest that destruction of beta-cells in syngeneic islets transplanted into NOD mice is promoted by cells producing Th1-type cytokines (IFN-gamma, IL-2, and TNF-alpha) and prevented by cells producing TH2-type cytokines (IL-4 and IL-10). Furthermore, both CD4+ and CD8+ IFN-gamma-producing T-cells in the islet grafts appear to be involved in beta-cell destruction and diabetes recurrence. 2-hop neighbor's text information:Title: Invariant NKT cells exacerbate type 1 diabetes induced by CD8 T cells. Abstract: Invariant NKT (iNKT) cells have been implicated in the regulation of autoimmune diseases. In several models of type 1 diabetes, increasing the number of iNKT cells prevents the development of disease. Because CD8 T cells play a crucial role in the pathogenesis of diabetes, we have investigated the influence of iNKT cells on diabetogenic CD8 T cells. In the present study, type 1 diabetes was induced by the transfer of CD8 T cells specific for the influenza virus hemagglutinin into recipient mice expressing the hemagglutinin Ag specifically in their beta pancreatic cells. In contrast to previous reports, high frequency of iNKT cells promoted severe insulitis and exacerbated diabetes. Analysis of diabetogenic CD8 T cells showed that iNKT cells enhance their activation, their expansion, and their differentiation into effector cells producing IFN-gamma. This first analysis of the influence of iNKT cells on diabetogenic CD8 T cells reveals that iNKT cells not only fail to regulate but in fact exacerbate the development of diabetes. Thus, iNKT cells can induce opposing effects dependent on the model of type 1 diabetes that is being studied. This prodiabetogenic capacity of iNKT cells should be taken into consideration when developing therapeutic approaches based on iNKT cell manipulation. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1 0 1 1,1	2	pubmed	train	29
Title: Analysis of the type 2 diabetes-associated single nucleotide polymorphisms in the genes IRS1, KCNJ11, and PPARG2 in type 1 diabetes. Abstract: It has been proposed that type 1 and 2 diabetes might share common pathophysiological pathways and, to some extent, genetic background. However, to date there has been no convincing data to establish a molecular genetic link between them. We have genotyped three single nucleotide polymorphisms associated with type 2 diabetes in a large type 1 diabetic family collection of European descent: Gly972Arg in the insulin receptor substrate 1 (IRS1) gene, Glu23Lys in the potassium inwardly-rectifying channel gene (KCNJ11), and Pro12Ala in the peroxisome proliferative-activated receptor gamma2 gene (PPARG2). We were unable to confirm a recently published association of the IRS1 Gly972Arg variant with type 1 diabetes. Moreover, KCNJ11 Glu23Lys showed no association with type 1 diabetes (P > 0.05). However, the PPARG2 Pro12Ala variant showed evidence of association (RR 1.15, 95% CI 1.04-1.28, P = 0.008). Additional studies need to be conducted to confirm this result. 1-hop neighbor's text information:Title: No association of the IRS1 and PAX4 genes with type I diabetes. Abstract: To reassess earlier suggested type I diabetes (T1D) associations of the insulin receptor substrate 1 (IRS1) and the paired domain 4 gene (PAX4) genes, the Type I Diabetes Genetics Consortium (T1DGC) evaluated single-nucleotide polymorphisms (SNPs) covering the two genomic regions. Sixteen SNPs were evaluated for IRS1 and 10 for PAX4. Both genes are biological candidate genes for T1D. Genotyping was performed in 2300 T1D families on both Illumina and Sequenom genotyping platforms. Data quality and concordance between the platforms were assessed for each SNP. Transmission disequilibrium testing neither show T1D association of SNPs in the two genes, nor did haplotype analysis. In conclusion, the earlier suggested associations of IRS1 and PAX4 to T1D were not supported, suggesting that they may have been false positive results. This highlights the importance of thorough quality control, selection of tagging SNPs, more than one genotyping platform in high throughput studies, and sufficient power to draw solid conclusions in genetic studies of human complex diseases. 1-hop neighbor's text information:Title: No association of multiple type 2 diabetes loci with type 1 diabetes. Abstract: AIMS/HYPOTHESIS: We used recently confirmed type 2 diabetes gene regions to investigate the genetic relationship between type 1 and type 2 diabetes, in an average of 7,606 type 1 diabetic individuals and 8,218 controls, providing >80% power to detect effects as small as an OR of 1.11 at a false-positive rate of 0.003. METHODS: The single nucleotide polymorphisms (SNPs) with the most convincing evidence of association in 12 type 2 diabetes-associated gene regions, PPARG, CDKAL1, HNF1B, WFS1, SLC30A8, CDKN2A-CDKN2B, IGF2BP2, KCNJ11, TCF7L2, FTO, HHEX-IDE and THADA, were analysed in type 1 diabetes cases and controls. PPARG and HHEX-IDE were additionally tested for association in 3,851 type 1 diabetes families. Tests for interaction with HLA class II genotypes, autoantibody status, sex, and age-at-diagnosis of type 1 diabetes were performed with all 12 gene regions. RESULTS: Only PPARG and HHEX-IDE showed any evidence of association with type 1 diabetes cases and controls (p = 0.004 and p = 0.003, respectively; p > 0.05 for other SNPs). The potential association of PPARG was supported by family analyses (p = 0.003; p (combined) = 1.0 x 10(-4)). No SNPs showed evidence of interaction with any covariate (p > 0.05). CONCLUSIONS/INTERPRETATION: We found no convincing genetic link between type 1 and type 2 diabetes. An association of PPARG (rs1801282/Pro12Ala) could be consistent with its known function in inflammation. Hence, our results reinforce evidence suggesting that type 1 diabetes is a disease of the immune system, rather than being due to inherited defects in beta cell function or regeneration or insulin resistance. 2-hop neighbor's text information:Title: A functional variant of IRS1 is associated with type 1 diabetes in families from the US and UK. Abstract: A collection of 767 multiplex type 1 diabetes families from the US and UK were tested for linkage to the IRS1 gene and for allelic association with a specific variant of IRS1, G972R. Pedigree disequilibrium testing revealed preferential transmission of the 972R allele to affected offspring in these families (P = 0.02). Linkage analyses conditioning on status at IRS1 position 972 suggest the possibility of interaction with an unidentified locus on chromosome 8. 2-hop neighbor's text information:Title: Optimized autoantibody-based risk assessment in family members. Implications for future intervention trials. Abstract: OBJECTIVE: To determine the best autoantibody-based testing strategy for recruiting relatives for future intervention trials and to establish the role of islet cell antibodies (ICAs) within this strategy. RESEARCH DESIGN AND METHODS: ICAs, insulin autoantibodies (IAAs), GAD antibodies, and IA-2 antibodies were determined in serum samples at study entry of 3,655 non-diabetic first-degree relatives of patients with type 1 diabetes who were followed for a median of 5.5 years. The cumulative risk of diabetes associated with single and combined antibody marker levels of > or = 97.5th percentile in schoolchildren was calculated by using life-table analysis. RESULTS: Of the 26 relatives who developed insulin-requiring diabetes during follow-up, 16 were aged < 20 years and 7 were aged 20-39 years at study entry. Of the 23 cases aged < 40 years, 83% had IA-2 and/or GAD antibodies, and 87% had IAA and/or GAD antibodies > or = 97.5th percentile compared with 61% who had ICAs of > or = 5 Juvenile Diabetes Foundation units (JDF U). A two-step strategy with parallel testing for IA-2/GAD antibodies followed by IAA testing identified 50% of cases aged < 20 years and was associated with a 71% risk within 10 years. In subjects aged 20-39 years, this strategy conferred a 51% risk, whereas using ICAs as the second test gave 86% sensitivity and a 74% risk. Primary screening for IA-2 and/or GAD antibodies followed by testing for IAA and/or ICA antibodies achieved the highest sensitivity in both age-groups and conferred a 63% risk. In contrast, ICAs of > or = 20 JDF U (the inclusion criteria for the European Nicotinamide Diabetes Intervention Trial) gave 48% sensitivity and 35% risk. CONCLUSIONS: ICA testing can be replaced as a primary screening measure by IA-2/GAD or IAA/GAD antibody testing. The sensitivity of ICAs (used alone or in combination with IAAs) gives them a useful role in second-line testing. Combination testing could reduce the size of screening populations needed for recruitment in future intervention trials by approximately 50% compared with testing based on ICAs alone. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1 1 1,1	2	pubmed	train	30
Title: IL-1alpha, IL-1beta, and IFN-gamma mark beta cells for Fas-dependent destruction by diabetogenic CD4(+) T lymphocytes. Abstract: Cytokines such as IL-1alpha, IL-1beta, and IFN-gamma have long been implicated in the pathogenesis of autoimmune diabetes, but the mechanisms through which they promote diabetogenesis remain unclear. Here we show that CD4(+) T lymphocytes propagated from transgenic nonobese diabetic (NOD) mice expressing the highly diabetogenic, beta cell-specific 4.1-T-cell receptor (4.1-TCR) can kill IL-1alpha-, IL-1beta-, and IFN-gamma-treated beta cells from NOD mice. Untreated NOD beta cells and cytokine-treated beta cells from Fas-deficient NOD.lpr mice are not targeted by these T cells. Killing of islet cells in vitro was associated with cytokine-induced upregulation of Fas on islet cells and was independent of MHC class II expression. Abrogation of Fas expression in 4.1-TCR-transgenic NOD mice afforded nearly complete protection from diabetes and did not interfere with the development of the transgenic CD4(+) T cells or with their ability to cause insulitis. In contrast, abrogation of perforin expression did not affect beta cell-specific cytotoxicity or the diabetogenic potential of these T cells. These data demonstrate a novel mechanism of action of IL-1alpha, IL-1beta, and IFN-gamma in autoimmune diabetes, whereby these cytokines mark beta cells for Fas-dependent lysis by autoreactive CD4(+) T cells. 1-hop neighbor's text information:Title: Mechanisms of beta cell death in diabetes: a minor role for CD95. Abstract: Insulin-dependent diabetes mellitus is an autoimmune disease, under polygenic control, manifested only when >90% of the insulin-producing beta cells are destroyed. Although the disease is T cell mediated, the demise of the beta cell results from a number of different insults from the immune system. It has been proposed that foremost amongst these effector mechanisms is CD95 ligand-induced beta cell death. Using the nonobese diabetic lpr mouse as a model system, we have found, to the contrary, that CD95 plays only a minor role in the death of beta cells. Islet grafts from nonobese diabetic mice that carry the lpr mutation and therefore lack CD95 were protected only marginally from immune attack when grafted into diabetic mice. An explanation to reconcile these differing results is provided. 1-hop neighbor's text information:Title: Beta cell MHC class I is a late requirement for diabetes. Abstract: Type 1 diabetes occurs as a result of an autoimmune attack on the insulin-producing beta cells. Although CD8 T cells have been implicated both early and late in this process, the requirement for direct interaction between these cells and MHC class I on the beta cells has not been demonstrated. By using nonobese diabetic mice lacking beta cell class I expression, we show that both initiation and progression of insulitis proceeds unperturbed. However, without beta cell class I expression, the vast majority of these mice do not develop hyperglycemia. These findings demonstrate that a direct interaction between CD8 T cells and beta cells is not required for initiation or early disease progression. The requirement for class I on beta cells is a relatively late checkpoint in the development of diabetes. 1-hop neighbor's text information:Title: Major histocompatibility complex class I-deficient NOD-B2mnull mice are diabetes and insulitis resistant. Abstract: Specific allelic combinations within the class II region of the major histocompatibility complex (MHC) represent a major genetic component for susceptibility to autoimmune insulin-dependent diabetes mellitus (IDDM) in humans. We produced and used a stock of NOD/Lt mice congenic for a functionally inactivated beta 2-microglobulin (B2mnull) locus to assess whether there was an absolute requirement for MHC class I expression and/or CD8+ T-cells in diabetogenesis. These NOD-B2mnull mice do not express cell surface MHC class I molecules or produce detectable levels of CD8+ T-cells and are diabetes and insulitis resistant. Previous results from transgenic mouse models indicated that intracellular accumulation of MHC class I molecules negatively affects pancreatic beta-cell function and can result in the development of nonautoimmune insulin-dependent diabetes mellitus (IDDM). MHC class I molecules have been shown to accumulate intracellularly in the presence of a disrupted B2m locus, but this mutation does not negatively affect plasma insulin levels in either NOD/Lt mice or in those of a mixed 129 and C57BL/6 genetic background. Interestingly, 14% of the male mice in this mixed background did develop hyperinsulinemia (> 1,500 pM) independent of the disrupted B2m locus, suggesting that these mice could conceivably develop insulin-resistant diabetes. However, none of these mice became diabetic at up to 22 months of age. Thus, elimination of cell surface MHC class I expression with a disrupted B2m gene blocks autoimmune diabetes in NOD/Lt mice, without engendering a separate, distinct form of glucose intolerance. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1 1,1	1	pubmed	train	32
Title: IL-1alpha, IL-1beta, and IFN-gamma mark beta cells for Fas-dependent destruction by diabetogenic CD4(+) T lymphocytes. Abstract: Cytokines such as IL-1alpha, IL-1beta, and IFN-gamma have long been implicated in the pathogenesis of autoimmune diabetes, but the mechanisms through which they promote diabetogenesis remain unclear. Here we show that CD4(+) T lymphocytes propagated from transgenic nonobese diabetic (NOD) mice expressing the highly diabetogenic, beta cell-specific 4.1-T-cell receptor (4.1-TCR) can kill IL-1alpha-, IL-1beta-, and IFN-gamma-treated beta cells from NOD mice. Untreated NOD beta cells and cytokine-treated beta cells from Fas-deficient NOD.lpr mice are not targeted by these T cells. Killing of islet cells in vitro was associated with cytokine-induced upregulation of Fas on islet cells and was independent of MHC class II expression. Abrogation of Fas expression in 4.1-TCR-transgenic NOD mice afforded nearly complete protection from diabetes and did not interfere with the development of the transgenic CD4(+) T cells or with their ability to cause insulitis. In contrast, abrogation of perforin expression did not affect beta cell-specific cytotoxicity or the diabetogenic potential of these T cells. These data demonstrate a novel mechanism of action of IL-1alpha, IL-1beta, and IFN-gamma in autoimmune diabetes, whereby these cytokines mark beta cells for Fas-dependent lysis by autoreactive CD4(+) T cells. 1-hop neighbor's text information:Title: In autoimmune diabetes the transition from benign to pernicious insulitis requires an islet cell response to tumor necrosis factor alpha. Abstract: The islet-infiltrating and disease-causing leukocytes that are a hallmark of insulin-dependent diabetes mellitus produce and respond to a set of cytokine molecules. Of these, interleukin 1beta, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma are perhaps the most important. However, as pleiotropic molecules, they can impact the path leading to beta cell apoptosis and diabetes at multiple points. To understand how these cytokines influence both the formative and effector phases of insulitis, it is critical to determine their effects on the assorted cell types comprising the lesion: the effector T cells, antigen-presenting cells, vascular endothelium, and target islet tissue. Here, we report using nonobese diabetic chimeric mice harboring islets deficient in specific cytokine receptors or cytokine-induced effector molecules to assess how these compartmentalized loss-of-function mutations alter the events leading to diabetes. We found that islets deficient in Fas, IFN-gamma receptor, or inducible nitric oxide synthase had normal diabetes development; however, the specific lack of TNF- alpha receptor 1 (p55) afforded islets a profound protection from disease by altering the ability of islet-reactive, CD4(+) T cells to establish insulitis and subsequently destroy islet beta cells. These results argue that islet cells play a TNF-alpha-dependent role in their own demise. 1-hop neighbor's text information:Title: All-trans retinoic acid inhibits type 1 diabetes by T regulatory (Treg)-dependent suppression of interferon-gamma-producing T-cells without affecting Th17 cells. Abstract: OBJECTIVE: All-trans retinoic acid (ATRA), a potent derivative of vitamin A, can regulate immune responses. However, its role in inducing immune tolerance associated with the prevention of islet inflammation and inhibition of type 1 diabetes remains unclear. RESEARCH DESIGN AND METHODS: We investigated the mechanisms underlying the potential immunoregulatory effect of ATRA on type 1 diabetes using an adoptive transfer animal model of the disease. RESULTS: Our data demonstrated that ATRA treatment inhibited diabetes in NOD mice with established insulitis. In addition, it suppressed interferon (IFN)-gamma-producing CD4(+) and CD8(+) T effector (Teff) cells and expanded T regulatory (Treg) cells in recipient mice transferred with diabetic NOD splenocytes, without affecting either interleukin (IL)-17--or IL-4-producing cells. Consistent with these results, ATRA reduced T-bet and STAT4 expression in T-cells and decreased islet-infiltrating CD8(+) T-cells, suppressing their activation and IFN-gamma/granzyme B expression. Depletion of CD4(+)CD25(+) Treg cells impaired the inhibitory effect of ATRA on islet-infiltrating T-cells and blocked its protective effect on diabetes. Therefore, ATRA treatment induced Treg cell-dependent immune tolerance by suppressing both CD4(+) and CD8(+) Teff cells while promoting Treg cell expansion. CONCLUSIONS: These results demonstrate that ATRA treatment promoted in vivo expansion of Treg cells and induced Treg cell-dependent immune tolerance by suppressing IFN-gamma-producing T-cells, without affecting Th17 cells. Our study also provides novel insights into how ATRA induces immune tolerance in vivo via its effects on Teff and Treg cells. 1-hop neighbor's text information:Title: The role of CD4+ and CD8+ T cells in the destruction of islet grafts by spontaneously diabetic mice. Abstract: Spontaneous development of diabetes in the nonobese diabetic (NOD) mouse is mediated by an immunological process. In disease-transfer experiments, the activation of diabetes has been reported to require participation of both CD4+ and CD8+ T-cell subsets. These findings seem to indicate that the CD4+ cells are the helper cells for the activation of cytotoxic CD8+ cells that directly destroy islet beta cells in type I diabetes. In this report we challenge this interpretation because of two observations: (i) Destruction of syngeneic islet grafts by spontaneously diabetic NOD mice (disease recurrence) is CD4+ and not CD8+ T-cell dependent. (ii) Disease recurrence in islet tissue grafted to diabetic NOD mice is not restricted by islet major histocompatibility complex antigens. From these observations we propose that islet destruction depends on CD4+ effector T cells that are restricted by major histocompatibility complex antigens expressed on NOD antigen-presenting cells. Both of these findings argue against the CD8+ T cell as a mediator of direct islet damage. We postulate that islet damage in the NOD mouse results from a CD4+ T-cell-dependent inflammatory response. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1 0,1	1	pubmed	train	33
Title: Onset of diabetes in Zucker diabetic fatty (ZDF) rats leads to improved recovery of function after ischemia in the isolated perfused heart. Abstract: The aim of this study was to determine whether the transition from insulin resistance to hyperglycemia in a model of type 2 diabetes leads to intrinsic changes in the myocardium that increase the sensitivity to ischemic injury. Hearts from 6-, 12-, and 24-wk-old lean (Control) and obese Zucker diabetic fatty (ZDF) rats were isolated, perfused, and subjected to 30 min of low-flow ischemia (LFI) and 60 min of reperfusion. At 6 wk, ZDF animals were insulin resistant but not hyperglycemic. By 12 wk, the ZDF group was hyperglycemic and became progressively worse by 24 wk. In spontaneously beating hearts rate-pressure product (RPP) was depressed in the ZDF groups compared with age-matched Controls, primarily due to lower heart rate. Pacing significantly increased RPP in all ZDF groups; however, this was accompanied by a significant decrease in left ventricular developed pressure. There was also greater contracture during LFI in the ZDF groups compared with the Control group; surprisingly, however, functional recovery upon reperfusion was significantly higher in the diabetic 12- and 24-wk ZDF groups compared with age-matched Control groups and the 6-wk ZDF group. This improvement in recovery in the ZDF diabetic groups was independent of substrate availability, severity of ischemia, and duration of diabetes. These data demonstrate that, although the development of type 2 diabetes leads to progressive contractile and metabolic abnormalities during normoxia and LFI, it was not associated with increased susceptibility to ischemic injury. 1-hop neighbor's text information:Title: Polyol pathway and modulation of ischemia-reperfusion injury in Type 2 diabetic BBZ rat hearts. Abstract: We investigated the role of polyol pathway enzymes aldose reductase (AR) and sorbitol dehydrogenase (SDH) in mediating injury due to ischemia-reperfusion (IR) in Type 2 diabetic BBZ rat hearts. Specifically, we investigated, (a) changes in glucose flux via cardiac AR and SDH as a function of diabetes duration, (b) ischemic injury and function after IR, (c) the effect of inhibition of AR or SDH on ischemic injury and function. Hearts isolated from BBZ rats, after 12 weeks or 48 weeks diabetes duration, and their non-diabetic littermates, were subjected to IR protocol. Myocardial function, substrate flux via AR and SDH, and tissue lactate:pyruvate (L/P) ratio (a measure of cytosolic NADH/NAD+), and lactate dehydrogenase (LDH) release (a marker of IR injury) were measured. Zopolrestat, and CP-470,711 were used to inhibit AR and SDH, respectively. Myocardial sorbitol and fructose content, and associated changes in L/P ratios were significantly higher in BBZ rats compared to non-diabetics, and increased with disease duration. Induction of IR resulted in increased ischemic injury, reduced ATP levels, increases in L/P ratio, and poor cardiac function in BBZ rat hearts, while inhibition of AR or SDH attenuated these changes and protected hearts from IR injury. These data indicate that AR and SDH are key modulators of myocardial IR injury in BBZ rat hearts and that inhibition of polyol pathway could in principle be used as a therapeutic adjunct for protection of ischemic myocardium in Type 2 diabetic patients. 2-hop neighbor's text information:Title: Initial steps of insulin signaling and glucose transport are defective in the type 2 diabetic rat heart. Abstract: OBJECTIVE: Whole body insulin resistance and diabetes are risk factors for cardiovascular diseases, yet little is known about insulin resistance in the diabetic heart. The aim of this work was to define the insulin response in hearts of the Goto-Kakizaki (GK) rat, a polygenic model of spontaneous type 2 diabetes. METHODS: We measured D[2-3H]glucose uptake before and after insulin stimulation, plus initial steps of the insulin signaling pathway after insulin infusion via the caudal vena cava in hearts from the male Wistar and spontaneously diabetic GK rats. RESULTS: Despite normal basal D[2-3H]glucose uptake, insulin-stimulated glucose uptake was 50% (p<0.03) lower in GK rat hearts compared with their Wistar controls. Total GLUT4 protein was depleted by 28% (p<0.01) in GK rat hearts. We found 31% (p<0.0001) and 38% (p<0.001) decreased protein levels of insulin receptor beta (IRbeta)-subunit and insulin receptor substrate-1 (IRS-1), respectively, in GK rat hearts with 37% (p<0.02) and 45% (p<0.01) lower insulin-stimulated tyrosine phosphorylation of these proteins. Owing to the decreased IRS-1 protein levels, GK rat hearts had a 41% (p<0.0001) decrease in insulin-stimulated IRS-1 protein association with the p85 subunit of phosphatidylinositol 3-kinase, despite normal phosphatidylinositol 3-kinase protein expression. Insulin-stimulated serine phosphorylation of protein kinase B was the same in all hearts, as was protein kinase B expression. CONCLUSION: We conclude that decreased insulin receptor beta, IRS-1 and GLUT4 proteins are associated with insulin resistance in type 2 diabetic rat hearts. 2-hop neighbor's text information:Title: Aldose reductase inhibition improves altered glucose metabolism of isolated diabetic rat hearts. Abstract: Alterations in glucose metabolism have been implicated in the cardiovascular complications of diabetes. Previous work in this laboratory demonstrated that hearts from diabetic animals have an elevated cytosolic redox ratio (NADH/NAD+) and that this redox imbalance is probably due to elevated polyol pathway flux. We therefore hypothesized that 1) the elevated cytosolic redox ratio of diabetic hearts could result in inhibition of glycolytic enzymes sensitive to the redox state, 2) polyol pathway inhibition could restore the abnormal glucose metabolism of diabetic hearts, and 3) the relative incorporation of mixed substrates into hearts from diabetic animals would demonstrate less glycolytic and more fatty acid oxidation. Hearts from diabetic (BB/W) and nondiabetic control rats were perfused with buffers containing 13C-labeled substrates, and the metabolism of these hearts was analyzed using 13C NMR spectroscopy. Tissue samples were analyzed for metabolite levels using biochemical assay. Compared with controls, diabetic hearts had glyceraldeyde 3-phosphate levels that were four times greater than nondiabetic hearts and exhibited 91% less 13C labeling of lactate and 92% less 13C labeling of glutamate (P < 0.03). Aldose reductase inhibition with zopolrestat restored the metabolite labeling of diabetic hearts. Diabetic hearts perfused with a mixture of substrates used 53% more acetate than nondiabetic control hearts (P < 0.05), and aldose reductase inhibition lowered the acetate utilization of diabetic hearts by 9% (P < 0.05). These data suggest that glycolytic flux in diabetic hearts is inhibited at glyceraldehyde-3-phosphate dehydrogenase and that inhibition of the polyol pathway with zopolrestat increases glycolytic flux in these hearts. Furthermore, hearts from diabetic animals showed a marked dependence on fatty acids for substrate utilization compared with nondiabetic controls, consistent with inhibition of the pyruvate dehydrogenase complex in diabetic hearts. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2 2 1,2	2	pubmed	train	34
Title: Prevalence and risk factors for urinary incontinence in women with type 2 diabetes and impaired fasting glucose: findings from the National Health and Nutrition Examination Survey (NHANES) 2001-2002. Abstract: OBJECTIVE: Diabetes is associated with increased risk of urinary incontinence. It is unknown whether women with pre-diabetes, or impaired fasting glucose (IFG), have increased prevalence of incontinence. We determined the prevalence of, and risk factors for, incontinence among U.S. women with diabetes and IFG. RESEARCH DESIGN AND METHODS: The 2001-2002 National Health and Nutrition Examination Survey measured fasting plasma glucose and obtained information about diabetes and urinary incontinence among 1,461 nonpregnant adult women. Self-reported weekly or more frequent incontinence, both overall and by type (urge and stress), was our outcome. RESULTS: Of the 1,461 women, 17% had diabetes and 11% met criteria for IFG. Prevalence of weekly incontinence was similar among women in these two groups (35.4 and 33.4%, respectively) and significantly higher than among women with normal fasting glucose (16.8%); both urge and stress incontinence were increased. In addition to well-recognized risk factors including age, weight, and oral estrogen use, two microvascular complications caused by diabetes, specifically macroalbuminuria and peripheral neuropathic pain, were associated with incontinence. CONCLUSIONS: Physicians should be alert for incontinence, an often unrecognized and therefore undertreated disorder, among women with diabetes and IFG, in particular those with microvascular complications. The additional prospect of improvements in their incontinence may help motivate some high-risk women to undertake difficult lifestyle changes to reduce their more serious risk of diabetes and its sequelae. 1-hop neighbor's text information:Title: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Abstract: BACKGROUND: Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial. METHODS: 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48-60 years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6.1-15.0 mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. In the conventional group, the aim was the best achievable FPG with diet alone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy. FINDINGS: Over 10 years, haemoglobin A1c (HbA1c) was 7.0% (6.2-8.2) in the intensive group compared with 7.9% (6.9-8.8) in the conventional group--an 11% reduction. There was no difference in HbA1c among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-related endpoint; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40, p=0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints between the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p<0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg). INTERPRETATION: Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes.(ABSTRACT TRUNCATED) 1-hop neighbor's text information:Title: Type 2 diabetes mellitus and risk of developing urinary incontinence. Abstract: OBJECTIVES: To evaluate the association between type 2 diabetes mellitus (DM) and development of urinary incontinence in women. DESIGN: Prospective, observational study. SETTING: The Nurses' Health Study cohort. PARTICIPANTS: Eighty-one thousand eight hundred forty-five women who reported information on urinary function in 1996. MEASUREMENTS: Self-reported, physician-diagnosed DM was ascertained using questionnaire from 1976 to 1996 and confirmed using standard criteria. Self-reported urinary incontinence, defined as leakage at least weekly, was ascertained in 1996 and 2000. Logistic regression models were used to calculate multivariate-adjusted relative risks (RRs) and 95% confidence intervals (CIs) for the relationship between DM (as of 1996) and prevalent and incident incontinence. RESULTS: The risk of prevalent incontinence (multivariate RR=1.28, 95% CI=1.18-1.39) and incident incontinence (multivariate RR=1.21, 95% CI=1.02-1.43) was significantly greater in women with DM than women without. Using a validated severity index, risk of developing severe incontinence was even more substantial in women with DM than in those without (multivariate RR=1.40, 95% CI=1.15-1.71 for leakage enough to wet the underwear; RR=1.97, 95% CI=1.24-3.12 for leakage enough to wet the outer clothing). In addition, risk of incontinence increased with duration of DM (P-trend=.03 for prevalent incontinence; P=.001 for incident incontinence). CONCLUSION: DM independently increases risk of urinary incontinence in women. Because risk of incontinence appeared associated with longer duration of DM, even delaying the onset of DM could have important public health implications. 1-hop neighbor's text information:Title: Urinary incontinence among women with type 1 diabetes--how common is it? Abstract: PURPOSE: We compared the prevalence, level of bother and effect on daily activities of urinary incontinence among women with type 1 diabetes enrolled in the Epidemiology of Diabetes Interventions and Complications study to a population based sample of women with normal glucose. MATERIALS AND METHODS: We performed a cross-sectional analysis of women with type 1 diabetes and normal glucose tolerance using 2 study populations. The Diabetes Control and Complications Trial cohort followup, Epidemiology of Diabetes Interventions and Complications, began in 1994. In 2004 women participants (550) completed a self-administered questionnaire on urinary incontinence. Our primary outcome was weekly or greater incontinence, overall and by type. Prevalence of urinary incontinence was compared to a subgroup of women with normal glucose in the 2001 to 2002 National Health and Nutrition Examination Survey (NHANES). RESULTS: Overall 65% of women with type 1 diabetes reported any urinary incontinence (17% reported weekly incontinence). Nearly 40% of these women were greatly bothered by their incontinence and 9% believed it affected their day-to-day activities. Women with type 1 diabetes had a nearly 2-fold greater prevalence of weekly urge incontinence compared to those without diabetes in the NHANES cohort (8.8% vs 4.5%, p = 0.01). CONCLUSIONS: Urinary incontinence is common in women with type 1 diabetes and the prevalence of weekly urge incontinence is far greater compared to that in women with normal glucose levels. Moreover, the prevalence of urinary incontinence in women with type 1 diabetes was greater than that of neuropathy, retinopathy and nephropathy. These findings highlight the importance of screening for urinary incontinence among women with type 1 diabetes. Studies examining factors associated with urinary incontinence in women with type 1 diabetes are warranted. 2-hop neighbor's text information:Title: Potential of liraglutide in the treatment of patients with type 2 diabetes. Abstract: Liraglutide is a long-acting analog of GLP-1, being developed by Novo Nordisk and currently undergoing regulatory review for the treatment of type 2 diabetes. Upon injection, liraglutide binds non-covalently to albumin, giving it a pharmacokinetic profile suitable for once-daily administration. In clinical trials of up to 1 year duration, liraglutide has been demonstrated to have beneficial effects on islet cell function, leading to improvements in glycemic control. Both fasting and postprandial glucose concentrations are lowered, and are associated with lasting reductions in HbA1c levels. Liraglutide is effective as monotherapy and in combination therapy with oral antidiabetic drugs, and reduces HbA1c by up to approximately 1.5% from baseline (8.2%-8.4%). Because of the glucose-dependency of its action, there is a low incidence of hypoglycemia. Liraglutide is associated with body weight loss, and reductions in systolic blood pressure have been observed throughout the clinical trials. The most common adverse events reported with liraglutide are gastrointestinal (nausea, vomiting and diarrhea). These tend to be most pronounced during the initial period of therapy and decline with time. Further clinical experience with liraglutide will reveal its long-term durability, safety and efficacy. 2-hop neighbor's text information:Title: The cost-effectiveness of lifestyle modification or metformin in preventing type 2 diabetes in adults with impaired glucose tolerance. Abstract: BACKGROUND: The Diabetes Prevention Program (DPP) demonstrated that interventions can delay or prevent the development of type 2 diabetes. OBJECTIVE: To estimate the lifetime cost-utility of the DPP interventions. DESIGN: Markov simulation model to estimate progression of disease, costs, and quality of life. DATA SOURCES: The DPP and published reports. TARGET POPULATION: Members of the DPP cohort 25 years of age or older with impaired glucose tolerance. TIME HORIZON: Lifetime. PERSPECTIVES: Health system and societal. INTERVENTIONS: Intensive lifestyle, metformin, and placebo interventions as implemented in the DPP. OUTCOME MEASURES: Cumulative incidence of diabetes, microvascular and neuropathic complications, cardiovascular complications, survival, direct medical and direct nonmedical costs, quality-adjusted life-years (QALYs), and cost per QALY. RESULTS OF BASE-CASE ANALYSIS: Compared with the placebo intervention, the lifestyle and metformin interventions were estimated to delay the development of type 2 diabetes by 11 and 3 years, respectively, and to reduce the absolute incidence of diabetes by 20% and 8%, respectively. The cumulative incidence of microvascular, neuropathic, and cardiovascular complications were reduced and survival was improved by 0.5 and 0.2 years. Compared with the placebo intervention, the cost per QALY was approximately 1100 dollars for the lifestyle intervention and $31 300 for the metformin intervention. From a societal perspective, the interventions cost approximately 8800 dollars and 29,900 dollars per QALY, respectively. From both perspectives, the lifestyle intervention dominated the metformin intervention. RESULTS OF SENSITIVITY ANALYSIS: Cost-effectiveness improved when the interventions were implemented as they might be in routine clinical practice. The lifestyle intervention was cost-effective in all age groups. The metformin intervention did not represent good use of resources for persons older than 65 years of age. LIMITATIONS: Simulation results depend on the accuracy of the underlying assumptions, including participant adherence. CONCLUSIONS: Health policy should promote diabetes prevention in high-risk individuals. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2 2 1 2 2,2	2	pubmed	train	36
Title: Globalization, coca-colonization and the chronic disease epidemic: can the Doomsday scenario be averted? Abstract: There are at present approximately 110 million people with diabetes in the world but this number will reach over 220 million by the year 2010, the majority of them with type 2 diabetes. Thus there is an urgent need for strategies to prevent the emerging global epidemic of type 2 diabetes to be implemented. Tackling diabetes must be part of an integrated program that addresses lifestyle related disorders. The prevention and control of type 2 diabetes and the other major noncommunicable diseases (NCDs) can be cost- and health-effective through an integrated (i.e. horizontal) approach to noncommunicable diseases disease prevention and control. With the re-emergence of devastating communicable diseases including AIDS, the Ebola virus and tuberculosis, the pressure is on international and regional agencies to see that the noncommunicable disease epidemic is addressed. The international diabetes and public health communities need to adopt a more pragmatic view of the epidemic of type 2 diabetes and other noncommunicable diseases. The current situation is a symptom of globalization with respect to its social, cultural, economic and political significance. Type 2 diabetes will not be prevented by traditional medical approaches; what is required are major and dramatic changes in the socio-economic and cultural status of people in developing countries and the disadvantaged, minority groups in developed nations. The international diabetes and public health communities must lobby and mobilize politicians, other international agencies such as UNDP, UNICEF, and the World Bank as well as other international nongovernmental agencies dealing with the noncommunicable diseases to address the socio-economic, behavioural, nutritional and public health issues that have led to the type 2 diabetes and noncommunicable diseases epidemic. A multidisciplinary Task Force representing all parties which can contribute to a reversal of the underlying socio-economic causes of the problem is an urgent priority. 1-hop neighbor's text information:Title: Duration of breast-feeding and the incidence of type 2 diabetes mellitus in the Shanghai Women's Health Study. Abstract: AIMS/HYPOTHESIS: The aim of this study was to examine the association between lifetime breast-feeding and the incidence of type 2 diabetes mellitus in a large population-based cohort study of middle-aged women. METHODS: This was a prospective study of 62,095 middle-aged parous women in Shanghai, China, who had no prior history of type 2 diabetes mellitus, cancer or cardiovascular disease at study recruitment. Breast-feeding history, dietary intake, physical activity and anthropometric measurements were assessed by in-person interviews. The Cox regression model was employed to evaluate the association between breast-feeding and the risk of type 2 diabetes mellitus. RESULTS: After 4.6 years of follow-up, 1,561 women were diagnosed with type 2 diabetes mellitus. Women who had breastfed their children tended to have a lower risk of diabetes mellitus than those who had never breastfed [relative risk (RR)=0.88; 95% CI, 0.76-1.02; p=0.08]. Increasing duration of breast-feeding was associated with a reduced risk of type 2 diabetes mellitus. The fully adjusted RRs for lifetime breast-feeding duration were 1.00, 0.88, 0.89, 0.88, 0.75 and 0.68 (p trend=0.01) for 0, >0 to 0.99, >0.99 to 1.99, >1.99 to 2.99, >2.99 to 3.99 and >or=4 years in analyses adjusted for age, daily energy intake, BMI, WHR, smoking, alcohol intake, physical activity, occupation, income level, education level, number of live births and presence of hypertension at baseline. CONCLUSIONS/INTERPRETATION: Breast-feeding may protect parous women from developing type 2 diabetes mellitus later in life. 1-hop neighbor's text information:Title: Legume and soy food intake and the incidence of type 2 diabetes in the Shanghai Women's Health Study. Abstract: BACKGROUND: It has been postulated that a diet high in legumes may be beneficial for the prevention of type 2 diabetes mellitus (type 2 DM). However, data linking type 2 DM risk and legume intake are limited. OBJECTIVE: The objective of the study was to examine the association between legume and soy food consumption and self-reported type 2 DM. DESIGN: The study was conducted in a population-based prospective cohort of middle-aged Chinese women. We followed 64,227 women with no history of type 2 DM, cancer, or cardiovascular disease at study recruitment for an average of 4.6 y. Participants completed in-person interviews that collected information on diabetes risk factors, including dietary intake and physical activity in adulthood. Anthropometric measurements were taken. Dietary intake was assessed with a validated food-frequency questionnaire at the baseline survey and at the first follow-up survey administered 2-3 y after study recruitment. RESULTS: We observed an inverse association between quintiles of total legume intake and 3 mutually exclusive legume groups (peanuts, soybeans, and other legumes) and type 2 DM incidence. The multivariate-adjusted relative risk of type 2 DM for the upper quintile compared with the lower quintile was 0.62 (95% CI: 0.51, 0.74) for total legumes and 0.53 (95% CI: 0.45, 0.62) for soybeans. The association between soy products (other than soy milk) and soy protein consumption (protein derived from soy beans and their products) with type 2 DM was not significant. CONCLUSIONS: Consumption of legumes, soybeans in particular, was inversely associated with the risk type 2 DM. 1-hop neighbor's text information:Title: Exercise therapy in type 2 diabetes. Abstract: Structured exercise is considered an important cornerstone to achieve good glycemic control and improve cardiovascular risk profile in Type 2 diabetes. Current clinical guidelines acknowledge the therapeutic strength of exercise intervention. This paper reviews the wide pathophysiological problems associated with Type 2 diabetes and discusses the benefits of exercise therapy on phenotype characteristics, glycemic control and cardiovascular risk profile in Type 2 diabetes patients. Based on the currently available literature, it is concluded that Type 2 diabetes patients should be stimulated to participate in specifically designed exercise intervention programs. More attention should be paid to cardiovascular and musculoskeletal deconditioning as well as motivational factors to improve long-term treatment adherence and clinical efficacy. More clinical research is warranted to establish the efficacy of exercise intervention in a more differentiated approach for Type 2 diabetes subpopulations within different stages of the disease and various levels of co-morbidity. 2-hop neighbor's text information:Title: Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Abstract: In obesity and type 2 diabetes, expression of the GLUT4 glucose transporter is decreased selectively in adipocytes. Adipose-specific Glut4 (also known as Slc2a4) knockout (adipose-Glut4(-/-)) mice show insulin resistance secondarily in muscle and liver. Here we show, using DNA arrays, that expression of retinol binding protein-4 (RBP4) is elevated in adipose tissue of adipose-Glut4(-/-) mice. We show that serum RBP4 levels are elevated in insulin-resistant mice and humans with obesity and type 2 diabetes. RBP4 levels are normalized by rosiglitazone, an insulin-sensitizing drug. Transgenic overexpression of human RBP4 or injection of recombinant RBP4 in normal mice causes insulin resistance. Conversely, genetic deletion of Rbp4 enhances insulin sensitivity. Fenretinide, a synthetic retinoid that increases urinary excretion of RBP4, normalizes serum RBP4 levels and improves insulin resistance and glucose intolerance in mice with obesity induced by a high-fat diet. Increasing serum RBP4 induces hepatic expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) and impairs insulin signalling in muscle. Thus, RBP4 is an adipocyte-derived 'signal' that may contribute to the pathogenesis of type 2 diabetes. Lowering RBP4 could be a new strategy for treating type 2 diabetes. 2-hop neighbor's text information:Title: Look AHEAD (Action for Health in Diabetes): design and methods for a clinical trial of weight loss for the prevention of cardiovascular disease in type 2 diabetes. Abstract: Overweight and obesity are major contributors to both type 2 diabetes and cardiovascular disease (CVD). Moreover, individuals with type 2 diabetes who are overweight or obese are at particularly high risk for CVD morbidity and mortality. Although short-term weight loss has been shown to ameliorate obesity-related metabolic abnormalities and CVD risk factors, the long-term consequences of intentional weight loss in overweight or obese individuals with type 2 diabetes have not been adequately examined. The primary objective of the Look AHEAD clinical trial is to assess the long-term effects (up to 11.5 years) of an intensive weight loss program delivered over 4 years in overweight and obese individuals with type 2 diabetes. Approximately 5000 male and female participants who have type 2 diabetes, are 45-74 years of age, and have a body mass index >or=25 kg/m(2) will be randomized to one of the two groups. The intensive lifestyle intervention is designed to achieve and maintain weight loss through decreased caloric intake and increased physical activity. This program is compared to a control condition given diabetes support and education. The primary study outcome is time to incidence of a major CVD event. The study is designed to provide a 0.90 probability of detecting an 18% difference in major CVD event rates between the two groups. Other outcomes include components of CVD risk, cost and cost-effectiveness, diabetes control and complications, hospitalizations, intervention processes, and quality of life. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2 2 2 2 2,2	2	pubmed	train	37
Title: Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects. Abstract: Mutations in several genes encoding transcription factors of the hepatocyte nuclear factor (HNF) cascade are associated with maturity-onset diabetes of the young (MODY), a monogenic form of early-onset diabetes mellitus. The ability of the orphan nuclear receptor small heterodimer partner (SHP, NR0B2) to modulate the transcriptional activity of MODY1 protein, the nuclear receptor HNF-4alpha, suggested SHP as a candidate MODY gene. We screened 173 unrelated Japanese subjects with early-onset diabetes for mutations in this gene and found five different mutations (H53fsdel10, L98fsdel9insAC, R34X, A195S, and R213C) in 6 subjects as well as one apparent polymorphism (R216H), all present in the heterozygous state. Interestingly, all of the subjects with the mutations were mildly or moderately obese at onset of diabetes, and analysis of the lineages of these individuals indicated that the SHP mutations were associated with obesity rather than with diabetes. Therefore, an additional group of 101 unrelated nondiabetic subjects with early-onset obesity was screened for mutations in the SHP gene. Two of the previously observed mutations (R34X and A195S) and two additional mutations (R57W and G189E) were identified in 6 subjects, whereas no mutations were identified in 116 young nondiabetic lean controls (P = 0.0094). Functional studies of the mutant proteins show that the mutations result in the loss of SHP activity. These results suggest that genetic variation in the SHP gene contributes to increased body weight and reveal a pathway leading to this common metabolic disorder in Japanese. 1-hop neighbor's text information:Title: Phenotypic characteristics of early-onset autosomal-dominant type 2 diabetes unlinked to known maturity-onset diabetes of the young (MODY) genes. Abstract: OBJECTIVE: To investigate whether there are forms of early-onset autosomal-dominant type 2 diabetes that are distinct from typical maturity-onset diabetes of the young (MODY) and to characterize their phenotypic characteristics. RESEARCH DESIGN AND METHODS: The study included 220 affected subjects from 29 families in which early-onset type 2 diabetes occurred in multiple generations and was not linked to known MODY genes (MODY gene-negative families). All individuals underwent an oral glucose tolerance test and other clinical measurements aimed at investigating the underlying metabolic defect and the presence of diabetic complications. For comparison, 79 affected carriers of MODY3 (hepatocyte nuclear factor [HNF]-1 alpha) mutations were similarly examined. RESULTS: Subjects from MODY gene-negative pedigrees were diagnosed with diabetes at an older age (36 +/- 17 vs. 21 +/- 10 years, P = 0.0001) and were more frequently obese (52 vs. 18%, P = 0.0001) than MODY3 individuals. MODY gene-negative patients who were insulin treated required more exogenous insulin than did MODY3 subjects (0.7 +/- 0.4 vs. 0.45 +/- 0.2 U.kg-1.day-1, P = 0.04), despite similar C-peptide levels. Among subjects not treated with insulin, MODY gene-negative subjects had significantly higher serum insulin levels, both fasting (16.5 +/- 15 vs. 6.5 +/- 5 microU/ml, P = 0.027) and 2 h after a glucose load (53 +/- 44 vs. 11 +/- 10, P = 0.002). They also had higher serum triglycerides (P = 0.02), higher cholesterol levels (P = 0.02), more hypertension (P = 0.0001), and more nephropathy (P = 0.001). Differences persisted when families were matched for age at diagnosis. CONCLUSIONS: Our findings indicate the existence of forms of early-onset autosomal-dominant type 2 diabetes that are distinct from MODY and are frequently characterized by insulin resistance, similar to later-onset type 2 diabetes. Because of the Mendelian pattern of inheritance, the goal of identifying the genes involved in these forms of diabetes appears to be particularly feasible. 1-hop neighbor's text information:Title: Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3) Abstract: The disease non-insulin-dependent (type 2) diabetes mellitus (NIDDM) is characterized by abnormally high blood glucose resulting from a relative deficiency of insulin. It affects about 2% of the world's population and treatment of diabetes and its complications are an increasing health-care burden. Genetic factors are important in the aetiology of NIDDM, and linkage studies are starting to localize some of the genes that influence the development of this disorder. Maturity-onset diabetes of the young (MODY), a single-gene disorder responsible for 2-5% of NIDDM, is characterized by autosomal dominant inheritance and an age of onset of 25 years or younger. MODY genes have been localized to chromosomes 7, 12 and 20 (refs 5, 7, 8) and clinical studies indicate that mutations in these genes are associated with abnormal patterns of glucose-stimulated insulin secretion. The gene on chromosome 7 (MODY2) encodes the glycolytic enzyme glucokinases which plays a key role in generating the metabolic signal for insulin secretion and in integrating hepatic glucose uptake. Here we show that subjects with the MODY3-form of NIDDM have mutations in the gene encoding hepatocyte nuclear factor-1alpha (HNF-1alpha, which is encoded by the gene TCF1). HNF-1alpha is a transcription factor that helps in the tissue-specific regulation of the expression of several liver genes and also functions as a weak transactivator of the rat insulin-I gene. 1-hop neighbor's text information:Title: Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Abstract: The steady-state basal plasma glucose and insulin concentrations are determined by their interaction in a feedback loop. A computer-solved model has been used to predict the homeostatic concentrations which arise from varying degrees beta-cell deficiency and insulin resistance. Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment of the contributions of insulin resistance and deficient beta-cell function to the fasting hyperglycaemia (homeostasis model assessment, HOMA). The accuracy and precision of the estimate have been determined by comparison with independent measures of insulin resistance and beta-cell function using hyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate of insulin resistance obtained by homeostasis model assessment correlated with estimates obtained by use of the euglycaemic clamp (Rs = 0.88, p less than 0.0001), the fasting insulin concentration (Rs = 0.81, p less than 0.0001), and the hyperglycaemic clamp, (Rs = 0.69, p less than 0.01). There was no correlation with any aspect of insulin-receptor binding. The estimate of deficient beta-cell function obtained by homeostasis model assessment correlated with that derived using the hyperglycaemic clamp (Rs = 0.61, p less than 0.01) and with the estimate from the intravenous glucose tolerance test (Rs = 0.64, p less than 0.05). The low precision of the estimates from the model (coefficients of variation: 31% for insulin resistance and 32% for beta-cell deficit) limits its use, but the correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop. 2-hop neighbor's text information:Title: Autoantibodies against CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase) that impair glucose-induced insulin secretion in noninsulin- dependent diabetes patients. Abstract: Cyclic ADP-ribose (cADPR) has been shown to be a mediator for intracellular Ca2+ mobilization for insulin secretion by glucose in pancreatic beta cells, and CD38 shows both ADP-ribosyl cyclase to synthesize cADPR from NAD+ and cADPR hydrolase to hydrolyze cADPR to ADP-ribose. We show here that 13.8% of Japanese non-insulin-dependent diabetes (NIDDM) patients examined have autoantibodies against CD38 and that the sera containing anti-CD38 autoantibodies inhibit the ADP-ribosyl cyclase activity of CD38 (P </= 0.05). Insulin secretion from pancreatic islets by glucose is significantly inhibited by the addition of the NIDDM sera with anti-CD38 antibodies (P </= 0.04-0.0001), and the inhibition of insulin secretion is abolished by the addition of recombinant CD38 (P </= 0.02). The increase of cADPR levels in pancreatic islets by glucose was also inhibited by the addition of the sera (P </= 0.05). These results strongly suggest that the presence of anti-CD38 autoantibodies in NIDDM patients can be one of the major causes of impaired glucose-induced insulin secretion in NIDDM. 2-hop neighbor's text information:Title: Beneficial effects of insulin on glycemic control and beta-cell function in newly diagnosed type 2 diabetes with severe hyperglycemia after short-term intensive insulin therapy. Abstract: OBJECTIVE: To evaluate whether treatment with insulin is advantageous compared with oral antidiabetes agents in newly diagnosed type 2 diabetes with severe hyperglycemia after short-term intensive insulin therapy. RESEARCH DESIGN AND METHODS: Newly diagnosed type 2 diabetic patients with severe hyperglycemia were hospitalized and treated with intensive insulin injections for 10-14 days. The oral glucose tolerance test (OGTT) was performed after intensive insulin treatment. After discharge, the patients were randomized to receive either insulin injections or oral antidiabetes drugs (OADs) for further management. The OGTT was repeated 6 months later, and beta-cell function and insulin sensitivity were evaluated again. These subjects were continually followed up for another 6 months to evaluate their long-term glycemic control. RESULTS: At the 6th month of the study, the A1C level was significantly lower in the insulin group than in the OAD group (6.33 +/- 0.70% vs. 7.50 +/- 1.50%; P = 0.002). During the follow-up visit, the A1C level was still better in the insulin group (6.78 +/- 1.21% vs. 7.84 +/- 1.74%; P = 0.009). All parameters regarding beta-cell function measured in the OGTT were improved significantly in both groups after 6 months of treatment. Compared with the OAD group, the homeostasis model assessment of beta-cell function index, insulin area under the curve, and insulinogenic index were better in the insulin group. CONCLUSIONS: A 6-month course of insulin therapy, compared with OAD treatment, could more effectively achieve adequate glycemic control and significant improvement of beta-cell function in new-onset type 2 diabetic patients with severe hyperglycemia. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2 2 2 2 2,2	2	pubmed	train	41
Title: Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects. Abstract: Mutations in several genes encoding transcription factors of the hepatocyte nuclear factor (HNF) cascade are associated with maturity-onset diabetes of the young (MODY), a monogenic form of early-onset diabetes mellitus. The ability of the orphan nuclear receptor small heterodimer partner (SHP, NR0B2) to modulate the transcriptional activity of MODY1 protein, the nuclear receptor HNF-4alpha, suggested SHP as a candidate MODY gene. We screened 173 unrelated Japanese subjects with early-onset diabetes for mutations in this gene and found five different mutations (H53fsdel10, L98fsdel9insAC, R34X, A195S, and R213C) in 6 subjects as well as one apparent polymorphism (R216H), all present in the heterozygous state. Interestingly, all of the subjects with the mutations were mildly or moderately obese at onset of diabetes, and analysis of the lineages of these individuals indicated that the SHP mutations were associated with obesity rather than with diabetes. Therefore, an additional group of 101 unrelated nondiabetic subjects with early-onset obesity was screened for mutations in the SHP gene. Two of the previously observed mutations (R34X and A195S) and two additional mutations (R57W and G189E) were identified in 6 subjects, whereas no mutations were identified in 116 young nondiabetic lean controls (P = 0.0094). Functional studies of the mutant proteins show that the mutations result in the loss of SHP activity. These results suggest that genetic variation in the SHP gene contributes to increased body weight and reveal a pathway leading to this common metabolic disorder in Japanese. 1-hop neighbor's text information:Title: Maturity-onset diabetes of the young (MODY). Abstract: This review summarized aspects of the widening scope, phenotypic expression, natural history, recognition, pathogeneses, and heterogenous nature of maturity-onset diabetes of the young (MODY), an autosomal dominant inherited subtype of NIDDM, which can be recognized at a young age. There are differences in metabolic, hormonal, and vascular abnormalities in different ethnic groups and even among Caucasian pedigrees. In MODY patients with low insulin responses, there is a delayed and decreased insulin and C-peptide secretory response to glucose from childhood or adolescence, even before glucose intolerance appears; it may represent the basic genetic defect. The nondiabetic siblings have had normal insulin responses for decades. The fasting hyperglycemia of some MODY has been treated successfully with sulfonylureas for more than 30 years. In a few, after years or decades of diabetes, the insulin and C-peptide responses to glucose are so low that they may resemble those of early Type I diabetes. The rate of progression of the insulin secretory defect over time does distinguish between these two types of diabetes. In contrast are patients from families who have very high insulin responses to glucose despite glucose intolerance and fasting hyperglycemia similar to those seen in patients with low insulin responses. In many of these patients, there is in vivo and in vitro evidence of insulin resistance. Whatever its mechanism, the compensatory insulin responses to nutrients must be insufficient to maintain normal carbohydrate tolerance. This suggests that diabetes occurs only in those patients who have an additional islet cell defect, i.e., insufficient beta cell reserve and secretory capacity. In a few MODY pedigrees with high insulin responses to glucose and lack of evidence of insulin resistance, an insulin is secreted which is a structurally abnormal, mutant insulin molecule that is biologically ineffective. No associations have been found between specific HLA antigens and MODY in Caucasian, black, and Asian pedigrees. Linkage studies of the insulin gene, the insulin receptor gene, the erythrocyte/Hep G2 glucose transporter locus, and the apolipoprotein B locus have shown no association with MODY. Vascular disease may be as prevalent as in conventional NIDDM. Because of autosomal dominant transmission and penetrance at a young age, MODY is a good model for further investigations of etiologic and pathogenetic factors in NIDDM, including the use of genetic linkage strategies to identify diabetogenic genes. 1-hop neighbor's text information:Title: Altered insulin secretory responses to glucose in diabetic and nondiabetic subjects with mutations in the diabetes susceptibility gene MODY3 on chromosome 12. Abstract: One form of maturity-onset diabetes of the young (MODY) results from mutations in a gene, designated MODY3, located on chromosome 12 in band q24. The present study was undertaken to define the interactions between glucose and insulin secretion rate (ISR) in subjects with mutations in MODY3. Of the 13 MODY3 subjects, six subjects with normal fasting glucose and glycosylated hemoglobin and seven overtly diabetic subjects were studied as were six nondiabetic control subjects. Each subject received graded intravenous glucose infusions on two occasions separated by a 42-h continuous intravenous glucose infusion designed to prime the beta-cell to secrete more insulin in response to glucose. ISRs were derived by deconvolution of peripheral C-peptide levels. Basal glucose levels were higher and insulin levels were lower in MODY3 subjects with diabetes compared with nondiabetic subjects or with normal healthy control subjects. In response to the graded glucose infusion, ISRs were significantly lower in the diabetic subjects over a broad range of glucose concentrations. ISRs in the nondiabetic MODY3 subjects were not significantly different from those of the control subjects at plasma glucose levels <8 mmol/l. As glucose rose above this level, however, the increase in insulin secretion in these subjects was significantly reduced. Administration of glucose by intravenous infusion for 42 h resulted in a significant increase in the amount of insulin secreted over the 5-9 mmol/l glucose concentration range in the control subjects and nondiabetic MODY3 subjects (by 38 and 35%, respectively), but no significant change was observed in the diabetic MODY3 subjects. In conclusion, in nondiabetic MODY3 subjects insulin secretion demonstrates a diminished ability to respond when blood glucose exceeds 8 mmol/l. The priming effect of glucose on insulin secretion is preserved. Thus, beta-cell dysfunction is present before the onset of overt hyperglycemia in this form of MODY. The defect in insulin secretion in the nondiabetic MODY3 subjects differs from that reported previously in nondiabetic MODY1 or mildly diabetic MODY2 subjects. 1-hop neighbor's text information:Title: Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1) Abstract: The disease maturity-onset diabetes of the young (MODY) is a genetically heterogeneous monogenic form of non-insulin-dependent (type 2) diabetes mellitus (NIDDM), characterized by early onset, usually before 25 years of age and often in adolescence or childhood, and by autosomal dominant inheritance. It has been estimated that 2-5% of patients with NIDDM may have this form of diabetes mellitus. Clinical studies have shown that prediabetic MODY subjects have normal insulin sensitivity but suffer from a defect in glucose-stimulated insulin secretion, suggesting that pancreatic beta-cell dysfunction rather than insulin resistance is the primary defect in this disorder. Linkage studies have localized the genes that are mutated in MODY on human chromosomes 20 (MODY1), 7 (MODY2) and 12 (MODY3), with MODY2 and MODY3 being allelic with the genes encoding glucokinase, a key regulator of insulin secretion, and hepatocyte nuclear factor-1alpha (HNF-1alpha), a transcription factor involved in tissue-specific regulation of liver genes but also expressed in pancreatic islets, insulinoma cells and other tissues. Here we show that MODY1 is the gene encoding HNF-4alpha (gene symbol, TCF14), a member of the steroid/thyroid hormone receptor superfamily and an upstream regulator of HNF-1alpha expression. 2-hop neighbor's text information:Title: Diabetes-associated mutations in a beta-cell transcription factor destabilize an antiparallel "mini-zipper" in a dimerization interface. Abstract: Maturity-onset diabetes of the young, a monogenic form of Type II diabetes mellitus, is most commonly caused by mutations in hepatic nuclear factor 1alpha (HNF-1alpha). Here, the dimerization motif of HNF-1alpha is shown to form an intermolecular four-helix bundle. One face contains an antiparallel coiled coil whereas the other contains splayed alpha-helices. The "mini-zipper" is complementary in structure and symmetry to the top surface of a transcriptional coactivator (dimerization cofactor of homeodomains). The bundle is destabilized by a subset of mutations associated with maturity-onset diabetes of the young. Impaired dimerization of a beta-cell transcription factor thus provides a molecular mechanism of metabolic deregulation in diabetes mellitus. 2-hop neighbor's text information:Title: A genomewide search for type 2 diabetes-susceptibility genes in indigenous Australians. Abstract: The prevalence of type 2 diabetes among Australian residents is 7.5%; however, prevalence rates up to six times higher have been reported for indigenous Australian communities. Epidemiological evidence implicates genetic factors in the susceptibility of indigenous Australians to type 2 diabetes and supports the hypothesis of the "thrifty genotype," but, to date, the nature of the genetic predisposition is unknown. We have ascertained clinical details from a community of indigenous Australian descent in North Stradbroke Island, Queensland. In this population, the phenotype is characterized by severe insulin resistance. We have conducted a genomewide scan, at an average resolution of 10 cM, for type 2 diabetes-susceptibility genes in a large multigeneration pedigree from this community. Parametric linkage analysis undertaken using FASTLINK version 4.1p yielded a maximum two-point LOD score of +2.97 at marker D2S2345. Multipoint analysis yielded a peak LOD score of +3.9 <1 cM from marker D2S2345, with an 18-cM 3-LOD support interval. Secondary peak LOD scores were noted on chromosome 3 (+1.8 at recombination fraction [theta] 0.05, at marker D3S1311) and chromosome 8 (+1.77 at theta=0.0, at marker D8S549). These chromosomal regions are likely to harbor novel susceptibility genes for type 2 diabetes in the indigenous Australian population. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2 2 2 2 2,2	2	pubmed	train	42
Title: Use of the GlucoWatch biographer in children with type 1 diabetes. Abstract: OBJECTIVE: To determine whether use of the GlucoWatch biographer improves glucose control in children and adolescents with type 1 diabetes. METHODS: Forty children in poor glucose control (glycohemoglobin [HbA1c] >8%) were randomized to diabetes management with or without glucose monitoring using the biographer. Conventional glucose monitoring was performed 4 times daily in both groups. Those randomized to the biographer group were asked to wear the device 4 times per week for 3 months (intervention phase) and to perform blood glucose monitoring if the biographer alerted them that glucose was < or =70 mg/dL (3.9 mmol/L) or > or =300 mg/dL (16.7 mmol/L). After 3 months, all patients received biographers and were followed for 6 months (observation phase). HbA1c values were determined at baseline and after 1, 3, 6, and 9 months. RESULTS: The median HbA1c was 8.6% and 8.9% (control versus biographer) at baseline and was significantly lower in the biographer group after 3 months (8.4% vs 9%). More hypoglycemia was detected when subjects were wearing the biographer, especially at night. No severe hypoglycemia occurred. During the observation phase, HbA1c values at 6 months were 8.5% and 8.3% and at 9 months were 8.6% and 8.4% in the control and biographer groups, respectively. Two children dropped out of the study, 1 because of skin irritation from using the device. CONCLUSIONS: The GlucoWatch biographer was well tolerated by children and adolescents and significantly improved glucose control compared with standard therapy. The use of the biographer with an alarm to detect nocturnal hypoglycemia has the potential to increase the safety of diabetes management in children. 1-hop neighbor's text information:Title: Response to nocturnal alarms using a real-time glucose sensor. Abstract: BACKGROUND: The objective of this study was to determine how subjects responded to alarms for hypo- and hyperglycemia while they were sleeping. RESEARCH DESIGN AND METHODS: Twenty subjects with type 1 diabetes (4-17 years old) were admitted to a clinical research center for approximately 24 h. Each subject wore two GlucoWatch G2 Biographers (GW2B) (Cygnus, Inc., Redwood City, CA) and was videotaped using an infrared camera from 9 p.m. to 7 a.m. The videotapes were reviewed to determine if the GW2B alarms were audible on the tape and to document the subject's response to the alarms. Because many alarms can occur surrounding a change in blood glucose, GW2B alarm "events" are defined as a one or more alarms separated from previous alarms by more than 30 min. RESULTS: Downloaded data from the biographers identified 240 individual alarms, 75% of which occurred while the subject was sleeping. Of the 240 alarms 68% were audible on the videotape. Subjects awoke to 29% of individual alarms and to 66% of alarm events. Subjects 4-6 years old responded to 17% of alarms, 7-11 year olds responded to 20% of alarms, adolescents responded to 53% of alarms, and parents responded to 37% of alarms. Subjects awoke to 40% of the first alarm during the night, but to only 28% of subsequent alarms. There were 11 events when the glucose was confirmed to be < or = 70 mg/dL, and in each case the subject was awoken. Fifty-five percent of alarm events occurred when there was no hypo- or hyperglycemia confirmed by a reference glucose value. CONCLUSIONS: Subjects awoke to 29% of individual alarms and to 66% of alarm events. Subjects awoke during all alarm events when hypoglycemia was confirmed, but there was a high incidence of false alarms. 1-hop neighbor's text information:Title: The accuracy of the GlucoWatch G2 biographer in children with type 1 diabetes: results of the diabetes research in children network (DirecNet) accuracy study. Abstract: The accuracy of the GlucoWatch G2 Biographer (GW2B; Cygnus, Inc., Redwood City, CA) was assessed in children and adolescents with type 1 diabetes mellitus (T1DM). During a 24-h clinical research center stay, 89 children and adolescents with T1DM (3.5-17.7 years old) wore 174 GW2Bs and had frequent serum glucose determinations during the day and night and during insulin-induced hypoglycemia and meal-induced hyperglycemia, resulting in 3672 GW2B-reference glucose pairs. The median relative absolute difference between the GW2B and reference glucose values was 16% (25th, 75th percentiles = 7%, 29%). The proposed International Organisation for Standardisation criteria were met for 60% of sensor values. Accuracy was better at higher serum glucose levels than low glucose levels. Accuracy degraded slightly as the sensor aged. Time of day, subject age, gender, or body mass index did not impact GW2B accuracy. There were no cases of serious skin reactions. Although the accuracy of this generation of sensor does not approach that of current home glucose meters, the majority of sensor glucose values are within 20% of the serum glucose. This level of accuracy may be sufficient for detecting trends and modifying diabetes management. Further longitudinal outpatient studies are needed to assess the utility of the GW2B as a management tool to improve glycemic control and decrease the incidence of severe hypoglycemia in children with diabetes. 1-hop neighbor's text information:Title: Youth and parent satisfaction with clinical use of the GlucoWatch G2 Biographer in the management of pediatric type 1 diabetes. Abstract: OBJECTIVE: A continuous glucose monitor satisfaction scale (CGM-SAT) was evaluated during a 6-month randomized controlled trial of the GlucoWatch G2 Biographer (GW2B) in youths with type 1 diabetes. RESEARCH DESIGN AND METHODS: At the end of the 6-month trial, 97 parents and 66 older children who had been randomized to the GW2B group completed the CGM-SAT, which assesses satisfaction on 37 items using a five-point Likert scale. Descriptive analysis, calculation of several reliability estimates, and assessment of concurrent validity were performed. RESULTS: The CGM-SAT demonstrated high internal reliability (Cronbach's alpha = 0.95 for parents and 0.94 for youths aged > or = 11 years), split-half reliability (rho = 0.91 for parents and 0.93 for youths), and parent-adolescent agreement (rho = 0.68, P < 0.001). Convergent validity was supported by marginally significant associations with treatment adherence and frequency of GW2B use. CGM-SAT scores did not correlate significantly with changes in treatment adherence, quality of life, or diabetes-related anxiety from baseline to 6 months. Mean scores on CGM-SAT items indicated that 81% of parental responses and 73% of youths' responses were less favorable than "neutral." Descriptive analysis indicated the GW2B requires substantial improvement before it can achieve widespread clinical utility and acceptance. CONCLUSIONS: The results supported the psychometric properties of the CGM-SAT. The CGM-SAT warrants further research use and cross-validation with other continuous glucose monitors. This study provides a benchmark for comparison with new glucose sensors. 2-hop neighbor's text information:Title: Hypoglycemia: incidence and clinical predictors in a large population-based sample of children and adolescents with IDDM. Abstract: OBJECTIVE: To determine the frequency of moderate and severe hypoglycemia and to identify clinical predictors associated with its occurrence in a large population-based sample of children and adolescents with IDDM. RESEARCH DESIGN AND METHODS: A total of 657 patients (age: 12.1 +/- 4.4 years, mean +/- SD) were included in the study, yielding 1,449 patient-years of data. A prospective assessment of severe hypoglycemia (an event resulting in a seizure or coma) and moderate hypoglycemia (an event requiring assistance of another, excluding severe episodes) was made over a 3-year period. Patients and caregivers detailed episodes of significant hypoglycemia (moderate and severe events) and these were recorded at each 3-month clinic visit along with HbA1c. Data were analyzed using generalized estimating equation models fitted with the exchange correlation structure. RESULTS: The overall incidence of severe events was 4.8/100 patient-years and of moderate events was 13.1/100 patient-years. Over 3 years, severe events occurred in 8.5% of children and moderate events occurred in 26.9%. Significant hypoglycemia was rare in the first 12 months after diagnosis. Rates of hypoglycemia were increased in children < 6 years of age versus > 6 years of age (40.9 vs. 16.6/100 patient-years, age < or = 6 years vs. age > 6 years, P < 0.001). Rates of hypoglycemia doubled when HbA1c fell below 8%, and children with HbA1c < 7% had a threefold increase in both moderate and severe hypoglycemia (e.g., severe episodes 14.9 vs. 4.1/100 patient-years, HbA1c < or = 7% vs. HbA1c > 7%, P < 0.001). Most severe events were seizures, and 75% of them occurred at night. The majority of events were related to missed meals or increased activity. However, in 38% no predisposing factor was evident. CONCLUSIONS: Newly diagnosed children appear to be protected from severe hypoglycemia. Rates increase with lower glycated hemoglobin, especially when mean HbA1c is < 8.0%. Younger children, who may be more susceptible to the adverse effects of neuroglycopenia, are at a particular risk of significant hypoglycemia. 2-hop neighbor's text information:Title: Correlation of fingerstick blood glucose measurements with GlucoWatch biographer glucose results in young subjects with type 1 diabetes. Abstract: OBJECTIVE: The purpose of this study was to compare measurements of glucose obtained via iontophoretic extraction with the GlucoWatch automatic glucose biographer (Cygnus, Inc., Redwood City, CA) with capillary blood glucose values that were determined 1) in a controlled outpatient clinic setting and 2) in a home setting. RESEARCH DESIGN AND METHODS: There were 76 GlucoWatch biographers used on 28 different young adults (21 women and 7 men) with type 1 diabetes (age 30.9 +/- 6.9 years and duration of diabetes 18.4 +/- 8.1 years [mean +/- SD]) in a controlled outpatient clinic setting. Some subjects participated on multiple days. Subjects wore two GlucoWatch biographers, each on the forearm (ventral aspect). Comparisons were made to HemoCue blood glucose analyzer (Aktiebolgat Leo, Helsingborg, Sweden) capillary blood glucose measurements. In addition, GlucoWatch biographers (one each day for 3 consecutive days) were used by 12 subjects (8 women, 4 men) in a home setting. Comparisons were made to capillary blood glucose values determined using the One Touch Profile meter (Johnson & Johnson, New Brunswick, NJ). RESULTS: GlucoWatch biographer glucose values correlated well with capillary blood glucose values determined using the HemoCue analyzer in the clinic setting (r = 0.90, 1,554 paired data points) and using the One Touch Profile meter in the home setting (r = 0.85, 204 paired data points). When 36 subjects wore two biographers simultaneously, the correlation between the two biographers was r = 0.94. The error grid analysis demonstrated that > 96% of biographer glucose values determined in the clinic or home setting were in the clinically acceptable A and B regions. CONCLUSIONS: This study confirms the accuracy and precision of glucose values as determined using the GlucoWatch biographer in clinic and home settings. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1 1 1 1,1	2	pubmed	train	44
Title: Birth weight and non-insulin dependent diabetes: thrifty genotype, thrifty phenotype, or surviving small baby genotype? Abstract: OBJECTIVE: To determine the prevalence of diabetes in relation to birth weight in Pima Indians. DESIGN: Follow up study of infants born during 1940-72 who had undergone a glucose tolerance test at ages 20-39 years. SETTING: Gila River Indian community, Arizona. SUBJECTS: 1179 American Indians. MAIN OUTCOME MEASURE: Prevalence of non-insulin dependent diabetes mellitus (plasma glucose concentration > or = 11.1 mmol/l two hours after ingestion of carbohydrate). RESULTS: The prevalence was greatest in those with the lowest and highest birth weights. The age adjusted prevalences for birth weights < 2500 g, 2500-4499 g, and > or = 4500 g were 30%, 17%, and 32%, respectively. When age, sex, body mass index, maternal diabetes during pregnancy, and birth year were controlled for, subjects with birth weights < 2500 g had a higher rate than those with weights 2500-4499 g (odds ratio 3.81; 95% confidence interval 1.70 to 8.52). The risk for subsequent diabetes among higher birthweight infants (> or = 4500 g) was associated with maternal diabetes during pregnancy. Most diabetes, however, occurred in subjects with intermediate birth weights (2500-4500 g). CONCLUSIONS: The relation of the prevalence of diabetes to birth weight in the Pima Indians is U shaped and is related to parental diabetes. Low birth weight is associated with non-insulin dependent diabetes. Given the high mortality of low birthweight infants selective survival in infancy of those genetically predisposed to insulin resistance and diabetes provides an explanation for the observed relation between low birth weight and diabetes and the high prevalence of diabetes in many populations. 1-hop neighbor's text information:Title: Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima Indians. Abstract: Impaired glucose tolerance often presages the development of non-insulin-dependent diabetes mellitus. We have studied insulin action and secretion in 24 Pima Indians before and after the development of impaired glucose tolerance and in 254 other subjects representing the whole spectrum of glucose tolerance, including subjects with overt non-insulin-dependent diabetes. The transition from normal to impaired glucose tolerance was associated with a decrease in glucose uptake during hyperinsulinemia, from 0.018 to 0.016 mmol per minute (from 3.3 to 2.8 mg per kilogram of fat-free body mass per minute) (P less than 0.0003). Mean plasma insulin concentrations increased during an oral glucose-tolerance test, from 1200 to 1770 pmol per liter (from 167 to 247 microU per milliliter). In 151 subjects with normal glucose tolerance, the insulin concentration measured during an oral glucose-tolerance test correlated with the plasma glucose concentration (r = 0.48, P less than or equal to 0.0001). This relation was used to predict an insulin concentration of 1550 pmol per liter (216 microU per milliliter) in subjects with impaired glucose tolerance (actual value, 1590 pmol per liter [222 microU per milliliter]; P not significant), suggesting that these subjects had normal secretion of insulin. In contrast, plasma insulin concentrations in the diabetics decreased as glucose concentrations increased (r = -0.75, P less than or equal to 0.0001), suggesting deficient secretion of insulin. This relative insulin deficiency first appears at the lower end of the second (diabetic) mode seen in population frequency distributions of plasma glucose concentrations. Our data show that impaired glucose tolerance in our study population is primarily due to impaired insulin action. In patients with non-insulin-dependent diabetes mellitus, by contrast, impaired insulin action and insulin secretory failure are both present. 1-hop neighbor's text information:Title: Congenital susceptibility to NIDDM. Role of intrauterine environment. Abstract: Non-insulin-dependent diabetes mellitus (NIDDM) during pregnancy in Pima Indian women results in offspring who have a higher prevalence of NIDDM (45%) at age 20-24 yr than in offspring of nondiabetic women (1.4%) or offspring of prediabetic women (8.6%), i.e., women who developed diabetes only after the pregnancy. These differences persist after taking into account paternal diabetes, age at onset of diabetes in the parents, and the offspring's weight relative to height. The findings suggest that the intrauterine environment is an important determinant of the development of diabetes and that its effect is in addition to effects of genetic factors. 1-hop neighbor's text information:Title: Type 2 diabetes in grandparents and birth weight in offspring and grandchildren in the ALSPAC study. Abstract: OBJECTIVE: To examine the association between a history of type 2 diabetes and birth weight of offspring and grandchildren. DESIGN: Prospective observational study. Diabetic status, as reported by mothers (F1 generation) was collected on grandparents (F0) of babies (F2) born to mothers (F1) who participated in a study of maternal and child health. Associations between risk of grandparental diabetes and birth weight in mothers (F1) and grandchildren (F2) were analysed using linear and logistic regression. SETTING: Avon: comprising of the city of Bristol and surrounding areas. PARTICIPANTS: 12 076 singleton babies (F2), their parents (F1) and maternal and paternal grandparents (F0). RESULTS: Women (F1) who had no parents with type 2 diabetes had lower birth weights than women with one or two diabetic parents, after controlling for the age of both parents. There was a U shaped association between maternal birth weight and grandmaternal diabetes, but no evidence of an association with grandpaternal diabetes. The grandchildren of maternal grandparents with type 2 diabetes were more likely to be in the top tertile of birth weight than grandchildren of non-diabetics. There was evidence for an inverted U shaped association between birth weight of grandchildren and diabetes in paternal grandmothers. CONCLUSIONS: This is the first study to show intergenerational associations between type 2 diabetes in one generation and birth weight in the subsequent two generations. While the study has limitations mainly because of missing data, the findings nevertheless provide some support for the role of developmental intrauterine effects and genetically determined insulin resistance in impaired insulin mediated growth in the fetus. 2-hop neighbor's text information:Title: Treatment update: thiazolidinediones in combination with metformin for the treatment of type 2 diabetes. Abstract: Type 2 diabetes mellitus (DM2) is characterized by excessive hepatic gluconeogenesis, increased insulin resistance and a progressive inability of pancreatic beta cells to produce sufficient insulin. DM2 evolves as a progression from normal glucose tolerance, to impaired glucose tolerance (IGT) to frank diabetes mellitus, reflecting the establishment of insulin resistance and beta cell dysfunction. Insulin resistance not only contributes to impaired glycemic control in DM2, but to the development of hypertension, dyslipidemia and endothelial dysfunction. Cardiovascular disease is the primary morbidity for patients with DM2. The onset of insulin resistance and cardiovascular insult likely occurs well before the onset of IGT is detected clinically. Biguanides and thiazolidinediones (TZDs) are two classes of oral agents for the management of DM2 that improve insulin resistance, and thus have potential cardiovascular benefits beyond glycemic control alone. Metformin additionally inhibits hepatic gluconeogenesis. The combined use of two of these agents targets key pathophysiologic defects in DM2. Single pill combinations of rosiglitazone/metformin and pioglitazone/metformin have recently been approved for use in the US and Europe. This article reviews the clinical data behind the use of metformin in combination with TZDs for the management of diabetes, its impact on vascular health, side effects and potential mechanisms of action for combined use. 2-hop neighbor's text information:Title: Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. Abstract: Intrauterine exposure to diabetes is associated with an excess of diabetes and obesity in the offspring, but the effects of intrauterine exposure are confounded by genetic factors. To determine the role of the intrauterine diabetic environment per se, the prevalence of diabetes and the mean BMI were compared in siblings born before and after their mother was recognized as having diabetes. Nuclear families in which at least one sibling was born before and one after the mother was diagnosed with type 2 diabetes were selected. Consequently, the siblings born before and after differed in their exposure to diabetes in utero. A total of 58 siblings from 19 families in which at least one sibling had diabetes were examined at similar ages (within 3 years). The risk of diabetes was significantly higher in siblings born after the mother developed diabetes than in those born before the mother's diagnosis of diabetes (odds ratio 3.7, P = 0.02). In 52 families, among 183 siblings without diabetes, the mean BMI was 2.6 kg/m2 higher in offspring of diabetic than in offspring of nondiabetic pregnancies (P = 0.003). In contrast, there were no significant differences in risk of diabetes or BMI between offspring born before and after the father was diagnosed with diabetes. Intrauterine exposure to diabetes per se conveys a high risk for the development of diabetes and obesity in offspring in excess of risk attributable to genetic factors alone. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2 2 2 2 2,2	2	pubmed	train	46
Title: Comparative trial between insulin glargine and NPH insulin in children and adolescents with type 1 diabetes mellitus. Abstract: The objective of this study was to compare the efficacy and safety of insulin glargine, a long-acting insulin analog, with NPH insulin in children and adolescents with type 1 diabetes mellitus (T1DM). In a multicenter, open-label, randomized, 6-month study, 349 patients with TIDM, aged 5-16 years, received insulin glargine once daily or NPH insulin either once or twice daily, based on their prior treatment regimen. Although there was no significant difference between the NPH insulin and insulin glargine treatment groups with respect to baseline to endpoint change in HbA1c levels, fasting blood glucose (FBG) levels decreased significantly more in the insulin glargine group (-1.29 mmol/l) than in the NPH insulin group (-0.68 mmol/L, p = 0.02). The percentage of symptomatic hypoglycemic events was similar between groups; however, fewer patients in the insulin glargine group reported severe hypoglycemia (23% vs 29%) and severe nocturnal hypoglycemia (13% vs 18%), although these differences were not statistically significant (p = 0.22 and p = 0.19, respectively). Fewer serious adverse events occurred in the insulin glargine group than in the NPH insulin group (p < 0.02). A once-daily subcutaneous dose of insulin glargine provides effective glycemic control and is well tolerated in children and adolescents with T1DM. 1-hop neighbor's text information:Title: Diabetes screening, diagnosis, and therapy in pediatric patients with type 2 diabetes. Abstract: The dramatic rise in the incidence and prevalence of type 2 diabetes mellitus in the pediatric and adolescent populations has been associated with the ongoing epidemic of overweight, obesity, insulin resistance, and metabolic syndrome seen in these age groups. Although the majority of pediatric patients diagnosed with diabetes are still classified as having type 1 diabetes, almost 50% of patients with diabetes in the pediatric age range (under 18 years) may have type 2 diabetes. Screening of high-risk patients for diabetes and prediabetes is important. Prompt diagnosis and accurate diabetes classification facilitate appropriate and timely treatment and may reduce the risk for complications. This is especially important in children because lifestyle interventions may be successful and the lifelong risk for complications is greatest. Treatment usually begins with dietary modification, weight loss, and a structured program of physical exercise. Oral antidiabetic agents are added when lifestyle intervention alone fails to maintain glycemic control. Given the natural history of type 2 diabetes, most if not all patients will eventually require insulin therapy. In those requiring insulin, improved glycemic control and reduced frequency of hypoglycemia can be achieved with insulin analogs. It is common to add insulin therapy to existing oral therapy only when oral agents no longer provide adequate glycemic control. 1-hop neighbor's text information:Title: Institution of basal-bolus therapy at diagnosis for children with type 1 diabetes mellitus. Abstract: OBJECTIVE: We studied whether the institution of basal-bolus therapy immediately after diagnosis improved glycemic control in the first year after diagnosis for children with newly diagnosed type 1 diabetes mellitus. METHODS: We reviewed the charts of 459 children > or =6 years of age who were diagnosed as having type 1 diabetes between July 1, 2002, and June 30, 2006 (212 treated with basal-bolus therapy and 247 treated with a more-conventional neutral protamine Hagedorn regimen). We abstracted data obtained at diagnosis and at quarterly clinic visits and compared groups by using repeated-measures, mixed-linear model analysis. We also reviewed the records of 198 children with preexisting type 1 diabetes mellitus of >1-year duration who changed from the neutral protamine Hagedorn regimen to a basal-bolus regimen during the review period. RESULTS: Glargine-treated subjects with newly diagnosed diabetes had lower hemoglobin A1c levels at 3, 6, 9, and 12 months after diagnosis than did neutral protamine Hagedorn-treated subjects (average hemoglobin A1c levels of 7.05% with glargine and 7.63% with neutral protamine Hagedorn, estimated across months 3, 6, 9, and 12, according to repeated-measures models adjusted for age at diagnosis and baseline hemoglobin A1c levels; treatment difference: 0.58%). Children with long-standing diabetes had no clinically important changes in their hemoglobin A1c levels in the first year after changing regimens. CONCLUSION: The institution of basal-bolus therapy with insulin glargine at the time of diagnosis of type 1 diabetes was associated with improved glycemic control, in comparison with more-conventional neutral protamine Hagedorn regimens, during the first year after diagnosis. 2-hop neighbor's text information:Title: Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. Abstract: CONTEXT: Treatment with diet alone, insulin, sulfonylurea, or metformin is known to improve glycemia in patients with type 2 diabetes mellitus, but which treatment most frequently attains target fasting plasma glucose (FPG) concentration of less than 7.8 mmol/L (140 mg/dL) or glycosylated hemoglobin A1c (HbA1c) below 7% is unknown. OBJECTIVE: To assess how often each therapy can achieve the glycemic control target levels set by the American Diabetes Association. DESIGN: Randomized controlled trial conducted between 1977 and 1997. Patients were recruited between 1977 and 1991 and were followed up every 3 months for 3, 6, and 9 years after enrollment. SETTING: Outpatient diabetes clinics in 15 UK hospitals. PATIENTS: A total of 4075 patients newly diagnosed as having type 2 diabetes ranged in age between 25 and 65 years and had a median (interquartile range) FPG concentration of 11.5 (9.0-14.4) mmol/L [207 (162-259) mg/dL], HbA1c levels of 9.1% (7.5%-10.7%), and a mean (SD) body mass index of 29 (6) kg/m2. INTERVENTIONS: After 3 months on a low-fat, high-carbohydrate, high-fiber diet, patients were randomized to therapy with diet alone, insulin, sulfonylurea, or metformin. MAIN OUTCOME MEASURES: Fasting plasma glucose and HbA1c levels, and the proportion of patients who achieved target levels below 7% HbA1c or less than 7.8 mmol/L (140 mg/dL) FPG at 3, 6, or 9 years following diagnosis. RESULTS: The proportion of patients who maintained target glycemic levels declined markedly over 9 years of follow-up. After 9 years of monotherapy with diet, insulin, or sulfonylurea, 8%, 42%, and 24%, respectively, achieved FPG levels of less than 7.8 mmol/L (140 mg/dL) and 9%, 28%, and 24% achieved HbA1c levels below 7%. In obese patients randomized to metformin, 18% attained FPG levels of less than 7.8 mmol/L (140 mg/dL) and 13% attained HbA1c levels below 7%. Patients less likely to achieve target levels were younger, more obese, or more hyperglycemic than other patients. CONCLUSIONS: Each therapeutic agent, as monotherapy, increased 2- to 3-fold the proportion of patients who attained HbA1c below 7% compared with diet alone. However, the progressive deterioration of diabetes control was such that after 3 years approximately 50% of patients could attain this goal with monotherapy, and by 9 years this declined to approximately 25%. The majority of patients need multiple therapies to attain these glycemic target levels in the longer term. 2-hop neighbor's text information:Title: Residual beta-cell function in children with type 1 diabetes: measurement and impact on glycemic control. Abstract: We studied residual beta-cell function in 84 children with IDDM to assess (1) relationship between basal and stimulated C-peptide concentrations; (2) reproducibility of testing (Group 1, n = 20); (3) the effect of exogenous insulin on test interpretation (Group II, n = 20); and (4) impact on metabolic control. Sustacal (a mixed liquid meal) was utilized as the test stimulus. In C-peptide positive subjects (n = 44) there was a strong correlation between basal and peak C-peptide concentrations (r = 0.88, p less than 0.001). In Group 1 subjects, Sustacal proved to be a highly reproducible test stimulus producing identical results on two tests 7-14 days apart. The results of the tests were not affected by the administration of subcutaneous regular insulin prior to the second test in Group II. Peak C-peptide correlated inversely with HbA1, insulin dose, and disease duration (r = -0.29, -0.40, and -0.33 respectively, p less than 0.05) and positively with age (r = 0.34, p less than 0.05). We conclude that Sustacal is a highly reproducible stimulus to residual beta-cell function in IDDM and is not affected by exogenous insulin. This residual insulin secretion has a small but significant effect on glycemic control. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2 1 2 1,1	2	pubmed	train	50
Title: Globalization, coca-colonization and the chronic disease epidemic: can the Doomsday scenario be averted? Abstract: There are at present approximately 110 million people with diabetes in the world but this number will reach over 220 million by the year 2010, the majority of them with type 2 diabetes. Thus there is an urgent need for strategies to prevent the emerging global epidemic of type 2 diabetes to be implemented. Tackling diabetes must be part of an integrated program that addresses lifestyle related disorders. The prevention and control of type 2 diabetes and the other major noncommunicable diseases (NCDs) can be cost- and health-effective through an integrated (i.e. horizontal) approach to noncommunicable diseases disease prevention and control. With the re-emergence of devastating communicable diseases including AIDS, the Ebola virus and tuberculosis, the pressure is on international and regional agencies to see that the noncommunicable disease epidemic is addressed. The international diabetes and public health communities need to adopt a more pragmatic view of the epidemic of type 2 diabetes and other noncommunicable diseases. The current situation is a symptom of globalization with respect to its social, cultural, economic and political significance. Type 2 diabetes will not be prevented by traditional medical approaches; what is required are major and dramatic changes in the socio-economic and cultural status of people in developing countries and the disadvantaged, minority groups in developed nations. The international diabetes and public health communities must lobby and mobilize politicians, other international agencies such as UNDP, UNICEF, and the World Bank as well as other international nongovernmental agencies dealing with the noncommunicable diseases to address the socio-economic, behavioural, nutritional and public health issues that have led to the type 2 diabetes and noncommunicable diseases epidemic. A multidisciplinary Task Force representing all parties which can contribute to a reversal of the underlying socio-economic causes of the problem is an urgent priority. 1-hop neighbor's text information:Title: Duration of breast-feeding and the incidence of type 2 diabetes mellitus in the Shanghai Women's Health Study. Abstract: AIMS/HYPOTHESIS: The aim of this study was to examine the association between lifetime breast-feeding and the incidence of type 2 diabetes mellitus in a large population-based cohort study of middle-aged women. METHODS: This was a prospective study of 62,095 middle-aged parous women in Shanghai, China, who had no prior history of type 2 diabetes mellitus, cancer or cardiovascular disease at study recruitment. Breast-feeding history, dietary intake, physical activity and anthropometric measurements were assessed by in-person interviews. The Cox regression model was employed to evaluate the association between breast-feeding and the risk of type 2 diabetes mellitus. RESULTS: After 4.6 years of follow-up, 1,561 women were diagnosed with type 2 diabetes mellitus. Women who had breastfed their children tended to have a lower risk of diabetes mellitus than those who had never breastfed [relative risk (RR)=0.88; 95% CI, 0.76-1.02; p=0.08]. Increasing duration of breast-feeding was associated with a reduced risk of type 2 diabetes mellitus. The fully adjusted RRs for lifetime breast-feeding duration were 1.00, 0.88, 0.89, 0.88, 0.75 and 0.68 (p trend=0.01) for 0, >0 to 0.99, >0.99 to 1.99, >1.99 to 2.99, >2.99 to 3.99 and >or=4 years in analyses adjusted for age, daily energy intake, BMI, WHR, smoking, alcohol intake, physical activity, occupation, income level, education level, number of live births and presence of hypertension at baseline. CONCLUSIONS/INTERPRETATION: Breast-feeding may protect parous women from developing type 2 diabetes mellitus later in life. 1-hop neighbor's text information:Title: Legume and soy food intake and the incidence of type 2 diabetes in the Shanghai Women's Health Study. Abstract: BACKGROUND: It has been postulated that a diet high in legumes may be beneficial for the prevention of type 2 diabetes mellitus (type 2 DM). However, data linking type 2 DM risk and legume intake are limited. OBJECTIVE: The objective of the study was to examine the association between legume and soy food consumption and self-reported type 2 DM. DESIGN: The study was conducted in a population-based prospective cohort of middle-aged Chinese women. We followed 64,227 women with no history of type 2 DM, cancer, or cardiovascular disease at study recruitment for an average of 4.6 y. Participants completed in-person interviews that collected information on diabetes risk factors, including dietary intake and physical activity in adulthood. Anthropometric measurements were taken. Dietary intake was assessed with a validated food-frequency questionnaire at the baseline survey and at the first follow-up survey administered 2-3 y after study recruitment. RESULTS: We observed an inverse association between quintiles of total legume intake and 3 mutually exclusive legume groups (peanuts, soybeans, and other legumes) and type 2 DM incidence. The multivariate-adjusted relative risk of type 2 DM for the upper quintile compared with the lower quintile was 0.62 (95% CI: 0.51, 0.74) for total legumes and 0.53 (95% CI: 0.45, 0.62) for soybeans. The association between soy products (other than soy milk) and soy protein consumption (protein derived from soy beans and their products) with type 2 DM was not significant. CONCLUSIONS: Consumption of legumes, soybeans in particular, was inversely associated with the risk type 2 DM. 1-hop neighbor's text information:Title: Exercise therapy in type 2 diabetes. Abstract: Structured exercise is considered an important cornerstone to achieve good glycemic control and improve cardiovascular risk profile in Type 2 diabetes. Current clinical guidelines acknowledge the therapeutic strength of exercise intervention. This paper reviews the wide pathophysiological problems associated with Type 2 diabetes and discusses the benefits of exercise therapy on phenotype characteristics, glycemic control and cardiovascular risk profile in Type 2 diabetes patients. Based on the currently available literature, it is concluded that Type 2 diabetes patients should be stimulated to participate in specifically designed exercise intervention programs. More attention should be paid to cardiovascular and musculoskeletal deconditioning as well as motivational factors to improve long-term treatment adherence and clinical efficacy. More clinical research is warranted to establish the efficacy of exercise intervention in a more differentiated approach for Type 2 diabetes subpopulations within different stages of the disease and various levels of co-morbidity. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2 2 2,2	1	pubmed	train	51
Title: Genetic requirements for acceleration of diabetes in non-obese diabetic mice expressing interleukin-2 in islet beta-cells. Abstract: Diabetes was dramatically accelerated in non-obese diabetic (NOD) transgenic mice that expressed interleukin-2 (IL-2) in their beta cells. A single cross to C57BL/6 completely prevented this effect and a further backcross to the NOD genetic background showed that at least two diabetes susceptibility loci (Idd1s and Idd3/10s) were required for the diabetes acceleration T cells activated to islet antigens were not circulating in the mice. The accelerating effect of IL-2 was present; but decreased, in NOD mice that lacked CD8+ T cells as well as in NOD SCID mice. The implications are that in the NOD genetic background, the production of cytokines, such as IL-2, by islet-specific CD4+ T cells can lead to beta cell damage and diabetes and that CD8+ T cells may have a role in accelerating diabetes onset. 1-hop neighbor's text information:Title: IL-10 is necessary and sufficient for autoimmune diabetes in conjunction with NOD MHC homozygosity. Abstract: Contrary to expectations based on in vitro experiments, we previously found that pancreatic IL-10 did not inhibit autoimmune diabetes but accelerated it in an MHC-dependent manner. Therefore, the ability of IL-10 to overcome the absence of all non-MHC diabetes susceptibility (Idd) alleles was studied in transgenic mice expressing pancreatic IL-10 backcrossed to B10.H2g7 congenic mice, which have no Idd alleles other than NOD MHC (H2g7). IL-10 transgenic backcross 1 (BC1) mice with H2g7/g7 haplotype developed clear-cut insulitis and diabetes, but neither transgenic mice with the H2g/b haplotype nor nontransgenic BC1 mice did so. Further implicating IL-10 in autoimmune diabetes, anti-IL-10 antibody treatment inhibited the development of insulitis in NOD mice. These results suggest that IL-10 may be necessary and sufficient for producing autoimmune diabetes in conjunction with NOD MHC homozygosity and that some Idd genes may be related to the regulation of IL-10. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1,1	1	pubmed	train	53
Title: Globalization, coca-colonization and the chronic disease epidemic: can the Doomsday scenario be averted? Abstract: There are at present approximately 110 million people with diabetes in the world but this number will reach over 220 million by the year 2010, the majority of them with type 2 diabetes. Thus there is an urgent need for strategies to prevent the emerging global epidemic of type 2 diabetes to be implemented. Tackling diabetes must be part of an integrated program that addresses lifestyle related disorders. The prevention and control of type 2 diabetes and the other major noncommunicable diseases (NCDs) can be cost- and health-effective through an integrated (i.e. horizontal) approach to noncommunicable diseases disease prevention and control. With the re-emergence of devastating communicable diseases including AIDS, the Ebola virus and tuberculosis, the pressure is on international and regional agencies to see that the noncommunicable disease epidemic is addressed. The international diabetes and public health communities need to adopt a more pragmatic view of the epidemic of type 2 diabetes and other noncommunicable diseases. The current situation is a symptom of globalization with respect to its social, cultural, economic and political significance. Type 2 diabetes will not be prevented by traditional medical approaches; what is required are major and dramatic changes in the socio-economic and cultural status of people in developing countries and the disadvantaged, minority groups in developed nations. The international diabetes and public health communities must lobby and mobilize politicians, other international agencies such as UNDP, UNICEF, and the World Bank as well as other international nongovernmental agencies dealing with the noncommunicable diseases to address the socio-economic, behavioural, nutritional and public health issues that have led to the type 2 diabetes and noncommunicable diseases epidemic. A multidisciplinary Task Force representing all parties which can contribute to a reversal of the underlying socio-economic causes of the problem is an urgent priority. 1-hop neighbor's text information:Title: Duration of breast-feeding and the incidence of type 2 diabetes mellitus in the Shanghai Women's Health Study. Abstract: AIMS/HYPOTHESIS: The aim of this study was to examine the association between lifetime breast-feeding and the incidence of type 2 diabetes mellitus in a large population-based cohort study of middle-aged women. METHODS: This was a prospective study of 62,095 middle-aged parous women in Shanghai, China, who had no prior history of type 2 diabetes mellitus, cancer or cardiovascular disease at study recruitment. Breast-feeding history, dietary intake, physical activity and anthropometric measurements were assessed by in-person interviews. The Cox regression model was employed to evaluate the association between breast-feeding and the risk of type 2 diabetes mellitus. RESULTS: After 4.6 years of follow-up, 1,561 women were diagnosed with type 2 diabetes mellitus. Women who had breastfed their children tended to have a lower risk of diabetes mellitus than those who had never breastfed [relative risk (RR)=0.88; 95% CI, 0.76-1.02; p=0.08]. Increasing duration of breast-feeding was associated with a reduced risk of type 2 diabetes mellitus. The fully adjusted RRs for lifetime breast-feeding duration were 1.00, 0.88, 0.89, 0.88, 0.75 and 0.68 (p trend=0.01) for 0, >0 to 0.99, >0.99 to 1.99, >1.99 to 2.99, >2.99 to 3.99 and >or=4 years in analyses adjusted for age, daily energy intake, BMI, WHR, smoking, alcohol intake, physical activity, occupation, income level, education level, number of live births and presence of hypertension at baseline. CONCLUSIONS/INTERPRETATION: Breast-feeding may protect parous women from developing type 2 diabetes mellitus later in life. 1-hop neighbor's text information:Title: Legume and soy food intake and the incidence of type 2 diabetes in the Shanghai Women's Health Study. Abstract: BACKGROUND: It has been postulated that a diet high in legumes may be beneficial for the prevention of type 2 diabetes mellitus (type 2 DM). However, data linking type 2 DM risk and legume intake are limited. OBJECTIVE: The objective of the study was to examine the association between legume and soy food consumption and self-reported type 2 DM. DESIGN: The study was conducted in a population-based prospective cohort of middle-aged Chinese women. We followed 64,227 women with no history of type 2 DM, cancer, or cardiovascular disease at study recruitment for an average of 4.6 y. Participants completed in-person interviews that collected information on diabetes risk factors, including dietary intake and physical activity in adulthood. Anthropometric measurements were taken. Dietary intake was assessed with a validated food-frequency questionnaire at the baseline survey and at the first follow-up survey administered 2-3 y after study recruitment. RESULTS: We observed an inverse association between quintiles of total legume intake and 3 mutually exclusive legume groups (peanuts, soybeans, and other legumes) and type 2 DM incidence. The multivariate-adjusted relative risk of type 2 DM for the upper quintile compared with the lower quintile was 0.62 (95% CI: 0.51, 0.74) for total legumes and 0.53 (95% CI: 0.45, 0.62) for soybeans. The association between soy products (other than soy milk) and soy protein consumption (protein derived from soy beans and their products) with type 2 DM was not significant. CONCLUSIONS: Consumption of legumes, soybeans in particular, was inversely associated with the risk type 2 DM. 1-hop neighbor's text information:Title: Exercise therapy in type 2 diabetes. Abstract: Structured exercise is considered an important cornerstone to achieve good glycemic control and improve cardiovascular risk profile in Type 2 diabetes. Current clinical guidelines acknowledge the therapeutic strength of exercise intervention. This paper reviews the wide pathophysiological problems associated with Type 2 diabetes and discusses the benefits of exercise therapy on phenotype characteristics, glycemic control and cardiovascular risk profile in Type 2 diabetes patients. Based on the currently available literature, it is concluded that Type 2 diabetes patients should be stimulated to participate in specifically designed exercise intervention programs. More attention should be paid to cardiovascular and musculoskeletal deconditioning as well as motivational factors to improve long-term treatment adherence and clinical efficacy. More clinical research is warranted to establish the efficacy of exercise intervention in a more differentiated approach for Type 2 diabetes subpopulations within different stages of the disease and various levels of co-morbidity. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2 2 2,2	1	pubmed	train	54
Title: Platelet expression of tumour necrosis factor-alpha (TNF-alpha), TNF receptors and intercellular adhesion molecule-1 (ICAM-1) in patients with proliferative diabetic retinopathy. Abstract: Microvascular complications of insulin-dependent diabetes mellitus (IDDM) have been strongly associated with platelet abnormalities, whilst TNF-alpha has been implicated in the pathogenesis of this condition. However, at present it is not clear whether human circulating platelets express TNF-alpha or TNF receptors (TNF-R) or whether impaired expression of these molecules and of the TNF-reactive adhesion molecule ICAM-1 may be associated with platelet abnormalities in patients with IDDM. On this basis we investigated the platelet expression of these molecules in patients with IDDM complicated or uncomplicated by proliferative diabetic retinopathy (PDR) and in healthy subjects. We observed that the proportion of platelets staining for TNF-alpha was significantly higher in IDDM patients with active PDR than in patients without microvascular complications (P = 0.0078), quiescent PDR (P = 0.003) or healthy subjects (P = 0.0013). Patients with active PDR also showed a higher proportion of platelets expressing TNF-RI (P = 0. 0052) and TNF-RII (P = 0.015) than healthy controls or patients with quiescent PDR (P = 0.009 and 0.0006, respectively). In addition, the percentage of ICAM-1+ platelets was significantly higher in patients with active PDR than in patients with quiescent PDR (P = 0.0065) or normal subjects (P = 0.013). There was a direct correlation between platelet expression of TNF-alpha and that of TNF-R in PDR patients, indicating that platelet staining for TNF-alpha may be due to binding of this cytokine to its receptors. The results suggest that increased platelet expression of TNF-alpha, TNF-R and ICAM-1 in IDDM patients may constitute important markers of thrombocyte abnormalities during the development of microvascular complications of diabetes mellitus. 1-hop neighbor's text information:Title: Accelerated beta-cell destruction in adoptively transferred autoimmune diabetes correlates with an increased expression of the genes coding for TNF-alpha and granzyme A in the intra-islet infiltrates. Abstract: Autoimmune destruction of beta-cells in nonobese diabetic (NOD) mice is greatly accelerated by adoptive cotransfer of syngeneic CD4+ and CD8+ T-cells from diabetic animals into newborn NOD mice. We followed, by in situ hybridization, the appearance of mRNA of the tumor necrosis factor (TNF)-alpha gene and, as a marker for activated cytotoxic T-cells, of the serine protease granzyme A gene in the cellular infiltrates generated by cell transfer at birth. Cells expressing the genes for granzyme A or TNF-alpha were seen in considerable numbers already on day 14, after adoptive transfer. These numbers gradually increased in the intra-islet infiltrates from day 14 through day 30 after adoptive transfer. Compared with our previous findings in NOD mice developing spontaneous insulin-dependent diabetes mellitus (IDDM) (Held W, MacDonald HR, Weissman IL, Hess MW, Mueller C: Genes encoding tumor necrosis factor alpha and granzyme A are expressed during development of autoimmune diabetes. Proc Natl Acad Sci USA 87:2239-2243, 1990), frequencies of cells with TNF-alpha and granzyme A mRNA were 2- and 12-fold higher, respectively, in transferred IDDM (trIDDM). TNF-alpha mRNA positive cells were predominantly found in the CD4+ T-cell subset of the pancreas-infiltrating cells, whereas granzyme A mRNA positive cells were mainly observed in the CD4- T-cell subset. The effects of the observed enhanced TNF expression upon the pathogenesis of trIDDM are as yet unknown.(ABSTRACT TRUNCATED AT 250 WORDS) 1-hop neighbor's text information:Title: Effect of tumor necrosis factor alpha on insulin-dependent diabetes mellitus in NOD mice. I. The early development of autoimmunity and the diabetogenic process. Abstract: Tumor necrosis factor (TNF) alpha is a cytokine that has potent immune regulatory functions. To assess the potential role of this cytokine in the early development of autoimmunity, we investigated the effect of TNF on the development of insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice, a spontaneous murine model for autoimmune, insulin-dependent type I diabetes. Treatment of newborn female NOD mice with TNF every other day for 3 wk, led to an earlier onset of disease (10 versus 15 wk of age in control mice) and 100% incidence before 20 wk of age (compared to 45% at 20 wk of age in control phosphate-buffered saline treated female mice). In contrast, administration of an anti-TNF monoclonal antibody, TN3.19.12, resulted in complete prevention of IDDM. In vitro proliferation assays demonstrated that mice treated with TNF developed an increased T cell response to a panel of beta cell autoantigens, whereas anti-TNF treatment resulted in unresponsiveness to the autoantigens. In addition, autoantibody responses to the panel of beta cell antigens paralleled the T cell responses. The effects mediated by TNF appear to be highly age dependent. Treatment of animals either from birth or from 2 wk of age had a similar effect. However, if treatment was initiated at 4 wk of age, TNF delayed disease onset. These data suggest that TNF has a critical role in the early development of autoimmunity towards beta-islet cells. 1-hop neighbor's text information:Title: An association in non-insulin-dependent diabetes mellitus subjects between susceptibility to retinopathy and tumor necrosis factor polymorphism. Abstract: In IDDM an association between diabetic retinopathy and polymorphic markers of MHC has been described. However, these associations are complicated by a primary association between the MHC and IDDM. Because the pathogenesis of retinopathy is likely to be the same in IDDM and NIDDM, NIDDM subjects with retinopathy would be the ideal population to study for an association with MHC markers. The following South Indian subjects were therefore studied: unselected NIDDM (n = 76), unselected IDDM (n = 99), non-diabetic controls (n = 96), NIDDM subjects with maculopathy (MAC), n = 55, NIDDM subjects with proliferative retinopathy (PR), n = 53, and without retinopathy (LTD), n = 46. DNA was amplified and studied using a microsatellite polymorphism located 3.5 kb upstream of TNF-beta within the MHC class III region on the short arm of chromosome 6. No differences in allelic distribution were observed between the random NIDDM subjects and controls (p = 0.17). Differences in allelic distribution were found between unselected IDDM and controls (P = 0.016) and between the NIDDM subjects with maculopathy and/or proliferative retinopathy and no retinopathy (P = 0.006). This association could be accounted for by those patients with proliferative retinopathy (MAC vs LTD, p = 0.23; MAC vs PR, p = 0.07; and PR vs LTD, p = 0.002). 2-hop neighbor's text information:Title: Progression from insulitis to beta-cell destruction in NOD mouse requires L3T4+ T-lymphocytes. Abstract: The identity of the cells responsible for beta-cell destruction in type I (insulin-dependent) diabetes is still uncertain. L3T4+ T-lymphocytes have a role in the initiation of insulitis and in damaging transplanted allogeneic islets in nonobese diabetic (NOD) mice. The role of L3T4+ T-lymphocytes in destruction of beta-cells of the NOD mouse was studied in cyclophosphamide (CY)-induced diabetic NOD mice with a rat anti-L3T4 monoclonal antibody (MoAb). After administration of CY, most untreated animals became diabetic, whereas all antibody-treated animals remained normoglycemic. Insulitis was still present in MoAb-treated animals, but immunocytochemical staining showed rat antibody blocking the L3T4 antigen on T-lymphocytes. This study provides further evidence that L3T4+ T-lymphocytes are critical to the process of beta-cell destruction in NOD mice. The means by which L3T4+ cells exert their effect remains to be clarified. 2-hop neighbor's text information:Title: Transfer of autoimmune diabetes mellitus with splenocytes from nonobese diabetic (NOD) mice. Abstract: The nonobese diabetic (NOD) mouse, a model of human type I diabetes, develops insulitis beginning at 4-6 wk of age. By 30 wk of age, 72% of females and 39% of males develop spontaneous diabetes, apparently because of an overwhelming autoimmune response to the insulin-producing beta-cells within the islets. To identify the immune mechanism responsible for destruction of beta-cells in the NOD mouse, we developed an adoptive transfer protocol that induces diabetes in NOD mice at an age when spontaneous diabetes is rarely observed. Splenocytes from overtly diabetic NOD mice were unable to transfer diabetes to very young (less than or equal to 6 wk) irradiated NOD mice but effectively transferred diabetes to irradiated NOD mice greater than 6 wk of age. In such transfers, overt diabetes was induced within 12-22 days in greater than 95% (79/82) of the recipients. Thus, transfer of splenocytes to young mice induces them to become diabetic at a higher frequency and at a younger age than their untreated littermates. Equally successful transfers with as few as 5 X 10(6) spleen cells have been performed in male and female NOD mice, even though males display a lower spontaneous incidence of diabetes than females. Splenocytes obtained from diabetic mice maintained on insulin for up to 2 mo also transferred diabetes. Because NOD mice display increasing levels of insulitis with age, spleen cells obtained from nondiabetic NOD mice of different ages were tested for their ability to transfer diabetes.(ABSTRACT TRUNCATED AT 250 WORDS) I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1 2 0 0,1	2	pubmed	train	55
Title: Comparative trial between insulin glargine and NPH insulin in children and adolescents with type 1 diabetes mellitus. Abstract: The objective of this study was to compare the efficacy and safety of insulin glargine, a long-acting insulin analog, with NPH insulin in children and adolescents with type 1 diabetes mellitus (T1DM). In a multicenter, open-label, randomized, 6-month study, 349 patients with TIDM, aged 5-16 years, received insulin glargine once daily or NPH insulin either once or twice daily, based on their prior treatment regimen. Although there was no significant difference between the NPH insulin and insulin glargine treatment groups with respect to baseline to endpoint change in HbA1c levels, fasting blood glucose (FBG) levels decreased significantly more in the insulin glargine group (-1.29 mmol/l) than in the NPH insulin group (-0.68 mmol/L, p = 0.02). The percentage of symptomatic hypoglycemic events was similar between groups; however, fewer patients in the insulin glargine group reported severe hypoglycemia (23% vs 29%) and severe nocturnal hypoglycemia (13% vs 18%), although these differences were not statistically significant (p = 0.22 and p = 0.19, respectively). Fewer serious adverse events occurred in the insulin glargine group than in the NPH insulin group (p < 0.02). A once-daily subcutaneous dose of insulin glargine provides effective glycemic control and is well tolerated in children and adolescents with T1DM. 1-hop neighbor's text information:Title: Diabetes screening, diagnosis, and therapy in pediatric patients with type 2 diabetes. Abstract: The dramatic rise in the incidence and prevalence of type 2 diabetes mellitus in the pediatric and adolescent populations has been associated with the ongoing epidemic of overweight, obesity, insulin resistance, and metabolic syndrome seen in these age groups. Although the majority of pediatric patients diagnosed with diabetes are still classified as having type 1 diabetes, almost 50% of patients with diabetes in the pediatric age range (under 18 years) may have type 2 diabetes. Screening of high-risk patients for diabetes and prediabetes is important. Prompt diagnosis and accurate diabetes classification facilitate appropriate and timely treatment and may reduce the risk for complications. This is especially important in children because lifestyle interventions may be successful and the lifelong risk for complications is greatest. Treatment usually begins with dietary modification, weight loss, and a structured program of physical exercise. Oral antidiabetic agents are added when lifestyle intervention alone fails to maintain glycemic control. Given the natural history of type 2 diabetes, most if not all patients will eventually require insulin therapy. In those requiring insulin, improved glycemic control and reduced frequency of hypoglycemia can be achieved with insulin analogs. It is common to add insulin therapy to existing oral therapy only when oral agents no longer provide adequate glycemic control. 1-hop neighbor's text information:Title: Institution of basal-bolus therapy at diagnosis for children with type 1 diabetes mellitus. Abstract: OBJECTIVE: We studied whether the institution of basal-bolus therapy immediately after diagnosis improved glycemic control in the first year after diagnosis for children with newly diagnosed type 1 diabetes mellitus. METHODS: We reviewed the charts of 459 children > or =6 years of age who were diagnosed as having type 1 diabetes between July 1, 2002, and June 30, 2006 (212 treated with basal-bolus therapy and 247 treated with a more-conventional neutral protamine Hagedorn regimen). We abstracted data obtained at diagnosis and at quarterly clinic visits and compared groups by using repeated-measures, mixed-linear model analysis. We also reviewed the records of 198 children with preexisting type 1 diabetes mellitus of >1-year duration who changed from the neutral protamine Hagedorn regimen to a basal-bolus regimen during the review period. RESULTS: Glargine-treated subjects with newly diagnosed diabetes had lower hemoglobin A1c levels at 3, 6, 9, and 12 months after diagnosis than did neutral protamine Hagedorn-treated subjects (average hemoglobin A1c levels of 7.05% with glargine and 7.63% with neutral protamine Hagedorn, estimated across months 3, 6, 9, and 12, according to repeated-measures models adjusted for age at diagnosis and baseline hemoglobin A1c levels; treatment difference: 0.58%). Children with long-standing diabetes had no clinically important changes in their hemoglobin A1c levels in the first year after changing regimens. CONCLUSION: The institution of basal-bolus therapy with insulin glargine at the time of diagnosis of type 1 diabetes was associated with improved glycemic control, in comparison with more-conventional neutral protamine Hagedorn regimens, during the first year after diagnosis. 2-hop neighbor's text information:Title: Type 1 diabetes intervention trials: what have we learned? A critical review of selected intervention trials. Abstract: Developing therapies to stop or slow the immune destruction of islets has been a goal of investigators in type 1 diabetes for several decades. This review of clinical interventions in patients with type 1 diabetes indicates both negative and positive outcomes with a variety of different therapeutic agents. An underlying theme of this article is that differences in study design may impact the outcome more than the therapy being tested. Thus, each of these results need to be considered in the context of important variables in study design. To date, there is no clear answer as to what study design is best to determine if an agent is effective against the diabetes disease process; however, the Immunology of Diabetes Society has recently developed guidelines for the conduct of these trials to facilitate comparisons of therapies in the future. 2-hop neighbor's text information:Title: Insulin glulisine provides improved glycemic control in patients with type 2 diabetes. Abstract: OBJECTIVE: Insulin glulisine is a novel analog of human insulin designed for use as a rapid-acting insulin. This study compared the safety and efficacy of glulisine with regular human insulin (RHI) in combination with NPH insulin. RESEARCH DESIGN AND METHODS: In total, 876 relatively well-controlled patients with type 2 diabetes (mean HbA1c 7.55%) were randomized and treated with glulisine/NPH (n = 435) or RHI/NPH (n = 441) for up to 26 weeks in this randomized, multicenter, multinational, open-label, parallel-group study. Subjects were allowed to continue the same dose of prestudy regimens of oral antidiabetic agent (OAD) therapy (unless hypoglycemia necessitated a dose change). RESULTS: A slightly greater reduction from baseline to end point of HbA1c was seen in the glulisine group versus RHI (-0.46 vs. -0.30% with RHI; P = 0.0029). Also, at end point, lower postbreakfast (156 vs. 162 mg/dl [8.66 vs. 9.02 mmol/l]; P < 0.05) and postdinner (154 vs. 163 mg/dl [8.54 vs. 9.05 mmol/l]; P < 0.05) blood glucose levels were noted. Symptomatic hypoglycemia (overall, nocturnal, and severe) and weight gain were comparable between the two treatment groups. There were no between-group differences in baseline-to-end point changes in insulin dose. CONCLUSIONS: Twice-daily glulisine associated with NPH can provide small improvements in glycemic control compared with RHI in patients with type 2 diabetes who are already relatively well controlled on insulin alone or insulin plus OADs. The clinical relevance of such a difference remains to be established. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2 1 1 2,1	2	pubmed	train	59
Title: Use of the GlucoWatch biographer in children with type 1 diabetes. Abstract: OBJECTIVE: To determine whether use of the GlucoWatch biographer improves glucose control in children and adolescents with type 1 diabetes. METHODS: Forty children in poor glucose control (glycohemoglobin [HbA1c] >8%) were randomized to diabetes management with or without glucose monitoring using the biographer. Conventional glucose monitoring was performed 4 times daily in both groups. Those randomized to the biographer group were asked to wear the device 4 times per week for 3 months (intervention phase) and to perform blood glucose monitoring if the biographer alerted them that glucose was < or =70 mg/dL (3.9 mmol/L) or > or =300 mg/dL (16.7 mmol/L). After 3 months, all patients received biographers and were followed for 6 months (observation phase). HbA1c values were determined at baseline and after 1, 3, 6, and 9 months. RESULTS: The median HbA1c was 8.6% and 8.9% (control versus biographer) at baseline and was significantly lower in the biographer group after 3 months (8.4% vs 9%). More hypoglycemia was detected when subjects were wearing the biographer, especially at night. No severe hypoglycemia occurred. During the observation phase, HbA1c values at 6 months were 8.5% and 8.3% and at 9 months were 8.6% and 8.4% in the control and biographer groups, respectively. Two children dropped out of the study, 1 because of skin irritation from using the device. CONCLUSIONS: The GlucoWatch biographer was well tolerated by children and adolescents and significantly improved glucose control compared with standard therapy. The use of the biographer with an alarm to detect nocturnal hypoglycemia has the potential to increase the safety of diabetes management in children. 1-hop neighbor's text information:Title: Psychological aspects of continuous glucose monitoring in pediatric type 1 diabetes. Abstract: Clinical use of near-continuous glucose monitors (CGMs) could have substantial impact on family management of pediatric type 1 diabetes and could generate both beneficial and adverse psychological reactions. In addition to glycemic benefits, CGM could possibly yield educational and motivational benefits. Conversely, CGM may also lead to information overload and increased treatment burden. Further, patients and families with certain affective, behavioral, and cognitive characteristics might derive greater benefit from CGM use. As information about these processes could facilitate optimal clinical use of CGM, the Diabetes Research in Children Network (DirecNet) included measurement of selected psychological variables in a recent randomized trial of the GlucoWatch G2 Biographer (GW2B, Cyngus, Inc., Redwood City, CA, USA). A multicenter sample of 200 youths with type 1 diabetes was randomized to 6 months of either continued usual care (UC) using a conventional home glucose meter for diabetes or supplementation of standard care with use of the GW2B. Diabetes treatment adherence, diabetes-specific quality of life, and diabetes-related anxiety were measured at baseline and at the end of the study. Satisfaction with use of the GW2B was measured at the end of the study. The results indicated neither adverse nor beneficial psychological effects of CGM use. More frequent GW2B use over the 6-month study was found among youths whose parents reported higher scores for treatment adherence and diabetes-related quality of life at baseline. The study illustrates the empiric assessment of the psychological context of CGM use and establishes methods that are applicable to new CGM devices as they emerge. 2-hop neighbor's text information:Title: Performance evaluation of the MiniMed continuous glucose monitoring system during patient home use. Abstract: BACKGROUND: The recent availability of a continuous glucose monitor offers the opportunity to match the demands of intensive diabetes management with a period of equally intensive blood glucose monitoring. The present study evaluates the performance of the MiniMed continuous glucose monitoring system (CGMS) in patients with diabetes during home use. METHODS: Performance data and demographic information were obtained from 135 patients who were (mean +/- SD) 40.5+/-14.5 years old, had an average duration of diabetes of 18.0+/-9.8 years, 50% were female, 90% were Caucasian, and 87% of whom had been diagnosed with type 1 diabetes. Patients were selected by their physician, trained on the use of the CGMS and wore the device at home for 3 days or more. The performance of the CGMS was evaluated against blood glucose measurements obtained using each patient's home blood glucose meter. Evaluation statistics included correlation, linear regression, mean difference and percent absolute difference scores, and Clarke error grid analysis. RESULTS: The CGMS values were compared to 2477 SMBG tests (r = 0.91, slope = 0.93, intercept = 14.5 mg/dL, mean absolute difference = 18.0%+/-19.8%). Clarke error grid analysis showed 96.2% of the data pairs falling within the clinically acceptable regions (zones A and B). CONCLUSIONS: These results demonstrate the agreement of the CGMS to blood glucose meter values, under conditions of home use, in patients selected by their physicians as candidates for continuous monitoring. The detailed glucose information provided by the CGMS should make successful management of diabetes more easily achieved. 2-hop neighbor's text information:Title: The PedsQL in type 1 and type 2 diabetes: reliability and validity of the Pediatric Quality of Life Inventory Generic Core Scales and type 1 Diabetes Module. Abstract: OBJECTIVE: The Pediatric Quality of Life Inventory (PedsQL) is a modular instrument designed to measure health-related quality of life (HRQOL) in children and adolescents aged 2-18 years. The PedsQL 4.0 Generic Core Scales are child self-report and parent proxy-report scales developed as the generic core measure to be integrated with the PedsQL disease-specific modules. The PedsQL 3.0 Type 1 Diabetes Module was designed to measure diabetes-specific HRQOL. RESEARCH DESIGN AND METHODS: The PedsQL Generic Core Scales and Diabetes Module were administered to 300 pediatric patients with type 1 or type 2 diabetes and 308 parents. RESULTS: Internal consistency reliability for the PedsQL Generic Core Total Scale score (alpha = 0.88 child, 0.89 parent-report) and most Diabetes Module scales (average alpha = 0.71 child, 0.77 parent-report) was acceptable for group comparisons. The PedsQL 4.0 distinguished between healthy children and children with diabetes. The Diabetes Module demonstrated intercorrelations with dimensions of generic and diabetes-specific HRQOL. CONCLUSIONS: The results demonstrate the reliability and validity of the PedsQL in diabetes. The PedsQL may be used as an outcome measure for diabetes clinical trials and research. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1 1,1	2	pubmed	train	60
Title: Reversed circadian blood pressure rhythm is associated with occurrences of both fatal and nonfatal vascular events in NIDDM subjects. Abstract: To assess the significance of reversed circadian blood pressure (BP) rhythms as a predictive factor of vascular events in NIDDM, vital status after an average 4-year follow-up was determined in 325 NIDDM subjects in whom the circadian BP profile had been monitored between 1988 and 1996. Circadian BP rhythm was analyzed by the COSINOR (a compound word for cosine and vector) method, as previously described. After exclusion of 37 dropped-out subjects, 288 were recruited to the further analysis, of which 201 had a normal circadian BP rhythm (group N) and the remaining 87 had a reversed one (group R). There was no difference in sex, HbA1c, the prevalence of smokers, serum lipids, or serum electrolytes between groups N and R at baseline, whereas age, the prevalence of hypertension, serum creatinine, and diabetic complications were more pronounced in group R than in group N. During the follow-up period (which averaged 52 months in group N and 36 months in group R), fatal and nonfatal vascular (cerebrovascular, cardiovascular, peripheral vascular arteries, and retinal artery) events occurred in 20 subjects in group N and 56 in group R. Unadjusted survival times and event-free times were estimated by the Kaplan-Meier product-limit method, and there was a significant difference in both unadjusted survival and event-free survival rates between groups N and R (P < 0.001 each; log-rank test). The Cox proportional-hazards model adjusted for age, sex, circadian BP pattern, duration of diabetes, therapy for diabetes, various diabetic complications, and hypertension demonstrated that circadian BP pattern and age exhibited significant, high adjusted relative risks for fatal events, and that diabetic nephropathy, postural hypotension, and hypertension as well as circadian BP pattern exhibited significant, high adjusted relative risks with respect to the occurrence of various nonfatal vascular events. These results suggest that reversed circadian BP rhythm is associated with occurrences of both fatal and nonfatal vascular events in NIDDM subjects. 1-hop neighbor's text information:Title: Diabetes and cardiovascular autonomic dysfunction: application of animal models. Abstract: When diabetes is associated with cardiovascular autonomic dysfunction, there is a poor prognosis and increased morbidity and mortality. Information on the mechanisms of diabetes-associated autonomic dysfunction has been provided by advanced studies using physiological, pharmacological, anatomical and molecular methods in experimental animal models of insulin deficiency and resistance. This has been augmented by new approaches which combine diabetes induction with genetically modified animal models. The aim of this review is to outline and discuss the animal models used for the study of insulin deficiency and insulin resistance with a focus on autonomic neural interactions. The goal is to better understand the clinical relevance of cardiovascular autonomic dysfunction associated with diabetes. 2-hop neighbor's text information:Title: Effect of age and methacholine on the rate and coronary flow of isolated hearts of diabetic rats. Abstract: 1. Isolated hearts perfused by the method of Langendorff from 6, 12 and 24 week streptozotocin (STZ) diabetic rats displayed a significant bradycardia following 60 min equilibration. The rate of hearts from 12-week diabetic rats (164 +/- 17) displayed the greatest bradycardia compared to age-matched controls (268 +/- 15; P less than 0.001), and diabetics treated with insulin (232 +/- 17; P less than 0.01), but by 52 weeks the heart rate of the 3 groups was similar. With advancing age the effect of STZ diabetes on the rate of rat isolated perfused hearts remained unchanged but the rate of the control and diabetic + insulin groups declined. 2. Hearts from 6-52 week STZ-treated rats were found to be more sensitive to the negative chronotropic effect of methacholine, the greatest difference occurring in hearts from the 12 week animals. Atropine (10(-7) M) did not affect the resting heart rate of age-matched controls or diabetics but blocked methacholine (2.6 x 10(-6) M)-induced bradycardia in both, suggesting that the site of action of diabetic bradycardia is not the muscarinic receptors. 3. At the end of equilibration there was a significant decrease in coronary flow in hearts from 12 week diabetic animals. In spontaneously beating diabetic rat hearts administration of methacholine (2.6 x 10(-6) M) produced a significantly greater decrease in coronary flow in the 12, 24 and 52 week diabetic hearts. When electrically paced (5 Hz) however, there was no difference in response to methacholine between the three groups except at 52 weeks between the age-matched control and diabetic groups. This suggests that the more pronounced reduction induced by methacholine on the coronary flow of diabetic hearts is secondary to its negative chronotropic effect. 4. In general, hearts from diabetic animals treated with insulin respond similarly to their agematched controls in the presence and absence of methacholine. 2-hop neighbor's text information:Title: Parasympathetic dysfunction is associated with baroreflex and chemoreflex impairment in streptozotocin-induced diabetes in rats. Abstract: This study explored physiological mechanisms of diabetic dysfunction in baroreceptors and chemoreceptors-mediated hemodynamic responses, and cholinergic neurotransmission in 30-day diabetic rats (n = 14) and controls (n = 14). Basal hemodynamic data and vagal response to electrical stimulation and methacholine injection were also evaluated. Muscarinic receptors were characterized using a radioligand receptor binding assay ([3H]N methylscopolamine). Experimental diabetes (50 mg/kg of STZ, i.v.) decreased systolic, diastolic, and mean arterial pressure and basal heart rate. Heart rate (HR) responses to vagal electrical stimulation (16, 32, and 64 Hz) were 15%, 11%, and 14% higher in diabetics vs non-diabetics, as were HR responses to methacholine injection (-130+/-24, -172+/-18, -206+/-15 bpm vs. -48+/-15, -116+/-12, -151+/-18 bpm, P < 0.05). Muscarinic receptor density was higher (267.4+/-11 vs 193.5+/-22 fmol/mg/prot, P < 0.05) in the atria of diabetic rats than in those of controls; the affinity was similar between groups. Diabetes-induced reduction of reflex responses to baro- (reflex bradycardia: -3.4+/-0.3 and -2.7+/-0.2 bpm/mm Hg; reflex tachycardia: -1.6+/-0.1 and -1.4+/-0.07 bpm/mm Hg, in control and diabetics, P < 0.05) and chemoreceptor stimulation, enhancement of HR responsiveness to cardiac vagal electrical stimulation and methacholine stimulation, plus an increase in the number of atrial muscarinic receptors indicates reduced parasympathetic activity, which is probably derived from central nervous system derangement. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	0 0 0,2	2	pubmed	train	61
Title: Accelerated diabetes in non-obese diabetic (NOD) mice differing in incidence of spontaneous disease. Abstract: The NOD mouse is an established model of autoimmune diabetes mellitus. Various lines of NOD mice differ in their incidence of spontaneous diabetes, e.g. 93% of female NOD/Lt mice compared with 46% of female NOD/Wehi mice develop diabetes by 250 days. These two lines were studied under conditions which greatly accelerate the onset of hyperglycaemia. It was hoped that their responses to these manipulations would reveal characteristic differences which would increase our understanding of diabetes resistance in the low incidence NOD/Wehi line. One dose of 300 mg/kg of cyclophosphamide (CP) produced hyperglycaemia in 50% of NOD mice within 2 weeks in both lines. They were also equally susceptible to diabetes induced by splenocyte transfer at 21 days of age from prediabetic 150-day-old NOD/Lt or NOD/Wehi females. Five daily 40 mg/kg doses of streptozotocin (STZ) resulted in a severity of diabetes in the NOD mice greater than in C57BL or SJL/mice. While the incidence and severity of diabetes induced in the two NOD lines were similar, this appeared to be principally due to sensitivity to the toxic effects of STZ rather than its ability to exacerbate autoimmune beta cell destruction. It has previously been shown that it is possible to prevent diabetes in susceptible NOD mice with simple, relatively benign therapies and here we show that it is possible to induce diabetes in resistant animals at a rate indistinguishable from fully predisposed individuals. It therefore appears that the prediabetic NOD mouse is poised in an immunologically precarious state with the onset of disease being highly dependent on factors which exacerbate or moderate autoimmune destruction. 1-hop neighbor's text information:Title: Transfer of autoimmune diabetes mellitus with splenocytes from nonobese diabetic (NOD) mice. Abstract: The nonobese diabetic (NOD) mouse, a model of human type I diabetes, develops insulitis beginning at 4-6 wk of age. By 30 wk of age, 72% of females and 39% of males develop spontaneous diabetes, apparently because of an overwhelming autoimmune response to the insulin-producing beta-cells within the islets. To identify the immune mechanism responsible for destruction of beta-cells in the NOD mouse, we developed an adoptive transfer protocol that induces diabetes in NOD mice at an age when spontaneous diabetes is rarely observed. Splenocytes from overtly diabetic NOD mice were unable to transfer diabetes to very young (less than or equal to 6 wk) irradiated NOD mice but effectively transferred diabetes to irradiated NOD mice greater than 6 wk of age. In such transfers, overt diabetes was induced within 12-22 days in greater than 95% (79/82) of the recipients. Thus, transfer of splenocytes to young mice induces them to become diabetic at a higher frequency and at a younger age than their untreated littermates. Equally successful transfers with as few as 5 X 10(6) spleen cells have been performed in male and female NOD mice, even though males display a lower spontaneous incidence of diabetes than females. Splenocytes obtained from diabetic mice maintained on insulin for up to 2 mo also transferred diabetes. Because NOD mice display increasing levels of insulitis with age, spleen cells obtained from nondiabetic NOD mice of different ages were tested for their ability to transfer diabetes.(ABSTRACT TRUNCATED AT 250 WORDS) 1-hop neighbor's text information:Title: Raised temperature reduces the incidence of diabetes in the NOD mouse. Abstract: An association between the incidence of childhood Type 1 (insulin-dependent) diabetes mellitus and the average yearly temperature in different countries has been reported, the incidence being higher in countries with a lower mean temperature. We have studied the effect of environmental temperature on the incidence of diabetes in an animal model of Type 1 diabetes, the non-obese diabetic (NOD) mouse. Female NOD mice were divided at weaning, with one group placed at a higher temperature (mean 23.7 +/- 1.7 degrees C) and the other at a lower temperature (21.0 +/- 1.8 degrees C). At 20 weeks of age 6 of 16 mice at lower temperature and 1 of 17 mice at higher temperature had developed diabetes (p less than 0.02); at 30 weeks 10 of 16 and 5 of 17 mice had developed diabetes (p less than 0.05). Non-diabetic animals in the low temperature group had a higher food intake than those in the high temperature group between 13-15 weeks of age (28.0 +/- 1.2 g/week vs 24.8 +/- 0.7 g/week, p less than 0.05). In a parallel experiment, histological examination showed that there were similar degrees of insulitis in the high and low temperature groups at seven weeks of age. We conclude that environmental temperature can affect the incidence of diabetes in the NOD mouse and that this may be related to alterations in food intake. 1-hop neighbor's text information:Title: Syngeneic transfer of autoimmune diabetes from diabetic NOD mice to healthy neonates. Requirement for both L3T4+ and Lyt-2+ T cells. Abstract: We have developed a model of syngeneic adoptive transfer for type I diabetes mellitus of NOD mice. This model consists in injecting spleen cells from diabetic adult mice into newborn NOD recipients. 50% of recipients inoculated with 20 X 10(6) cells develop diabetes within the first 10 wk of life, at a time when none of the control littermates have yet become diabetic. The earliest successful transfers are observed at 3 wk of age, at a time when controls do not even exhibit histological changes in their pancreas. In addition we have shown that: (a) both males and females can be adoptively transferred, despite the fact that males rarely develop spontaneous diabetes in our colony; (b) diabetes transfer is a dose-dependent phenomenon that provides an in vivo assay for comparing the autoimmune potential of spleen cells from mice at various stages of their natural history; (c) the susceptibility of the recipients to the transfer is limited in time and declines after 3 wk; and (d) both L3T4+ and Lyt-2+ T cell subsets are necessary for the successful transfer. The neonatal syngeneic transfer provides an effective model for studies of the cellular events involved at regulatory and effector stages of autoimmune type I diabetes. 2-hop neighbor's text information:Title: Mechanisms of beta cell death in diabetes: a minor role for CD95. Abstract: Insulin-dependent diabetes mellitus is an autoimmune disease, under polygenic control, manifested only when >90% of the insulin-producing beta cells are destroyed. Although the disease is T cell mediated, the demise of the beta cell results from a number of different insults from the immune system. It has been proposed that foremost amongst these effector mechanisms is CD95 ligand-induced beta cell death. Using the nonobese diabetic lpr mouse as a model system, we have found, to the contrary, that CD95 plays only a minor role in the death of beta cells. Islet grafts from nonobese diabetic mice that carry the lpr mutation and therefore lack CD95 were protected only marginally from immune attack when grafted into diabetic mice. An explanation to reconcile these differing results is provided. 2-hop neighbor's text information:Title: Viruses as therapeutic agents. I. Treatment of nonobese insulin-dependent diabetes mice with virus prevents insulin-dependent diabetes mellitus while maintaining general immune competence. Abstract: A situation in which virus can be used as a therapeutic agent to prevent a lethal autoimmune disease is explored. Nonobese insulin-dependent diabetes (NOD) mice spontaneously develop insulin-dependent diabetes mellitus (IDDM), characterized by lymphocytic infiltration into the islets of Langerhans and beta cell destruction, resulting in hypoinsulinemia, hyperglycemia, ketoacidosis, and death. Infection of NOD mice with lymphocytic choriomeningitis virus (LCMV) aborts the autoimmune manifestations and resultant IDDM. The viruses' effect is on a subset of CD4+ lymphocytes. Ablating this autoimmune diabetes does not significantly alter immune responses to a variety of non-LCMV antigens that require CD4+ lymphocyte participation. The prevention of IDDM associated with viral therapy is maintained throughout the life spans of NOD mice. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	0 0 0 1 1,0	2	pubmed	train	63
Title: IL-1alpha, IL-1beta, and IFN-gamma mark beta cells for Fas-dependent destruction by diabetogenic CD4(+) T lymphocytes. Abstract: Cytokines such as IL-1alpha, IL-1beta, and IFN-gamma have long been implicated in the pathogenesis of autoimmune diabetes, but the mechanisms through which they promote diabetogenesis remain unclear. Here we show that CD4(+) T lymphocytes propagated from transgenic nonobese diabetic (NOD) mice expressing the highly diabetogenic, beta cell-specific 4.1-T-cell receptor (4.1-TCR) can kill IL-1alpha-, IL-1beta-, and IFN-gamma-treated beta cells from NOD mice. Untreated NOD beta cells and cytokine-treated beta cells from Fas-deficient NOD.lpr mice are not targeted by these T cells. Killing of islet cells in vitro was associated with cytokine-induced upregulation of Fas on islet cells and was independent of MHC class II expression. Abrogation of Fas expression in 4.1-TCR-transgenic NOD mice afforded nearly complete protection from diabetes and did not interfere with the development of the transgenic CD4(+) T cells or with their ability to cause insulitis. In contrast, abrogation of perforin expression did not affect beta cell-specific cytotoxicity or the diabetogenic potential of these T cells. These data demonstrate a novel mechanism of action of IL-1alpha, IL-1beta, and IFN-gamma in autoimmune diabetes, whereby these cytokines mark beta cells for Fas-dependent lysis by autoreactive CD4(+) T cells. 1-hop neighbor's text information:Title: In autoimmune diabetes the transition from benign to pernicious insulitis requires an islet cell response to tumor necrosis factor alpha. Abstract: The islet-infiltrating and disease-causing leukocytes that are a hallmark of insulin-dependent diabetes mellitus produce and respond to a set of cytokine molecules. Of these, interleukin 1beta, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma are perhaps the most important. However, as pleiotropic molecules, they can impact the path leading to beta cell apoptosis and diabetes at multiple points. To understand how these cytokines influence both the formative and effector phases of insulitis, it is critical to determine their effects on the assorted cell types comprising the lesion: the effector T cells, antigen-presenting cells, vascular endothelium, and target islet tissue. Here, we report using nonobese diabetic chimeric mice harboring islets deficient in specific cytokine receptors or cytokine-induced effector molecules to assess how these compartmentalized loss-of-function mutations alter the events leading to diabetes. We found that islets deficient in Fas, IFN-gamma receptor, or inducible nitric oxide synthase had normal diabetes development; however, the specific lack of TNF- alpha receptor 1 (p55) afforded islets a profound protection from disease by altering the ability of islet-reactive, CD4(+) T cells to establish insulitis and subsequently destroy islet beta cells. These results argue that islet cells play a TNF-alpha-dependent role in their own demise. 1-hop neighbor's text information:Title: All-trans retinoic acid inhibits type 1 diabetes by T regulatory (Treg)-dependent suppression of interferon-gamma-producing T-cells without affecting Th17 cells. Abstract: OBJECTIVE: All-trans retinoic acid (ATRA), a potent derivative of vitamin A, can regulate immune responses. However, its role in inducing immune tolerance associated with the prevention of islet inflammation and inhibition of type 1 diabetes remains unclear. RESEARCH DESIGN AND METHODS: We investigated the mechanisms underlying the potential immunoregulatory effect of ATRA on type 1 diabetes using an adoptive transfer animal model of the disease. RESULTS: Our data demonstrated that ATRA treatment inhibited diabetes in NOD mice with established insulitis. In addition, it suppressed interferon (IFN)-gamma-producing CD4(+) and CD8(+) T effector (Teff) cells and expanded T regulatory (Treg) cells in recipient mice transferred with diabetic NOD splenocytes, without affecting either interleukin (IL)-17--or IL-4-producing cells. Consistent with these results, ATRA reduced T-bet and STAT4 expression in T-cells and decreased islet-infiltrating CD8(+) T-cells, suppressing their activation and IFN-gamma/granzyme B expression. Depletion of CD4(+)CD25(+) Treg cells impaired the inhibitory effect of ATRA on islet-infiltrating T-cells and blocked its protective effect on diabetes. Therefore, ATRA treatment induced Treg cell-dependent immune tolerance by suppressing both CD4(+) and CD8(+) Teff cells while promoting Treg cell expansion. CONCLUSIONS: These results demonstrate that ATRA treatment promoted in vivo expansion of Treg cells and induced Treg cell-dependent immune tolerance by suppressing IFN-gamma-producing T-cells, without affecting Th17 cells. Our study also provides novel insights into how ATRA induces immune tolerance in vivo via its effects on Teff and Treg cells. 1-hop neighbor's text information:Title: The role of CD4+ and CD8+ T cells in the destruction of islet grafts by spontaneously diabetic mice. Abstract: Spontaneous development of diabetes in the nonobese diabetic (NOD) mouse is mediated by an immunological process. In disease-transfer experiments, the activation of diabetes has been reported to require participation of both CD4+ and CD8+ T-cell subsets. These findings seem to indicate that the CD4+ cells are the helper cells for the activation of cytotoxic CD8+ cells that directly destroy islet beta cells in type I diabetes. In this report we challenge this interpretation because of two observations: (i) Destruction of syngeneic islet grafts by spontaneously diabetic NOD mice (disease recurrence) is CD4+ and not CD8+ T-cell dependent. (ii) Disease recurrence in islet tissue grafted to diabetic NOD mice is not restricted by islet major histocompatibility complex antigens. From these observations we propose that islet destruction depends on CD4+ effector T cells that are restricted by major histocompatibility complex antigens expressed on NOD antigen-presenting cells. Both of these findings argue against the CD8+ T cell as a mediator of direct islet damage. We postulate that islet damage in the NOD mouse results from a CD4+ T-cell-dependent inflammatory response. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1 0,1	1	pubmed	train	66
Title: The problem of tissue oxygenation in diabetes mellitus. Abstract: In order to study the determining factors for oxygen transport the oxyhaemoglobin dissociation curve (ODC), red cell 2,3-diphosphoglycerate (2,3-DPG), and plasma inorganic phosphate were estimated in insulin-requiring juvenile and adult diabetics in various conditions of metabolic control. 2,3-DPG has been shown to vary much more in diabetics than in normals, depending upon the state of metabolic control. These fluctuations of 2,3-DPG are mediated by variations in plasma inorganic phosphate as indicated by a close correlation. While 2,3-DPG was markedly decreased in diabetic ketoacidosis, it tended to be increased in ambulatory, non-acidotic patients. Since in the non-acidotic patients the oxygen-carrying capacity, i.e. the haemoglobin concentration was simultaneously elevated, these findings suggest the presence of relative tissue hypoxia in diabetes. Both in non-acidotic and in ketoacidotic patients there was a strong correlation between the amount of 2,3-DPG and the P50 at actual pH as an experssion of the oxygen affinity of haemoglobin. In order to guarantee an optimal erythrocyte oxygen release in diabetics the content of red cell 2,3-DPG and plasma inorganic phosphate should be higher than normal. 1-hop neighbor's text information:Title: Impact of diabetes, chronic heart failure, congenital heart disease and chronic obstructive pulmonary disease on acute and chronic exercise responses. Abstract: Several chronic diseases are known to negatively affect the ability of an individual to perform exercise. However, the altered exercise capacity observed in these patients is not solely associated with the heart and lungs dysfunction. Exercise has also been shown to play an important role in the management of several pathologies encountered in the fields of cardiology and pneumology. Studies conducted in our institution regarding the influence of diabetes, chronic heart failure, congenital heart disease and chronic pulmonary obstructive disease on the acute and chronic exercise responses, along with the beneficial effects of exercise training in these populations, are reviewed. 2-hop neighbor's text information:Title: Influence of metabolic control on the ventilatory threshold in adults with non insulin-dependent diabetes mellitus. Abstract: Metabolic control, as assessed by glycosylated hemoglobin (HbA1c), has been reported to have a relationship to various submaximal exercise responses. However, due to the narrow range of HbA1c and the limited exercise data from previous studies on individuals with diabetes, little support for the above statement exists in the literature. The current study assessed the relationship between HbA1c and submaximal, or ventilatory threshold (VT), and maximal exercise (VO2 peak) responses in subjects with non-insulin-dependent diabetes mellitus (NIDDM). Sixteen subjects (age = 56.5 +/- 14.4 yrs; Wt = 82.6 +/- 17.2 kg; B.M.I. = 29.5 +/- 2.7 kg.m-2) performed a ramp (20 watts.min-1) leg cycle ergometer test (GXT). Their HbA1c was 11.8 +/- 2.8% (range 6.5 to 16.6%). Breath by breath respiratory analysis was performed using a Med Graphics 2001 cart. Ventilatory threshold (VT) was determined using the V-slope method. The VT was 1,151 +/- 487 ml.min-1 or 70.2 +/- 10% VO2peak; VO2peak was 1,645 +/- 740 ml.min-1. There were no significant relationships found between HbA1c and the VO2 at the VT (r = 0.04), the % of VO2peak at the VT (r = 0.23), and the VO2peak (r = 0.17). In conclusion, metabolic control, as assessed by HbA1c, did not influence selected submaximal and maximal exercise responses in NIDDM. Therefore, exercise prescription for individuals with NIDDM may not need to consider the individual's HbA1c concentration as a modifier of their exercise response. 2-hop neighbor's text information:Title: Impact of fasting and postprandial state on plasma carnitine concentrations during aerobic exercise in type 2 diabetes. Abstract: The effects of metabolic states of fasting and post-absorption on plasma concentrations of free carnitine (FC), acylcarnitine (AC) and total carnitine (TC) were compared during submaximal exercise in subjects with type 2 diabetes mellitus. Ten sedentary men (54+/-5 years) treated with oral hypoglycaemic agents were tested on two separate occasions: following an overnight fast and 2 h after a 395-kcal standardised breakfast. Exercise was performed at 60% of [Formula: see text]O(2peak) on a cycle ergometer for 60 min. Blood samples were drawn at rest for baseline values and following 60 min of exercise and 30 min of recovery. Our results show that: (1) baseline levels of TC, FC and AC were similar in fasted and postprandial groups, (2) TC and AC levels were increased during exercise in the fasted group only, (3) FC levels were decreased during exercise in both fasted and postprandial state and (4) the AC/FC ratio increased during exercise in the fasted group. Our results indicate that the metabolic state of the diabetic patient is associated with a different plasma carnitine status. These patterns may reflect differences in energy metabolism associated with fasting and postprandial hyperglycaemia. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2 2 2,1	2	pubmed	train	67
Title: Accumulation of fructosyl-lysine and advanced glycation end products in the kidney, retina and peripheral nerve of streptozotocin-induced diabetic rats. Abstract: The accumulation of AGEs (advanced glycation end products) in diabetes mellitus has been implicated in the biochemical dysfunction associated with the chronic development of microvascular complications of diabetes--nephropathy, retinopathy and peripheral neuropathy. We investigated the concentrations of fructosyl-lysine and AGE residues in protein extracts of renal glomeruli, retina, peripheral nerve and plasma protein of streptozotocin-induced diabetic rats and normal healthy controls. Glycation adducts were determined by LC with tandem MS detection. In diabetic rats, the fructosyl-lysine concentration was increased markedly in glomeruli, retina, sciatic nerve and plasma protein. The concentrations of N (epsilon)-carboxymethyl-lysine and N (epsilon)-carboxyethyl-lysine were increased in glomeruli, sciatic nerve and plasma protein, and N(epsilon)-carboxymethyl-lysine also in the retina. Hydroimidazolone AGEs derived from glyoxal, methylglyoxal and 3-deoxylglucosone were major AGEs quantitatively. They were increased in the retina, nerve, glomeruli and plasma protein. AGE accumulation in renal glomeruli, retina, peripheral nerve and plasma proteins is consistent with a role for AGEs in the development of nephropathy, retinopathy and peripheral neuropathy in diabetes. High-dose therapy with thiamine and Benfotiamine suppressed the accumulation of AGEs, and is a novel approach to preventing the development of diabetic complications. 1-hop neighbor's text information:Title: Inhibition of advanced glycation and absence of galectin-3 prevent blood-retinal barrier dysfunction during short-term diabetes. Abstract: Breakdown of the inner blood-retinal barrier (iBRB) occurs early in diabetes and is central to the development of sight-threatening diabetic macular edema (DME) as retinopathy progresses. In the current study, we examined how advanced glycation end products (AGEs) forming early in diabetes could modulate vasopermeability factor expression in the diabetic retina and alter inter-endothelial cell tight junction (TJ) integrity leading to iBRB dysfunction. We also investigated the potential for an AGE inhibitor to prevent this acute pathology and examined a role of the AGE-binding protein galectin-3 (Gal-3) in AGE-mediated cell retinal pathophysiology. Diabetes was induced in C57/BL6 wild-type (WT) mice and in Gal-3(-/-) transgenic mice. Blood glucose was monitored and AGE levels were quantified by ELISA and immunohistochemistry. The diabetic groups were subdivided, and one group was treated with the AGE-inhibitor pyridoxamine (PM) while separate groups of WT and Gal-3(-/-) mice were maintained as nondiabetic controls. iBRB integrity was assessed by Evans blue assay alongside visualisation of TJ protein complexes via occludin-1 immunolocalization in retinal flat mounts. Retinal expression levels of the vasopermeability factor VEGF were quantified using real-time RT-PCR and ELISA. WT diabetic mice showed significant AGE -immunoreactivity in the retinal microvasculature and also showed significant iBRB breakdown (P < .005). These diabetics had higher VEGF mRNA and protein expression in comparison to controls (P < .01). PM-treated diabetics had normal iBRB function and significantly reduced diabetes-mediated VEGF expression. Diabetic retinal vessels showed disrupted TJ integrity when compared to controls, while PM-treated diabetics demonstrated near-normal configuration. Gal-3(-/-) mice showed significantly less diabetes-mediated iBRB dysfunction, junctional disruption, and VEGF expression changes than their WT counterparts. The data suggests an AGE-mediated disruption of iBRB via upregulation of VEGF in the diabetic retina, possibly modulating disruption of TJ integrity, even after acute diabetes. Prevention of AGE formation or genetic deletion of Gal-3 can effectively prevent these acute diabetic retinopathy changes. 1-hop neighbor's text information:Title: Glycation and carboxymethyllysine levels in skin collagen predict the risk of future 10-year progression of diabetic retinopathy and nephropathy in the diabetes control and complications trial and epidemiology of diabetes interventions and complications participants with type 1 diabetes. Abstract: Several mechanistic pathways linking hyperglycemia to diabetes complications, including glycation of proteins and formation of advanced glycation end products (AGEs), have been proposed. We investigated the hypothesis that skin collagen glycation and AGEs predict the risk of progression of microvascular disease. We measured glycation products in the skin collagen of 211 Diabetes Control and Complications Trial (DCCT) volunteers in 1992 who continued to be followed in the Epidemiology of Diabetes Interventions and Complications study for 10 years. We determined whether the earlier measurements of glycated collagen and AGE levels correlated with the risk of progression of retinopathy and nephropathy from the end of the DCCT to 10 years later. In multivariate analyses, the combination of furosine (glycated collagen) and carboxymethyllysine (CML) predicted the progression of retinopathy (chi2 = 59.4, P < 0.0001) and nephropathy (chi2 = 18.2, P = 0.0001), even after adjustment for mean HbA(1c) (A1C) (chi2 = 32.7, P < 0.0001 for retinopathy) and (chi2 = 12.8, P = 0.0016 for nephropathy). The predictive effect of A1C vanished after adjustment for furosine and CML (chi2 = 0.0002, P = 0.987 for retinopathy and chi2 = 0.0002, P = 0.964 for nephropathy). Furosine explained more of the variation in the 10-year progression of retinopathy and nephropathy than did CML. These results strengthen the role of glycation of proteins and AGE formation in the pathogenesis of retinopathy and nephropathy. Glycation and subsequent AGE formation may explain the risk of these complications associated with prior A1C and provide a rational basis for the phenomenon of "metabolic memory" in the pathogenesis of these diabetes complications. 2-hop neighbor's text information:Title: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. Abstract: BACKGROUND: Long-term microvascular and neurologic complications cause major morbidity and mortality in patients with insulin-dependent diabetes mellitus (IDDM). We examined whether intensive treatment with the goal of maintaining blood glucose concentrations close to the normal range could decrease the frequency and severity of these complications. METHODS: A total of 1441 patients with IDDM--726 with no retinopathy at base line (the primary-prevention cohort) and 715 with mild retinopathy (the secondary-intervention cohort) were randomly assigned to intensive therapy administered either with an external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin injections. The patients were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly. RESULTS: In the primary-prevention cohort, intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76 percent (95 percent confidence interval, 62 to 85 percent), as compared with conventional therapy. In the secondary-intervention cohort, intensive therapy slowed the progression of retinopathy by 54 percent (95 percent confidence interval, 39 to 66 percent) and reduced the development of proliferative or severe nonproliferative retinopathy by 47 percent (95 percent confidence interval, 14 to 67 percent). In the two cohorts combined, intensive therapy reduced the occurrence of microalbuminuria (urinary albumin excretion of > or = 40 mg per 24 hours) by 39 percent (95 percent confidence interval, 21 to 52 percent), that of albuminuria (urinary albumin excretion of > or = 300 mg per 24 hours) by 54 percent (95 percent confidence interval 19 to 74 percent), and that of clinical neuropathy by 60 percent (95 percent confidence interval, 38 to 74 percent). The chief adverse event associated with intensive therapy was a two-to-threefold increase in severe hypoglycemia. CONCLUSIONS: Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM. 2-hop neighbor's text information:Title: Skin collagen glycation, glycoxidation, and crosslinking are lower in subjects with long-term intensive versus conventional therapy of type 1 diabetes: relevance of glycated collagen products versus HbA1c as markers of diabetic complications. DCCT Skin Collagen Ancillary Study Group. Diabetes Control and Complications Trial. Abstract: The relationships between long-term intensive control of glycemia and indicators of skin collagen glycation (furosine), glycoxidation (pentosidine and N(epsilon)-[carboxymethyl]-lysine [CML]), and crosslinking (acid and pepsin solubility) were examined in 216 patients with type 1 diabetes from the primary prevention and secondary intervention cohorts of the Diabetes Control and Complications Trial. By comparison with conventional treatment, 5 years of intensive treatment was associated with 30-32% lower furosine, 9% lower pentosidine, 9-13% lower CML, 24% higher acid-soluble collagen, and 50% higher pepsin-soluble collagen. All of these differences were statistically significant in the subjects of the primary prevention cohort (P < 0.006-0.001) and also of the secondary intervention cohort (P < 0.015-0.001) with the exception of CML and acid-soluble collagen. Age- and duration-adjusted collagen variables were significantly associated with the HbA1c value nearest the biopsy and with cumulative prior HbA1c values. Multiple logistic regression analyses with six nonredundant collagen parameters as independent variables and various expressions of retinopathy, nephropathy, and neuropathy outcomes as dependent variables showed that the complications were significantly associated with the full set of collagen variables. Surprisingly, the percentage of total variance (R2) in complications explained by the collagen variables ranged from 19 to 36% with the intensive treatment and from 14 to 51% with conventional treatment. These associations generally remained significant even after adjustment for HbA1c, and, most unexpectedly, in conventionally treated subjects, glycated collagen was the parameter most consistently associated with diabetic complications. Continued monitoring of these subjects may determine whether glycation products in the skin, and especially the early Amadori product (furosine), have the potential to be predictors of the future risk of developing complications, and perhaps be even better predictors than glycated hemoglobin (HbA1c). I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	0 1 1 1,0	2	pubmed	train	70
Title: Transplantation of cultured pancreatic islets to BB rats. Abstract: Pancreatic islets held in tissue culture before transplantation into artificially induced diabetics are not rejected. In animals and human identical twin transplants, the autoimmunity of naturally occurring diabetes may destroy islets, even if rejection is avoided. Therefore we studied whether autoimmune damage of islets can be avoided by pretransplant culture. Recipients were BB rats, which spontaneously developed diabetes. Donors were either Wistar Furth (WF) (major histocompatibility [MHC] identical to BB rats) or Lewis (MHC nonidentical to BB rats). Islets were inoculated into the portal vein either immediately after isolation or after 14 days in tissue culture (95% air, 5% CO2, 24 degrees C). Recipients of cultured islets received a single injection of 1 ml of antilymphocyte serum at the time of transplant. Recurrence of diabetes after transplantation of freshly isolated MHC incompatible Lewis islets occurred rapidly on the basis of rejection or autoimmune damage (or both). Precultured Lewis islets had prolonged or permanent survival. Freshly isolated MHC compatible WF islets were destroyed, and no improvement was seen with culture. We conclude that autoimmune destruction of transplanted islets can be avoided by tissue culture, as can rejection. This is important because this strategy is effective only if recipient and donor differ at the MHC locus. Islet donors may need to be selected on the basis of disparity of histocompatibility factors. 1-hop neighbor's text information:Title: The role of CD4+ and CD8+ T cells in the destruction of islet grafts by spontaneously diabetic mice. Abstract: Spontaneous development of diabetes in the nonobese diabetic (NOD) mouse is mediated by an immunological process. In disease-transfer experiments, the activation of diabetes has been reported to require participation of both CD4+ and CD8+ T-cell subsets. These findings seem to indicate that the CD4+ cells are the helper cells for the activation of cytotoxic CD8+ cells that directly destroy islet beta cells in type I diabetes. In this report we challenge this interpretation because of two observations: (i) Destruction of syngeneic islet grafts by spontaneously diabetic NOD mice (disease recurrence) is CD4+ and not CD8+ T-cell dependent. (ii) Disease recurrence in islet tissue grafted to diabetic NOD mice is not restricted by islet major histocompatibility complex antigens. From these observations we propose that islet destruction depends on CD4+ effector T cells that are restricted by major histocompatibility complex antigens expressed on NOD antigen-presenting cells. Both of these findings argue against the CD8+ T cell as a mediator of direct islet damage. We postulate that islet damage in the NOD mouse results from a CD4+ T-cell-dependent inflammatory response. 1-hop neighbor's text information:Title: Intrathymic islet transplantation in the spontaneously diabetic BB rat. Abstract: Recently it was demonstrated that pancreatic islet allografts transplanted to the thymus of rats made diabetic chemically are not rejected and induce specific unresponsiveness to subsequent extrathymic transplants. The authors report that the thymus can also serve as an effective islet transplantation site in spontaneously diabetic BB rats, in which autoimmunity and rejection can destroy islets. Intrathymic Lewis islet grafts consistently reversed hyperglycemia for more than 120 days in these rats, and in three of four recipients the grafts promoted subsequent survival of intraportal islets. In contrast intraportal islet allografts in naive BB hosts all failed rapidly. The authors also show that the immunologically privileged status of the thymus cannot prevent rejection of islet allografts in Wistar Furth (WF) rats sensitized with donor strain skin and that suppressor cells are not likely to contribute to the unresponsive state because adoptive transfer of spleen cells from WF rats bearing established intrathymic Lewis islets fails to prolong islet allograft survival in secondary hosts. 2-hop neighbor's text information:Title: Allotransplantation of dispersed single pancreatic endocrine cells in diabetic rats. Abstract: Dispersed pancreatic endocrine cells (PECs) were recently shown to survive indefinitely in the brain of allogeneic diabetic rat recipients across the major histocompatibility barrier without immunosuppression. Purified PECs (2-3 X 10(6) cells) prepared from Wistar rat islets were transplanted in 10 different sites in streptozocin-induced diabetic ACI rats. Blood glucose and body weight changes were monitored throughout the study. PEC isografts (n = 5) and allografts (n = 6) were nonfunctional when transplanted in intramuscular, intravenous, and intrahepatic sites. When transplanted intraportally (n = 6) and intraperitoneally (n = 6), similar grafts were functional but had a short survival period (6.6 +/- 1.5 and 15.3 +/- 16.6 days, respectively). Prolonged graft survival in some recipients was observed when kidney capsule [5, 9, 10, 240, 282, and 300 (2 rats) days], omentum pocket (7, 8, 10, 90, 105, 154, 155, and 157 days), and testis (7, 8, 12, 150, 230, and 234 days) were the transplantation sites. Permanent graft survival was achieved in 20 of 20 recipients with intracerebral transplantation and 21 of 22 recipients with intrathecal transplantation. These findings confirm that dispersed single PECs can be transplanted as a permanent functional graft and can normalize the hyperglycemia of the diabetic recipients. The duration of PEC graft survival is variable and depends on the transplantation site. Both the cerebral cortex and subarachnoid space, which are immunologically privileged sites, have provided the best allograft protection. 2-hop neighbor's text information:Title: Autoimmune diabetes in NOD mouse is L3T4 T-lymphocyte dependent. Abstract: Cultured BALB/c islets fail to function when transplanted into diabetic nonobese diabetic (NOD) mice; such grafted tissue is rapidly destroyed by disease recurrence. The cellular requirements for this graft damage are unclear. This study was designed to investigate the role of the L3T4+ T-lymphocyte subset in disease recurrence in the NOD mouse. L3T4+ T-lymphocytes were depleted by the in vivo administration of the L3T4-specific monoclonal antibody GK1.5. This treatment reduced the level of L3T4+ T-lymphocytes from an initial 43% of the peripheral blood lymphocytes to less than 4%. L3T4 levels remained at this low level for approximately 2 wk after withdrawal of GK1.5 treatment, after which the L3T4 levels slowly began to increase in the periphery. Grafting of cultured BALB/c islet tissue into GK1.5-treated diabetic NOD mice resulted in a rapid return to normoglycemia that persisted for 2-4 wk. The gradual return to the hyperglycemic condition roughly correlated with the reappearance of L3T4+ T-lymphocytes in the peripheral circulation. From these findings we conclude that the disease process in the NOD mouse is L3T4 T-lymphocyte dependent. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	0 0 0 0,0	2	pubmed	train	72
Title: HLA and insulin gene associations with IDDM. Abstract: The HLA DR genotype frequencies in insulin-dependent diabetes mellitus (IDDM) patients and the frequencies of DR alleles transmitted from affected parent to affected child both indicate that the DR3-associated predisposition is more "recessive" and the DR4-associated predisposition more "dominant" in inheritance after allowing for the DR3/DR4 synergistic effect. B locus distributions on patient haplotypes indicate that only subsets of both DR3 and DR4 are predisposing. Heterogeneity is detected for both the DR3 and DR4 predisposing haplotypes based on DR genotypic class. With appropriate use of the family structure of the data a control population of "unaffected" alleles can be defined. Application of this method confirms the predisposing effect associated with the class 1 allele of the polymorphic region 5' to the insulin gene. 1-hop neighbor's text information:Title: Evidence of a non-MHC susceptibility locus in type I diabetes linked to HLA on chromosome 6. Abstract: Linkage studies have led to the identification of several chromosome regions that may contain susceptibility loci to type I diabetes (IDDM), in addition to the HLA and INS loci. These include two on chromosome 6q, denoted IDDM5 and IDDM8, that are not linked to HLA. In a previous study, we noticed that the evidence for linkage to IDDM susceptibility around the HLA locus extended over a total distance of 100 cM, which suggested to us that another susceptibility locus could reside near HLA. We developed a statistical method to test this hypothesis in a panel of 523 multiplex families from France, the United States, and Denmark (a total of 667 affected sib pairs, 536 with both parents genotyped), and here present evidence (P = .00003) of a susceptibility locus for IDDM located 32 cM from HLA in males but not linked to HLA in females and distinct from IDDM5 and IDDM8. A new statistical method to test for the presence of a second susceptibility locus linked to a known first susceptibility locus (here HLA) is presented. In addition, we analyzed our current family panel with markers for IDDM5 and IDDM8 on chromosome 6 and found suggestions of linkage for both of these loci (P = .002 and .004, respectively, on the complete family panel). When cumulated with previously published results, with overlapping families removed, the affected-sib-pair tests had a significance of P = .0001 for IDDM5 and P = .00004 for IDDM8. 1-hop neighbor's text information:Title: Genetic analysis of type 1 diabetes using whole genome approaches. Abstract: Whole genome linkage analysis of type 1 diabetes using affected sib pair families and semi-automated genotyping and data capture procedures has shown how type 1 diabetes is inherited. A major proportion of clustering of the disease in families can be accounted for by sharing of alleles at susceptibility loci in the major histocompatibility complex on chromosome 6 (IDDM1) and at a minimum of 11 other loci on nine chromosomes. Primary etiological components of IDDM1, the HLA-DQB1 and -DRB1 class II immune response genes, and of IDDM2, the minisatellite repeat sequence in the 5' regulatory region of the insulin gene on chromosome 11p15, have been identified. Identification of the other loci will involve linkage disequilibrium mapping and sequencing of candidate genes in regions of linkage. 1-hop neighbor's text information:Title: Testing parental imprinting in insulin-dependent diabetes mellitus by the marker-association-segregation-chi 2 method. Abstract: Among patients with insulin-dependent diabetes mellitus (IDDM), an excess of DR3 and DR4 alleles is classically described when compared with the general population. In addition, an excess of maternal DR3 and paternal DR4 alleles among patients (DR3DR4) is observed. In order to explain these observations, two alternative hypotheses can be tested: maternal effect and parental imprinting. Maternal effect has been tested and not rejected on a sample of 416 caucasians affected with IDDM. Under this hypothesis, the children of a DR3 mother are expected to have an earlier exposure and, hence, an earlier age at onset. However, we did not observe such a difference in age at onset in this data set. Using the marker-association-segregation-chi 2 method, we have tested four hypotheses with different parental effects of two susceptibility alleles, alpha 0 and beta 0, at two different closely linked loci. Under the hypothesis that best fitted the data, the probability of being affected depended on the parental inheritance of the susceptibility alleles, suggesting parental imprinting (i.e., differential role of maternal and paternal allele), without evidence for a cis-trans effect. We conclude that parental imprinting on a specific allelic combination may explain the observations on the HLA genotypes of the patients and their relatives. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1 1,1	1	pubmed	train	74
Title: IL-1alpha, IL-1beta, and IFN-gamma mark beta cells for Fas-dependent destruction by diabetogenic CD4(+) T lymphocytes. Abstract: Cytokines such as IL-1alpha, IL-1beta, and IFN-gamma have long been implicated in the pathogenesis of autoimmune diabetes, but the mechanisms through which they promote diabetogenesis remain unclear. Here we show that CD4(+) T lymphocytes propagated from transgenic nonobese diabetic (NOD) mice expressing the highly diabetogenic, beta cell-specific 4.1-T-cell receptor (4.1-TCR) can kill IL-1alpha-, IL-1beta-, and IFN-gamma-treated beta cells from NOD mice. Untreated NOD beta cells and cytokine-treated beta cells from Fas-deficient NOD.lpr mice are not targeted by these T cells. Killing of islet cells in vitro was associated with cytokine-induced upregulation of Fas on islet cells and was independent of MHC class II expression. Abrogation of Fas expression in 4.1-TCR-transgenic NOD mice afforded nearly complete protection from diabetes and did not interfere with the development of the transgenic CD4(+) T cells or with their ability to cause insulitis. In contrast, abrogation of perforin expression did not affect beta cell-specific cytotoxicity or the diabetogenic potential of these T cells. These data demonstrate a novel mechanism of action of IL-1alpha, IL-1beta, and IFN-gamma in autoimmune diabetes, whereby these cytokines mark beta cells for Fas-dependent lysis by autoreactive CD4(+) T cells. 1-hop neighbor's text information:Title: Perforin-independent beta-cell destruction by diabetogenic CD8(+) T lymphocytes in transgenic nonobese diabetic mice. Abstract: Autoimmune diabetes in nonobese diabetic (NOD) mice results from destruction of pancreatic beta cells by T lymphocytes. It is believed that CD8(+) cytotoxic T lymphocytes (CTLs) effect the initial beta-cell insult in diabetes, but the mechanisms remain unclear. Studies of NOD.lpr mice have suggested that disease initiation is a Fas-dependent process, yet perforin-deficient NOD mice rarely develop diabetes despite expressing Fas. Here, we have investigated the role of perforin and Fas in the ability of beta cell-reactive CD8(+) T cells bearing a T-cell receptor (8.3-TCR) that is representative of TCRs used by CD8(+) CTLs propagated from the earliest insulitic lesions of NOD mice, and that targets an immunodominant peptide/H-2Kd complex on beta cells, to effect beta-cell damage in vitro and in vivo. In vitro, 8.3-CTLs killed antigenic peptide-pulsed non-beta-cell targets via both perforin and Fas, but they killed NOD beta cells via Fas exclusively. Perforin-deficient 8.3-TCR-transgenic NOD mice expressing an oligoclonal or monoclonal T-cell repertoire developed diabetes even more frequently than their perforin-competent littermates. These results demonstrate that diabetogenic CD8(+) CTLs representative of CTLs putatively involved in the initiation of autoimmune diabetes kill beta cells in a Fas-dependent and perforin-independent manner. 1-hop neighbor's text information:Title: Antigen-presenting cells in adoptively transferred and spontaneous autoimmune diabetes. Abstract: Histological techniques were used to identify antigen-presenting cells (APC) in adoptively transferred diabetes in NOD mice and Ins-HA transgenic mice, and in spontaneously diabetic NOD mice. In adoptively transferred disease, CD4+ T cells and F4/80+ macrophages dominated early infiltrates. By contrast, in spontaneously developing diabetes in NOD mice, lymphocytic infiltrates appeared to be well organized around a network of VCAM-1+ NLDC-145+ ICAM-1+ dendritic cells. Thus, the primary APC spontaneous autoimmune disease appears to be the strongly stimulatory dendritic cell rather than the normally resident macrophage. Next, we used chimeric animals to demonstrate that insulitis and diabetes could occur even when responding T cells were unable to recognize islet-specific antigen directly on beta cells. Altogether, the results demonstrate that immune-mediated damage does not require direct contact between CD4+ T cells and beta cells. Moreover, despite the induction of ICAM-1, VCAM-1, and class II on vascular endothelium near islet infiltrates, these experiments show that recruitment of lymphocytes occurs even when antigen presentation is not possible on vascular endothelium. 1-hop neighbor's text information:Title: Beta 2-microglobulin-deficient NOD mice do not develop insulitis or diabetes. Abstract: The role of CD8+ T-cells in the development of diabetes in the nonobese diabetic (NOD) mouse remains controversial. Although it is widely agreed that class II-restricted CD4+ T-cells are essential for the development of diabetes in the NOD model, some studies have suggested that CD8+ T-cells are not required for beta-cell destruction. To assess the contribution of CD8+ T-cells to diabetes, we have developed a class of NOD mouse that lacks expression of beta 2-microglobulin (NOD-B2mnull). NOD-B2mnull mice, which lack both class I expression and CD8+ T-cells in the periphery, not only failed to develop diabetes but were completely devoid of insulitis. These results demonstrate an essential role for CD8+ T-cells in the initiation of the autoimmune response to beta-cells in the NOD mouse. 2-hop neighbor's text information:Title: T helper cell subsets in insulin-dependent diabetes. Abstract: It has been proposed that the development of insulin-dependent diabetes is controlled by the T helper 1 (TH1) versus TH2 phenotype of autoreactive TH cells: TH1 cells would promote diabetes, whereas TH2 cells would actually protect from disease. This proposition was tested by establishing cultures of TH1 and TH2 cells that express an identical diabetogenic T cell receptor and comparing their ability to initiate disease in neonatal nonobese diabetic mice. TH1-like cells actively promoted diabetes; TH2-like cells invaded the islets but did not provoke disease--neither did they provide substantial protection. 2-hop neighbor's text information:Title: Epitope specificity, cytokine production profile and diabetogenic activity of insulin-specific T cell clones isolated from NOD mice. Abstract: T cells are known to play an important role in beta cell destruction in the nonobese diabetic (NOD) mouse model of Type I diabetes and islet-specific T cell clones have been demonstrated to be capable of adoptive transfer of diabetes. One important issue involves the identity of beta cell antigens that are recognized by nominally islet cell-specific T cell clones. We have previously reported that insulin-specific T cells are a predominant component of islet-specific T cells isolated from islet infiltrates of pre-diabetic NOD mice. In this report we examine six independently derived insulin-specific T cell clones established from islet infiltrates of pre-diabetic NOD mice in detail. All six clones were found to be specific to a region of the insulin molecule defined by a synthetic peptide encompassing residues 9-23 of the B chain. Despite this restricted specificity, each member of this panel exhibited a distinct receptor specificity defined either by V beta usage or antigen fine specificity. Five clones produced interferon (IFN)-gamma but not interleukin (IL)-4, placing them in the T helper type 1 (TH1)-like category whereas one clone produced both IL-4 and IFN-gamma, a characteristic of TH0 cells. All six clones were capable of either acceleration of diabetes in young NOD mice or adoptive transfer to NODscid mice. Taken together, these results suggest that spontaneously arising insulin-specific T cells participate in beta cell destruction during development of diabetes in NOD mice. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 0 1 1 1,1	2	pubmed	train	76
Title: Prevalence and risk factors for urinary incontinence in women with type 2 diabetes and impaired fasting glucose: findings from the National Health and Nutrition Examination Survey (NHANES) 2001-2002. Abstract: OBJECTIVE: Diabetes is associated with increased risk of urinary incontinence. It is unknown whether women with pre-diabetes, or impaired fasting glucose (IFG), have increased prevalence of incontinence. We determined the prevalence of, and risk factors for, incontinence among U.S. women with diabetes and IFG. RESEARCH DESIGN AND METHODS: The 2001-2002 National Health and Nutrition Examination Survey measured fasting plasma glucose and obtained information about diabetes and urinary incontinence among 1,461 nonpregnant adult women. Self-reported weekly or more frequent incontinence, both overall and by type (urge and stress), was our outcome. RESULTS: Of the 1,461 women, 17% had diabetes and 11% met criteria for IFG. Prevalence of weekly incontinence was similar among women in these two groups (35.4 and 33.4%, respectively) and significantly higher than among women with normal fasting glucose (16.8%); both urge and stress incontinence were increased. In addition to well-recognized risk factors including age, weight, and oral estrogen use, two microvascular complications caused by diabetes, specifically macroalbuminuria and peripheral neuropathic pain, were associated with incontinence. CONCLUSIONS: Physicians should be alert for incontinence, an often unrecognized and therefore undertreated disorder, among women with diabetes and IFG, in particular those with microvascular complications. The additional prospect of improvements in their incontinence may help motivate some high-risk women to undertake difficult lifestyle changes to reduce their more serious risk of diabetes and its sequelae. 1-hop neighbor's text information:Title: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. Abstract: OBJECTIVE: To determine whether tight control of blood pressure prevents macrovascular and microvascular complications in patients with type 2 diabetes. DESIGN: Randomised controlled trial comparing tight control of blood pressure aiming at a blood pressure of <150/85 mm Hg (with the use of an angiotensin converting enzyme inhibitor captopril or a beta blocker atenolol as main treatment) with less tight control aiming at a blood pressure of <180/105 mm Hg. SETTING: 20 hospital based clinics in England, Scotland, and Northern Ireland. SUBJECTS: 1148 hypertensive patients with type 2 diabetes (mean age 56, mean blood pressure at entry 160/94 mm Hg); 758 patients were allocated to tight control of blood pressure and 390 patients to less tight control with a median follow up of 8.4 years. MAIN OUTCOME MEASURES: Predefined clinical end points, fatal and non-fatal, related to diabetes, deaths related to diabetes, and all cause mortality. Surrogate measures of microvascular disease included urinary albumin excretion and retinal photography. RESULTS: Mean blood pressure during follow up was significantly reduced in the group assigned tight blood pressure control (144/82 mm Hg) compared with the group assigned to less tight control (154/87 mm Hg) (P<0.0001). Reductions in risk in the group assigned to tight control compared with that assigned to less tight control were 24% in diabetes related end points (95% confidence interval 8% to 38%) (P=0.0046), 32% in deaths related to diabetes (6% to 51%) (P=0.019), 44% in strokes (11% to 65%) (P=0.013), and 37% in microvascular end points (11% to 56%) (P=0.0092), predominantly owing to a reduced risk of retinal photocoagulation. There was a non-significant reduction in all cause mortality. After nine years of follow up the group assigned to tight blood pressure control also had a 34% reduction in risk in the proportion of patients with deterioration of retinopathy by two steps (99% confidence interval 11% to 50%) (P=0.0004) and a 47% reduced risk (7% to 70%) (P=0.004) of deterioration in visual acuity by three lines of the early treatment of diabetic retinopathy study (ETDRS) chart. After nine years of follow up 29% of patients in the group assigned to tight control required three or more treatments to lower blood pressure to achieve target blood pressures. CONCLUSION: Tight blood pressure control in patients with hypertension and type 2 diabetes achieves a clinically important reduction in the risk of deaths related to diabetes, complications related to diabetes, progression of diabetic retinopathy, and deterioration in visual acuity. 1-hop neighbor's text information:Title: Cardiovascular risk factors in confirmed prediabetic individuals. Does the clock for coronary heart disease start ticking before the onset of clinical diabetes? Abstract: Although type II diabetes is associated with both microvascular and macrovascular complications, duration of diabetes and severity of glycemia are strongly associated only with the former. Since prediabetic individuals are hyperinsulinemia, and since hyperinsulinemia may be a cardiovascular risk factor, we hypothesized that prediabetic individuals might have an atherogenic pattern of risk factors even before the onset of clinical diabetes, thereby explaining the relative lack of an association of macrovascular complications with either glycemic severity or disease duration. We documented the cardiovascular risk factor status of 614 initially nondiabetic Mexican Americans who later participated in an 8-year follow-up of the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease. Individuals who were nondiabetic at the time of baseline examination, but who subsequently developed type II diabetes (ie, confirmed prediabetic subjects, n = 43), had higher levels of total and low-density lipoprotein cholesterol, triglyceride, fasting glucose and insulin, 2-hour glucose, body mass index, and blood pressure, and lower levels of high-density lipoprotein cholesterol than subjects who remained nondiabetic (n = 571). Most of these differences persisted after adjustment for obesity and/or level of glycemia, but were abolished after adjustment for fasting insulin concentration. When subjects with impaired glucose tolerance at baseline (n = 106) were eliminated, the more atherogenic pattern of cardiovascular risk factors was still evident (and statistically significant) among initially normoglycemic prediabetic subjects. These results indicate that prediabetic subjects have an atherogenic pattern of risk factors (possibly caused by obesity, hyperglycemia, and especially hyperinsulinemia), which may be present for many years and may contribute to the risk of macrovascular disease as much as the duration of clinical diabetes itself. 1-hop neighbor's text information:Title: Diabetes and the risk of multi-system aging phenotypes: a systematic review and meta-analysis. Abstract: BACKGROUND: Observational studies suggested an association between diabetes and the risk of various geriatric conditions (i.e., cognitive impairment, dementia, depression, mobility impairment, disability, falls, and urinary incontinence). However, the magnitude and impact of diabetes on older adults have not been reviewed. METHODOLOGY/PRINCIPAL FINDINGS: MEDLINE and PSYCINFO databases were searched through November 2007 for published studies, supplemented by manual searches of bibliographies of key articles. Population-based, prospective cohort studies that reported risk of geriatric outcomes in relation to diabetes status at baseline were selected. Two authors independently extracted the data, including study population and follow-up duration, ascertainment of diabetes status at baseline, outcomes of interest and their ascertainment, adjusted covariates, measures of association, and brief results. Fifteen studies examined the association of DM with cognitive dysfunction. DM was associated with a faster decline in cognitive function among older adults. The pooled adjusted risk ratio (RR) for all dementia when persons with DM were compared to those without was 1.47 (95% CI, 1.25 to 1.73). Summary RRs for Alzheimer's disease and vascular dementia comparing persons with DM to those without were 1.39 (CI, 1.16 to 1.66) and 2.38 (CI, 1.79 to 3.18), respectively. Four of 5 studies found significant association of DM with faster mobility decline and incident disability. Two studies examined the association of diabetes with falls in older women. Both found statistically significant associations. Insulin users had higher RR for recurrent falls. One study for urinary incontinence in older women found statistically significant associations. Two studies for depression did not suggest that DM was an independent predictor of incident depression. CONCLUSIONS/SIGNIFICANCE: Current evidence supports that DM is associated with increased risk for selected geriatric conditions. Clinicians should increase their awareness and provide appropriate care. Future research is required to elucidate the underlying pathological pathway. 2-hop neighbor's text information:Title: Is diabetes associated with cognitive impairment and cognitive decline among older women? Study of Osteoporotic Fractures Research Group. Abstract: BACKGROUND: The long-term effect of type 2 diabetes on cognitive function is uncertain. OBJECTIVE: To determine whether older women with diabetes have an increased risk of cognitive impairment and cognitive decline. DESIGN: Prospective cohort study. SETTING: Four research centers in the United States (Baltimore, Md; Portland, Ore; Minneapolis, Minn; and the Monongahela Valley, Pennsylvania). PARTICIPANTS: Community-dwelling white women 65 years and older (n = 9679). MEASUREMENTS: Physician-diagnosed diabetes and other aspects of health history were assessed by interview. Three tests of cognitive function, the Digit Symbol test, the Trails B test, and a modified version of the Mini-Mental State Examination (m-MMSE), were administered at baseline and 3 to 6 years later. Change in cognitive function was defined by the change in the score for each test. Major cognitive decline was defined as the worst 10th percentile change in the score for each test. RESULTS: Women with diabetes (n = 682 [7.0%]) had lower baseline scores than those without diabetes on all 3 tests of cognitive function (Digit Symbol and Trials B tests, P<.01; m-MMSE, P = .03) and experienced an accelerated cognitive decline as measured by the Digit Symbol test (P<.01) and m-MMSE (P = .03). Diabetes was also associated with increased odds of major cognitive decline as determined by scores on the Digit Symbol (odds ratio = 1.63; 95% confidence interval, 1.20-2.23) and Trails B (odds ratio, 1.74; 95% confidence interval, 1.27-2.39) tests when controlled for age, education, depression, stroke, visual impairment, heart disease, hypertension, physical activity, estrogen use, and smoking. Women who had diabetes for more than 15 years had a 57% to 114% greater risk of major cognitive decline than women without diabetes. CONCLUSION: Diabetes is associated with lower levels of cognitive function and greater cognitive decline among older women. 2-hop neighbor's text information:Title: The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XXII the twenty-five-year progression of retinopathy in persons with type 1 diabetes. Abstract: OBJECTIVE: To examine the 25-year cumulative progression and regression of diabetic retinopathy (DR) and its relation to various risk factors. DESIGN: Population-based study. PARTICIPANTS: A total of 955 insulin-taking persons living in an 11-county area in southern Wisconsin with type 1 diabetes diagnosed before age 30 years who participated in a baseline examination (1980-1982) and at least 1 of 4 follow-up (4-, 10-, 14-, and 25-year) examinations or died before the first follow-up examination (n = 64). METHODS: Stereoscopic color fundus photographs were graded using the modified Airlie House classification and the Early Treatment Diabetic Retinopathy Study retinopathy severity scheme. MAIN OUTCOME MEASURES: Progression and regression of DR status. RESULTS: The 25-year cumulative rate of progression of DR was 83%, progression to proliferative DR (PDR) was 42%, and improvement of DR was 18%. Progression of DR was more likely with less severe DR, male sex, higher glycosylated hemoglobin, an increase in glycosylated hemoglobin level, and an increase in diastolic blood pressure level from the baseline to the 4-year follow-up. Increased risk of incidence of PDR was associated with higher glycosylated hemoglobin, higher systolic blood pressure, proteinuria greater body mass index at baseline, and an increase in the glycosylated hemoglobin between the baseline and 4-year follow-up examinations. Lower glycosylated hemoglobin and male sex, as well as decreases in glycosylated hemoglobin and diastolic blood pressure during the first 4 years of follow-up, were associated with improvement in DR. Persons diagnosed most recently with a similar duration of diabetes had a lower prevalence of PDR independently of glycosylated hemoglobin level, blood pressure level, and presence of proteinuria. CONCLUSIONS: These data show relatively high 25-year cumulative rates of progression of DR and incidence of PDR. The lower risk of prevalent PDR in more recently diagnosed persons possibly reflects improvement in care over the period of the study. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2 2 2 2 1,2	2	pubmed	train	77
Title: Administering glutamic acid decarboxylase to NOD mice prevents diabetes. Abstract: Type 1 diabetes is the result of an ongoing autoimmune response to specific proteins expressed by the insulin producing beta cells. Recently, a number of beta cell autoantigens have been identified. However, their role in mediating the diabetogenic response is not known. Here we assess the relative importance of a panel of beta cell autoantigens in the disease process. The approach was to inhibit T cell proliferation to a given autoantigen by either i.t. or i.v. injections, and then determine the effect this had on the diabetogenic response. We show that administering murine glutamic acid decarboxylase (GAD) to 3-week-old NOD females can reduce the frequency of insulitis and prevent the onset of diabetes. In contrast, carboxypeptidase H or peripherin do not induce a similar protective effect, suggesting that GAD has a critical role in the diabetogenic response. These results also suggest that GAD may provide a useful target for antigen-specific immunotherapy. 1-hop neighbor's text information:Title: Modulation of diabetes in NOD mice by GAD65-specific monoclonal antibodies is epitope specific and accompanied by anti-idiotypic antibodies. Abstract: Type 1 diabetes is caused by the autoimmune destruction of pancreatic beta cells. Here we show that administration of a human monoclonal antibody (b96.11) specific to the 65-kDa isoform of glutamate decarboxylase (GAD65) to prediabetic non-obese diabetic (NOD) mice significantly delays the onset of autoimmune diabetes. We found this effect to be epitope-specific, as only b96.11 showed this therapeutic property, while a GAD65-specific human monoclonal control antibody (b78) derived from the same patient, but specific to a different determinant of GAD65, had no significant effect on the progression of disease. Administration of b96.11 or b78 to NOD mice was accompanied by the generation of anti-idiotypic antibodies. Importantly, the induced anti-idiotypic antibodies were specific for the immunizing antibody and blocked the binding of GAD65 by the respective antibody. These findings suggest a potential role for the internal image of the GAD65 determinant recognized by b96.11 in the anti-idiotypic antibody, supporting an immunomodulatory role for GAD65-specific autoantibodies, as originally postulated by Jerne. 1-hop neighbor's text information:Title: Autoreactive human T-cell receptor initiates insulitis and impaired glucose tolerance in HLA DR4 transgenic mice. Abstract: A human T-cell receptor (TcR) derived from an autoreactive T-cell specific for GAD65, from a subject at high risk for autoimmune diabetes, was introduced into HLA-DR4 transgenic mice. The source of TcR was a CD4(+) T(H)1(+) T-cell clone which responded to an immunodominant epitope of the human islet protein GAD65, an epitope shared with both GAD65 and GAD67 in the mouse. The resulting HLA-DR4/GAD-TcR transgenic mice on a Rag2(o/o)/I-Ab(o/o)/B6 background exhibited a CD4(+) infiltrate into pancreatic islets that correlated with a loss of insulin in infiltrated islets. These mice also exhibited a subclinical impaired tolerance to exogenously fed glucose as assayed by an intraperitoneal glucose tolerance test. T cells containing the GAD65/67 (555-567) responsive TcR undergo strong negative selection as evidenced by a 10-fold lower thymocyte cellularity compared to non-TcR transgenic mice, and clonotype peripheral T cells represented approximately 1% of CD4(+) T cells in Rag2 sufficient mice. Upon in vitro stimulation, GAD65/67 555-567 responsive T cells secrete interferon-gamma, minimal interleukin (IL)-2 and tumor necrosis factor-alpha, and no IL-4, IL-5, IL-10, or IL-17, consistent with a T(H)1 profile. These data demonstrate that CD4(+) T cells specific for a naturally processed epitope within GAD can specifically home to pancreatic islets and lead to impaired islet beta-cell function in diabetes-associated HLA-DR4 transgenic mice on the relatively non-autoimmune C57BL/6 background. The relatively slow progression and patchy insulitis are reminiscent of the chronic pre-clinical phase similar to a majority of human at-risk subjects, and models these indolent features of human T1D. 1-hop neighbor's text information:Title: Absence of significant Th2 response in diabetes-prone non-obese diabetic (NOD) mice. Abstract: Accumulating evidence suggests that Th1 T cells play a pivotal role in the development of autoimmune diabetes. Conversely, promoting a Th2 response inhibits disease progression. However, it has not been determined whether Th2 cells are regulatory T cells that fail at the time of diabetes development in naive non-diabetic NOD mice. Therefore, in order to evaluate cytokine secretion by spleen and islet infiltrating T cells in NOD mice at different stages of the autoimmune process, we developed an ELISPOT assay that detects IL-2, IL-4, and interferon-gamma (IFN-gamma) secretion in vitro at the single-cell level. We showed that, whatever the age considered, IFN-gamma is predominantly secreted, and that no IL-4-secreting cells are detected in the islets of male and female NOD mice. Spleen cells from 8-week-old female NOD mice, which include regulatory suppressor T cells, do not secrete IL-4, either upon presentation of islet cell antigens in vitro, or after transfer in vivo, but do secrete IFN-gamma. IFN-gamma secretion by T cells from diabetic mice results from CD4 but not CD8 T cells in transfer experiments into NOD/severe combined immunodeficient (SCID) recipients. These results suggest that (i) detection of regulatory CD4 T cells in NOD mice is not paralleled by a Th2 response; (ii) beta cell destruction does not depend on a switch from a Th2 to a Th1-type response; and (iii) CD8 T cells do not participate in induction of diabetes by secreting IFN-gamma. 2-hop neighbor's text information:Title: Absence of autoantibodies against glutamate decarboxylase (GAD) in the non-obese diabetic (NOD) mouse and low expression of the enzyme in mouse islets. Abstract: GAD is a major islet cell autoantigen in human type 1 diabetes mellitus. Autoantibodies are preferentially directed against the 65-kD isoform of the enzyme which is the only form expressed in human islets of Langerhans. The NOD mouse is a spontaneous model of type 1 diabetes, frequently employed in studies dealing with the immunopathogenesis of the disease. In the present study the reactivity of sera from 34 prediabetic and 15 diabetic NOD mice was tested against GAD protein present in islets of Langerhans and cerebellum, and against recombinant, semi-purified GAD-65 and GAD-67. A rabbit antiserum (K2) raised against GAD-67 could readily recognize the recombinant GAD-67 and the isoform present in rat and mouse islets and mouse brain. A MoAb (GAD-6) specific for the GAD-65 isoform reacted against the recombinant GAD-65 and the isoform present in rat islets and mouse brain, whereas no reactivity was observed when using mouse islets. However, when testing the NOD mice sera by immunohistochemistry, immunoprecipitation and Western blot, no reactivity against any of the isoforms of GAD could be detected. Using reverse transcription polymerase chain reaction (PCR), GAD-67 mRNA could be detected in mouse and rat islets and in mouse brain. GAD-65 mRNA could also be detected in rat islets and mouse brain, but apparently a much lower copy number is present in mouse islets. These findings stress important differences in the immune response occurring in the animal model NOD mouse compared with human type 1 diabetes, and emphasize that human and animal type 1 diabetes possibly represent the final outcome of several different etiological factors. 2-hop neighbor's text information:Title: A comprehensive review of interventions in the NOD mouse and implications for translation. Abstract: Type 1 diabetes (T1D) animal models such as the nonobese diabetic (NOD) mouse have improved our understanding of disease pathophysiology, but many candidate therapeutics identified therein have failed to prevent/cure human disease. We have performed a comprehensive evaluation of disease-modifying agents tested in the NOD mouse based on treatment timing, duration, study length, and efficacy. Interestingly, some popular tenets regarding NOD interventions were not confirmed: all treatments do not prevent disease, treatment dose and timing strongly influence efficacy, and several therapies have successfully treated overtly diabetic mice. The analysis provides a unique perspective on NOD interventions and suggests that the response of this model to therapeutic interventions can be a useful predictor of the human response as long as careful consideration is given to treatment dose, timing, and protocols; more thorough investigation of these parameters should improve clinical translation. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1 1 1 1,1	2	pubmed	train	79
Title: Accelerated diabetes in non-obese diabetic (NOD) mice differing in incidence of spontaneous disease. Abstract: The NOD mouse is an established model of autoimmune diabetes mellitus. Various lines of NOD mice differ in their incidence of spontaneous diabetes, e.g. 93% of female NOD/Lt mice compared with 46% of female NOD/Wehi mice develop diabetes by 250 days. These two lines were studied under conditions which greatly accelerate the onset of hyperglycaemia. It was hoped that their responses to these manipulations would reveal characteristic differences which would increase our understanding of diabetes resistance in the low incidence NOD/Wehi line. One dose of 300 mg/kg of cyclophosphamide (CP) produced hyperglycaemia in 50% of NOD mice within 2 weeks in both lines. They were also equally susceptible to diabetes induced by splenocyte transfer at 21 days of age from prediabetic 150-day-old NOD/Lt or NOD/Wehi females. Five daily 40 mg/kg doses of streptozotocin (STZ) resulted in a severity of diabetes in the NOD mice greater than in C57BL or SJL/mice. While the incidence and severity of diabetes induced in the two NOD lines were similar, this appeared to be principally due to sensitivity to the toxic effects of STZ rather than its ability to exacerbate autoimmune beta cell destruction. It has previously been shown that it is possible to prevent diabetes in susceptible NOD mice with simple, relatively benign therapies and here we show that it is possible to induce diabetes in resistant animals at a rate indistinguishable from fully predisposed individuals. It therefore appears that the prediabetic NOD mouse is poised in an immunologically precarious state with the onset of disease being highly dependent on factors which exacerbate or moderate autoimmune destruction. 1-hop neighbor's text information:Title: An explanation for the protective effect of the MHC class II I-E molecule in murine diabetes. Abstract: Insulin-dependent diabetes mellitus is widely believed to be an autoimmune disease. Recent onset diabetics show destruction of insulin-secreting pancreatic beta-cells associated with a lymphocytic infiltrate (insulitis), with autoantibodies to beta-cells being found even before the onset of symptoms. Susceptibility to the disease is strongly influenced by major histocompatibility complex (MHC) class II polymorphism in both man and experimental animal models such as the non-obese diabetic (NOD) mouse. As MHC class II molecules are usually associated with dominant immune responsiveness, it was surprising that introduction of a transgenic class II molecule, I-E, protected NOD mice from insulitis and diabetes. This could be explained by a change either in the target tissue or in the T cells presumed to be involved in beta-cell destruction. Recently, several studies have shown that I-E molecules are associated with ontogenetic deletion of T cells bearing antigen/MHC receptors encoded in part by certain T-cell receptor V beta gene segments. To determine the mechanism of the protective effect of I-E, we have produced cloned CD4+ and CD8+ T-cell lines from islets of recently diabetic NOD mice. These cloned lines are islet-specific and pathogenic in both I-E- and I-E+ mice. Both CD4+ and CD8+ cloned T cells bear receptors encoded by a V beta 5 gene segment, known to be deleted during development in I-E expressing mice. Our data provide, therefore, an explanation for the puzzling effect of I-E on susceptibility to diabetes in NOD mice. 1-hop neighbor's text information:Title: Prevention of type I diabetes in nonobese diabetic mice by virus infection. Abstract: The nonobese diabetic (NOD) mouse is an animal model of type I diabetes and develops a characteristic autoimmune lesion in the islets of Langerhans with lymphocytic infiltration and destruction of pancreatic beta cells. The result is hypoinsulinemia, hyperglycemia, ketoacidosis, and death. Diabetes usually begins by the sixth month of age but can occur earlier when young NOD mice are infused with lymphocytes from older NOD donors. When newborn or adult NOD mice were infected with a lymphotropic virus they did not become diabetic. The interaction between viruses and lymphocytes is pivotal in aborting diabetes, as established by experiments in which lymphocytes from virus-infected donors failed to transfer diabetes. In contrast, lymphocytes from age- and sex-matched uninfected donors caused disease. Therefore, viruses and, presumably, their products can be developed to be beneficial and may have potential as a component for treatment of human diseases. Further, these results point to the utility of viruses as probes for dissecting the pathogenesis of a nonviral disease. 1-hop neighbor's text information:Title: Cyclophosphamide-induced diabetes in NOD/WEHI mice. Evidence for suppression in spontaneous autoimmune diabetes mellitus. Abstract: Nonobese diabetic (NOD) mice spontaneously develop a lymphocytic infiltration of pancreatic islets (insulitis) that may progress to overt diabetes. Virtually all NOD/WEHI mice develop insulitis, but very few progress to diabetes. However, cyclophosphamide (CY) can promote the onset of diabetes in NOD mice, including the NOD/WEHI strain. The means by which CY produces diabetes was investigated in NOD/WEHI mice, in which it was hypothesized that active suppression mechanisms prevented the progression from insulitis to diabetes. A study of the time course of insulitis in the islets after CY was given showed that insulitis was initially reduced but rapidly increased over 16 days, and T-lymphocytes were predominant in the lesion. This suggested a compression of the normal time course of the disease seen in NOD mice. CY did not produce diabetes in any of 11 non-NOD strains studied. Fetal isografts in NOD mice given CY several days before were subjected to lymphocytic infiltration and beta-cell destruction. These findings suggested that CY was not directly beta-cell toxic and that altered beta-cells were not essential for beta-cell destruction. This was further demonstrated with subdiabetogenic doses of streptozocin, which significantly damaged beta-cells but did not increase the severity of insulitis or induce diabetes as did CY. Most important, the transfer of mononuclear cells from nondiabetic NOD mice to mice given CY prevented diabetes, which indicated that the likely effect of CY was via immunomodulation, possibly by allowing poised effector cells to act on beta-cells.(ABSTRACT TRUNCATED AT 250 WORDS) 2-hop neighbor's text information:Title: Selective activation of T cells in newly diagnosed insulin-dependent diabetic patients: evidence for heterogeneity of T cell receptor usage. Abstract: Cell surface phenotyping of 58 newly diagnosed diabetic children and 25 controls confirmed the presence of activated T cells, expressing HLA class II antigens or receptors for interleukin-2 (IL-2R, CD25) in the majority of the patients. Some of these cells putatively include those involved in islet cell destruction, as reported previously. Monoclonal antibodies recognizing three families of the variable regions of the beta chain (V beta) of the T cell receptor were used to determine the percentage of peripheral blood cells expressing those specific gene segment products. The number of the activated T cells from each V beta family was compared with that of the resting T cells of the same family in the patients and the controls. In 18 out of 58 (31%) of these patients there was evidence of oligoclonal proliferation of activated T cells as judged by marked increases in cells expressing a V beta family in the IL-2R+ T cell pool, compared with the total T cell pool. However, different V beta families were augmented in individual patients, indicating considerable heterogeneity of T cell activation in different patients. These results are in contrast to murine models of autoimmunity, where virtually monoclonal T cell activation, restricted to a single V beta family has been reported. 2-hop neighbor's text information:Title: Genetic and physiological association of diabetes susceptibility with raised Na+/H+ exchange activity. Abstract: Insulin-dependent diabetes mellitus is a multigenic autoimmune disease, for which one of the best animal models is the nonobese diabetic (NOD) mouse strain. In both humans and NOD mice, major histocompatibility complex genes are implicated as risk factors in the disease process. Other susceptibility genes are also involved, and a number have been mapped in the mouse to specific chromosomal locations. To identify further susceptibility genes, diabetic backcross mice, produced after crossing NOD/Lt to the nondiabetic strains SJL and C57BL/6 (B6), were examined for markers not previously associated with disease susceptibility. Linkage was found to loci on chromosomes 4 and 14. Of the candidate loci on chromosome 4, the gene encoding the Na+/H+ exchanger-1, Nhe-1, was the most likely, since the NOD allele was different from that of both nondiabetic strains. NOD lymphocytes were found to have a higher level of Na+/H+ exchange activity than lymphocytes from either B6 or SJL mice. Since the chromosome 4 susceptibility gene is recessive, the B6 allele should prevent diabetes. This prediction was tested in fourth-generation backcross mice, selected for retention of the B6 allele at Nhe-1. Mice homozygous for Nhe-1 developed diabetes after cyclophosphamide treatment, but heterozygotes were largely protected from disease. These results implicate the Na+/H+ exchanger (antiporter) in the development of type 1 diabetes and may provide a screening test for at-risk individuals as well as offering prospects for disease prevention. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	0 0 0 1 1,0	2	pubmed	train	80
Title: Prevalence and risk factors for urinary incontinence in women with type 2 diabetes and impaired fasting glucose: findings from the National Health and Nutrition Examination Survey (NHANES) 2001-2002. Abstract: OBJECTIVE: Diabetes is associated with increased risk of urinary incontinence. It is unknown whether women with pre-diabetes, or impaired fasting glucose (IFG), have increased prevalence of incontinence. We determined the prevalence of, and risk factors for, incontinence among U.S. women with diabetes and IFG. RESEARCH DESIGN AND METHODS: The 2001-2002 National Health and Nutrition Examination Survey measured fasting plasma glucose and obtained information about diabetes and urinary incontinence among 1,461 nonpregnant adult women. Self-reported weekly or more frequent incontinence, both overall and by type (urge and stress), was our outcome. RESULTS: Of the 1,461 women, 17% had diabetes and 11% met criteria for IFG. Prevalence of weekly incontinence was similar among women in these two groups (35.4 and 33.4%, respectively) and significantly higher than among women with normal fasting glucose (16.8%); both urge and stress incontinence were increased. In addition to well-recognized risk factors including age, weight, and oral estrogen use, two microvascular complications caused by diabetes, specifically macroalbuminuria and peripheral neuropathic pain, were associated with incontinence. CONCLUSIONS: Physicians should be alert for incontinence, an often unrecognized and therefore undertreated disorder, among women with diabetes and IFG, in particular those with microvascular complications. The additional prospect of improvements in their incontinence may help motivate some high-risk women to undertake difficult lifestyle changes to reduce their more serious risk of diabetes and its sequelae. 1-hop neighbor's text information:Title: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Abstract: BACKGROUND: Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial. METHODS: 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48-60 years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6.1-15.0 mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. In the conventional group, the aim was the best achievable FPG with diet alone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy. FINDINGS: Over 10 years, haemoglobin A1c (HbA1c) was 7.0% (6.2-8.2) in the intensive group compared with 7.9% (6.9-8.8) in the conventional group--an 11% reduction. There was no difference in HbA1c among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-related endpoint; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40, p=0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints between the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p<0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg). INTERPRETATION: Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes.(ABSTRACT TRUNCATED) 1-hop neighbor's text information:Title: Type 2 diabetes mellitus and risk of developing urinary incontinence. Abstract: OBJECTIVES: To evaluate the association between type 2 diabetes mellitus (DM) and development of urinary incontinence in women. DESIGN: Prospective, observational study. SETTING: The Nurses' Health Study cohort. PARTICIPANTS: Eighty-one thousand eight hundred forty-five women who reported information on urinary function in 1996. MEASUREMENTS: Self-reported, physician-diagnosed DM was ascertained using questionnaire from 1976 to 1996 and confirmed using standard criteria. Self-reported urinary incontinence, defined as leakage at least weekly, was ascertained in 1996 and 2000. Logistic regression models were used to calculate multivariate-adjusted relative risks (RRs) and 95% confidence intervals (CIs) for the relationship between DM (as of 1996) and prevalent and incident incontinence. RESULTS: The risk of prevalent incontinence (multivariate RR=1.28, 95% CI=1.18-1.39) and incident incontinence (multivariate RR=1.21, 95% CI=1.02-1.43) was significantly greater in women with DM than women without. Using a validated severity index, risk of developing severe incontinence was even more substantial in women with DM than in those without (multivariate RR=1.40, 95% CI=1.15-1.71 for leakage enough to wet the underwear; RR=1.97, 95% CI=1.24-3.12 for leakage enough to wet the outer clothing). In addition, risk of incontinence increased with duration of DM (P-trend=.03 for prevalent incontinence; P=.001 for incident incontinence). CONCLUSION: DM independently increases risk of urinary incontinence in women. Because risk of incontinence appeared associated with longer duration of DM, even delaying the onset of DM could have important public health implications. 1-hop neighbor's text information:Title: Urinary incontinence among women with type 1 diabetes--how common is it? Abstract: PURPOSE: We compared the prevalence, level of bother and effect on daily activities of urinary incontinence among women with type 1 diabetes enrolled in the Epidemiology of Diabetes Interventions and Complications study to a population based sample of women with normal glucose. MATERIALS AND METHODS: We performed a cross-sectional analysis of women with type 1 diabetes and normal glucose tolerance using 2 study populations. The Diabetes Control and Complications Trial cohort followup, Epidemiology of Diabetes Interventions and Complications, began in 1994. In 2004 women participants (550) completed a self-administered questionnaire on urinary incontinence. Our primary outcome was weekly or greater incontinence, overall and by type. Prevalence of urinary incontinence was compared to a subgroup of women with normal glucose in the 2001 to 2002 National Health and Nutrition Examination Survey (NHANES). RESULTS: Overall 65% of women with type 1 diabetes reported any urinary incontinence (17% reported weekly incontinence). Nearly 40% of these women were greatly bothered by their incontinence and 9% believed it affected their day-to-day activities. Women with type 1 diabetes had a nearly 2-fold greater prevalence of weekly urge incontinence compared to those without diabetes in the NHANES cohort (8.8% vs 4.5%, p = 0.01). CONCLUSIONS: Urinary incontinence is common in women with type 1 diabetes and the prevalence of weekly urge incontinence is far greater compared to that in women with normal glucose levels. Moreover, the prevalence of urinary incontinence in women with type 1 diabetes was greater than that of neuropathy, retinopathy and nephropathy. These findings highlight the importance of screening for urinary incontinence among women with type 1 diabetes. Studies examining factors associated with urinary incontinence in women with type 1 diabetes are warranted. 2-hop neighbor's text information:Title: Anaemia and kidney dysfunction in Caribbean type 2 diabetic patients. Abstract: BACKGROUND: Anaemia has been shown in previous studies to be a risk factor for cardiovascular disease in diabetic patients with chronic kidney disorder. This study was aimed to assess the prevalence of anaemia and kidney dysfunction in Caribbean type 2 diabetic patients that have been previously shown to have a high prevalence of the metabolic syndrome. METHODS: 155 type 2 diabetic patients and 51 non-diabetic subjects of African origin were studied. Anthropometric parameters were measured and fasting blood samples were collected for glucose, creatinine, glycated hemoglobin and complete blood count. Anaemia was defined as haemoglobin < 12 g/dl (F) or < 13 g/dl (M). Kidney function was assessed using glomerular filtration rate (GFR) as estimated by the four-variable Modification of Diet in Renal Disease (MDRD) study equation. Subjects were considered to have chronic kidney disease when the estimated GFR was < 60 ml/min per 1.73 m2. Comparisons for within- and between-gender, between diabetic and non-diabetic subjects were performed using Student's t-test while chi-square test was employed for categorical variables. RESULTS: The diabetic patients were older than the non-diabetic subjects. While male non-diabetic subjects had significantly higher red blood cell count (RBC), haemoglobin and hematocrit concentrations than non-diabetic female subjects (p < 0.001), the RBC and hematocrit concentrations were similar in male and female diabetic patients. Furthermore, irrespective of gender, diabetic patients had significantly higher prevalence rate of anemia than non-diabetic subjects (p < 0.05). Anaemic diabetes patients had significantly lower GFR (67.1 +/- 3.0 vs. 87.9 +/- 5.4 ml/min per 1.73 m2, p < 0.001) than non-anaemic patients. CONCLUSION: A high prevalence of anaemia was identified in this group of type 2 diabetic patients previously shown to have a high prevalence of the metabolic syndrome. It is therefore recommended that diagnostic laboratories in developing countries and elsewhere should include complete blood count in routine laboratory investigations in the management of diabetic patients. 2-hop neighbor's text information:Title: Individualized electronic decision support and reminders to improve diabetes care in the community: COMPETE II randomized trial. Abstract: BACKGROUND: Diabetes mellitus is a complex disease with serious complications. Electronic decision support, providing information that is shared and discussed by both patient and physician, encourages timely interventions and may improve the management of this chronic disease. However, it has rarely been tested in community-based primary care. METHODS: In this pragmatic randomized trial, we randomly assigned adult primary care patients with type 2 diabetes to receive the intervention or usual care. The intervention involved shared access by the primary care provider and the patient to a Web-based, colour-coded diabetes tracker, which provided sequential monitoring values for 13 diabetes risk factors, their respective targets and brief, prioritized messages of advice. The primary outcome measure was a process composite score. Secondary outcomes included clinical composite scores, quality of life, continuity of care and usability. The outcome assessors were blinded to each patient's intervention status. RESULTS: We recruited sequentially 46 primary care providers and then 511 of their patients (mean age 60.7 [standard deviation 12.5] years). Mean follow-up was 5.9 months. The process composite score was significantly better for patients in the intervention group than for control patients (difference 1.27, 95% confidence interval [CI] 0.79-1.75, p < 0.001); 61.7% (156/253) of patients in the intervention group, compared with 42.6% (110/258) of control patients, showed improvement (difference 19.1%, p < 0.001). The clinical composite score also had significantly more variables with improvement for the intervention group (0.59, 95% CI 0.09-1.10, p = 0.02), including significantly greater declines in blood pressure (-3.95 mm Hg systolic and -2.38 mm Hg diastolic) and glycated hemoglobin (-0.2%). Patients in the intervention group reported greater satisfaction with their diabetes care. INTERPRETATION: A shared electronic decision-support system to support the primary care of diabetes improved the process of care and some clinical markers of the quality of diabetes care. (ClinicalTrials.gov trial register no. NCT00813085.). I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2 2 1 2 2,2	2	pubmed	train	81
Title: IL-1alpha, IL-1beta, and IFN-gamma mark beta cells for Fas-dependent destruction by diabetogenic CD4(+) T lymphocytes. Abstract: Cytokines such as IL-1alpha, IL-1beta, and IFN-gamma have long been implicated in the pathogenesis of autoimmune diabetes, but the mechanisms through which they promote diabetogenesis remain unclear. Here we show that CD4(+) T lymphocytes propagated from transgenic nonobese diabetic (NOD) mice expressing the highly diabetogenic, beta cell-specific 4.1-T-cell receptor (4.1-TCR) can kill IL-1alpha-, IL-1beta-, and IFN-gamma-treated beta cells from NOD mice. Untreated NOD beta cells and cytokine-treated beta cells from Fas-deficient NOD.lpr mice are not targeted by these T cells. Killing of islet cells in vitro was associated with cytokine-induced upregulation of Fas on islet cells and was independent of MHC class II expression. Abrogation of Fas expression in 4.1-TCR-transgenic NOD mice afforded nearly complete protection from diabetes and did not interfere with the development of the transgenic CD4(+) T cells or with their ability to cause insulitis. In contrast, abrogation of perforin expression did not affect beta cell-specific cytotoxicity or the diabetogenic potential of these T cells. These data demonstrate a novel mechanism of action of IL-1alpha, IL-1beta, and IFN-gamma in autoimmune diabetes, whereby these cytokines mark beta cells for Fas-dependent lysis by autoreactive CD4(+) T cells. 1-hop neighbor's text information:Title: RIP-beta 2-microglobulin transgene expression restores insulitis, but not diabetes, in beta 2-microglobulin null nonobese diabetic mice. Abstract: Beta2m-deficient nonobese diabetic (NODbeta2mnull) do not develop insulitis or diabetes. Expression of a beta2m transgene controlled by the rat insulin promoter (RIP-beta2m) in NODbeta2mnull mice resulted in reconstitution of IFN-gamma-inducible cell surface MHC class I protein on pancreatic beta-cells. These mice developed insulitis, but did not develop diabetes. Transfer of T cells from diabetic NOD mice to NODbeta2mnull recipients resulted in insulitis, which took several months to progress to diabetes. In contrast, transgenic RIP-beta2m/NODbeta2mnull mice with islet MHC class I reconstitution developed diabetes rapidly after transfer of diabetic NOD spleen cells. Administration of cyclophosphamide, which accelerates diabetes in NOD mice, resulted in 43% of RIPbeta2m/NODbeta2mnull mice becoming diabetic compared with 75% of wild-type mice and 0% of NODbeta2mnull mice. Acceleration of diabetes by cyclophosphamide was prevented by anti-CD8 mAb treatment. FACS analysis of peripheral blood and lymphoid organs from transgene-bearing animals did not show an increase in the number of CD8+ T cells compared with that in NODbeta2mnull mice. In summary, beta-cell expression of beta2m in NODbeta2mnull mice resulted in a return of insulitis, but not spontaneous diabetes. These studies demonstrate that beta2m and cell surface MHC class I expression on beta-cells are essential for the initiation of diabetes in the NOD mouse and further confirm that efficient progression to diabetes requires both CD4+ and CD8+ T cells. 1-hop neighbor's text information:Title: Acceleration of spontaneous diabetes in TCR-beta-transgenic nonobese diabetic mice by beta-cell cytotoxic CD8+ T cells expressing identical endogenous TCR-alpha chains. Abstract: The role of target cell autoantigens and their repertoire vs those of foreign Ags, superantigens, or non-Ag-specific stimuli in the activation and recruitment of effector T cells in most spontaneous models of autoimmune diseases remains elusive. Here we report on the use of single TCR-beta transgenic mice to study the mechanisms that drive the accumulation of pathogenic T cells in the pancreatic islets of nonobese diabetic (NOD) mice, a model for insulin-dependent diabetes mellitus. Expression of the V(beta)8.1+ TCR-beta rearrangement of a diabetogenic H-2Kd-restricted beta cell cytotoxic CD8+ T cell (beta-CTL) clone in NOD mice caused a 10-fold increase in the peripheral precursor frequency of beta-CTL and a selective acceleration of the recruitment of CD8+ T cells to the pancreatic islets of prediabetic animals. This resulted in an earlier onset and a faster progression of beta cell depletion, and led to a dramatic acceleration of the onset of diabetes. Most islet-derived beta-CTL from diabetic transgenic NOD mice expressed an endogenously-derived TCR-alpha sequence identical to that of the clonotype donating the TCR-beta transgene, and a TCR-alpha-CDR3 sequence homologous to those expressed by most islet-derived beta-CTL from nontransgenic NOD mice. TCR-beta transgene expression did not change the peripheral frequency of beta cell-specific CD4+ T cells, the rate at which these cells accumulated in the pancreatic islets, or the incidence of diabetes. Taken together, our data indicate that retention of CD8+ and CD4+ T cells in the pancreatic islets of NOD mice is driven by beta cell autoantigens, rather than by local superantigens or non-Ag-specific stimuli, and that beta-CTL are major effectors of beta cell damage in spontaneous insulin-dependent diabetes mellitus. 1-hop neighbor's text information:Title: A mechanism for the major histocompatibility complex-linked resistance to autoimmunity. Abstract: Certain major histocompatibility complex (MHC) class II haplotypes encode elements providing either susceptibility or dominant resistance to the development of spontaneous autoimmune diseases via mechanisms that remain undefined. Here we show that a pancreatic beta cell-reactive, I-Ag7-restricted, transgenic TCR that is highly diabetogenic in nonobese diabetic mice (H-2(g7)) undergoes thymocyte negative selection in diabetes-resistant H-2(g7/b), H-2(g7/k), H-2(g7/q), and H-2(g7/nb1) NOD mice by engaging antidiabetogenic MHC class II molecules on thymic bone marrow-derived cells, independently of endogenous superantigens. Thymocyte deletion is complete in the presence of I-Ab, I-Ak + I-Ek or I-Anb1 + I-Enb1 molecules, partial in the presence of I-Aq or I-Ak molecules alone, and absent in the presence of I-As molecules. Mice that delete the transgenic TCR develop variable degrees of insulitis that correlate with the extent of thymocyte deletion, but are invariably resistant to diabetes development. These results provide an explanation as to how protective MHC class II genes carried on one haplotype can override the genetic susceptibility to an autoimmune disease provided by allelic MHC class II genes carried on a second haplotype. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1 1,1	1	pubmed	train	82
Title: Distal neuropathy in experimental diabetes mellitus. Abstract: Although nerve conduction slowing is a well-accepted abnormality in rats with acute experimental diabetes, reports of neuropathological changes in diabetic rat nerves have been inconsistent. To examine this further, we studied electrophysiological and morphological features of posterior tibial nerves and their distal branches from four-week streptozotocin-induced diabetic rats and matched controls. Diabetic rat posterior tibial motor conduction was slowed (mean +/- 1 SD, 34.8 +/- 3.1 m/sec; controls, 41.2 +/- 2.5 m/sec), and evoked muscle response amplitudes were only half of control values. Using quantitative techniques, we documented a diminution in number of the largest myelinated fibers in otherwise normal mid posterior tibial nerves, with an increase in the smaller sizes, indicating either a degree of axonal atrophy or impaired fiber growth during development. The principal pathological finding was active breakdown of myelinated fibers in the most distal motor twigs of hindfoot muscles supplied by posterior tibial branches, with preservation of fibers in more proximal segments of these nerves. This anatomical lesion in diabetic nerves could account for both oberved conduction slowing and lowered muscle response amplitudes. A consistent feature in both diabetic and control mid lateral plantar nerves was a zone of demyelination that apparently occurs at this natural site of nerve entrapment in rats. Taken together, the pathological abnormalities of peripheral nerve in acute experimental diabetes are best explained as resulting from a distal axonopathy. 1-hop neighbor's text information:Title: Reduced myelinated fiber size correlates with loss of axonal neurofilaments in peripheral nerve of chronically streptozotocin diabetic rats. Abstract: Peripheral sensory nerve abnormalities were investigated in long-term streptozotocin diabetic rats using quantitative analysis. To determine whether the characteristic structural changes occur with a proximodistal gradient, three levels of the sensory peripheral nervous system were investigated: the postganglionic segment of the dorsal root, the midportion of the sciatic nerve, and the distal sural nerve. Reduction of myelinated fiber size due to reduced axonal caliber was the most characteristic change at both proximal and distal levels of the peripheral nerve. The relationship between axonal size and myelin spiral length indicated a more severe axonal atrophy in the distal portion. The axonal atrophy was related to a proportional loss of axonal neurofilaments at proximal levels, whereas in the distal sural nerve the loss of neurofilaments exceeded that which would be expected for axonal size. The universal reduction of axonal size in diabetic nerve may be accounted for by impaired supply of neurofilaments or reduced neurofilament synthesis. Such cytoskeletal defects may, in turn, lead to distal axonal degeneration or contribute to the susceptibility of diabetic nerve to various external noxi, including ischemia and hypoglycemia. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	0,0	1	pubmed	train	83
Title: Prevalence and risk factors for urinary incontinence in women with type 2 diabetes and impaired fasting glucose: findings from the National Health and Nutrition Examination Survey (NHANES) 2001-2002. Abstract: OBJECTIVE: Diabetes is associated with increased risk of urinary incontinence. It is unknown whether women with pre-diabetes, or impaired fasting glucose (IFG), have increased prevalence of incontinence. We determined the prevalence of, and risk factors for, incontinence among U.S. women with diabetes and IFG. RESEARCH DESIGN AND METHODS: The 2001-2002 National Health and Nutrition Examination Survey measured fasting plasma glucose and obtained information about diabetes and urinary incontinence among 1,461 nonpregnant adult women. Self-reported weekly or more frequent incontinence, both overall and by type (urge and stress), was our outcome. RESULTS: Of the 1,461 women, 17% had diabetes and 11% met criteria for IFG. Prevalence of weekly incontinence was similar among women in these two groups (35.4 and 33.4%, respectively) and significantly higher than among women with normal fasting glucose (16.8%); both urge and stress incontinence were increased. In addition to well-recognized risk factors including age, weight, and oral estrogen use, two microvascular complications caused by diabetes, specifically macroalbuminuria and peripheral neuropathic pain, were associated with incontinence. CONCLUSIONS: Physicians should be alert for incontinence, an often unrecognized and therefore undertreated disorder, among women with diabetes and IFG, in particular those with microvascular complications. The additional prospect of improvements in their incontinence may help motivate some high-risk women to undertake difficult lifestyle changes to reduce their more serious risk of diabetes and its sequelae. 1-hop neighbor's text information:Title: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. Abstract: BACKGROUND: Type 2 diabetes affects approximately 8 percent of adults in the United States. Some risk factors--elevated plasma glucose concentrations in the fasting state and after an oral glucose load, overweight, and a sedentary lifestyle--are potentially reversible. We hypothesized that modifying these factors with a lifestyle-intervention program or the administration of metformin would prevent or delay the development of diabetes. METHODS: We randomly assigned 3234 nondiabetic persons with elevated fasting and post-load plasma glucose concentrations to placebo, metformin (850 mg twice daily), or a lifestyle-modification program with the goals of at least a 7 percent weight loss and at least 150 minutes of physical activity per week. The mean age of the participants was 51 years, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 34.0; 68 percent were women, and 45 percent were members of minority groups. RESULTS: The average follow-up was 2.8 years. The incidence of diabetes was 11.0, 7.8, and 4.8 cases per 100 person-years in the placebo, metformin, and lifestyle groups, respectively. The lifestyle intervention reduced the incidence by 58 percent (95 percent confidence interval, 48 to 66 percent) and metformin by 31 percent (95 percent confidence interval, 17 to 43 percent), as compared with placebo; the lifestyle intervention was significantly more effective than metformin. To prevent one case of diabetes during a period of three years, 6.9 persons would have to participate in the lifestyle-intervention program, and 13.9 would have to receive metformin. CONCLUSIONS: Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk. The lifestyle intervention was more effective than metformin. 1-hop neighbor's text information:Title: Lifestyle intervention is associated with lower prevalence of urinary incontinence: the Diabetes Prevention Program. Abstract: OBJECTIVE: Diabetes is associated with increased urinary incontinence risk. Weight loss improves incontinence, but exercise may worsen this condition. We examined whether an intensive lifestyle intervention or metformin therapy among overweight pre-diabetic women was associated with a lower prevalence of incontinence. RESEARCH DESIGN AND METHODS: We analyzed data from the Diabetes Prevention Program, a randomized controlled trial in 27 U.S. centers. Of the 1,957 women included in this analysis, 660 (34%) were randomized to intensive lifestyle therapy, 636 (32%) to metformin, and 661 (34%) to placebo with standard lifestyle advice. The main outcome measure was incontinence symptoms by frequency and type by a validated questionnaire completed at the end-of-trial visit (mean 2.9 years). RESULTS: The prevalence of total (stress or urge) weekly incontinence was lower among women in the intensive lifestyle group (38.3%) than those randomized to metformin (48.1%) or placebo (45.7%). This difference was most apparent among women with stress incontinence (31.3% for intensive lifestyle group vs. 39.7% for metformin vs. 36.7% for placebo, P = 0.006). Changes in weight accounted for most of the protective effect of the intensive lifestyle intervention on stress incontinence. CONCLUSIONS: Less-frequent urinary incontinence may be a powerful motivator for women to choose lifestyle modification to prevent diabetes. 1-hop neighbor's text information:Title: Look AHEAD (Action for Health in Diabetes): design and methods for a clinical trial of weight loss for the prevention of cardiovascular disease in type 2 diabetes. Abstract: Overweight and obesity are major contributors to both type 2 diabetes and cardiovascular disease (CVD). Moreover, individuals with type 2 diabetes who are overweight or obese are at particularly high risk for CVD morbidity and mortality. Although short-term weight loss has been shown to ameliorate obesity-related metabolic abnormalities and CVD risk factors, the long-term consequences of intentional weight loss in overweight or obese individuals with type 2 diabetes have not been adequately examined. The primary objective of the Look AHEAD clinical trial is to assess the long-term effects (up to 11.5 years) of an intensive weight loss program delivered over 4 years in overweight and obese individuals with type 2 diabetes. Approximately 5000 male and female participants who have type 2 diabetes, are 45-74 years of age, and have a body mass index >or=25 kg/m(2) will be randomized to one of the two groups. The intensive lifestyle intervention is designed to achieve and maintain weight loss through decreased caloric intake and increased physical activity. This program is compared to a control condition given diabetes support and education. The primary study outcome is time to incidence of a major CVD event. The study is designed to provide a 0.90 probability of detecting an 18% difference in major CVD event rates between the two groups. Other outcomes include components of CVD risk, cost and cost-effectiveness, diabetes control and complications, hospitalizations, intervention processes, and quality of life. 2-hop neighbor's text information:Title: Lifestyle interventions for type 2 diabetes. Relevance for clinical practice. Abstract: OBJECTIVE: To review evidence from literature on type 2 diabetes pertinent to physical activity and diet and lifestyle modification, and to determine the relevance of this evidence to clinical practice. QUALITY OF EVIDENCE: Direct (level I) evidence supports interventions for physical activity and diet modification for primary prevention and management of type 2 diabetes. Few studies examine the effectiveness of primary health care providers' making such interventions. MAIN MESSAGE: Family physicians have an important role in identifying people at risk of developing type 2 diabetes and managing those diagnosed with the disease, yet they struggle to deliver practice-based interventions that promote sustainable behaviour change among their patients. CONCLUSION: It is evident that supporting patients to make changes in their physical activity and dietary habits can prevent onset of type 2 diabetes. Translating this finding into effective recommendations for clinical practice requires further effort and evaluation. 2-hop neighbor's text information:Title: Treating prediabetes with metformin: systematic review and meta-analysis. Abstract: OBJECTIVE: To determine if the use of metformin in people with prediabetes (impaired glucose tolerance or impaired fasting glucose) would prevent or delay the onset of frank type 2 diabetes mellitus. DATA SOURCES: MEDLINE was searched from January 1966 to the present, and articles meeting the selection criteria were hand searched. STUDY SELECTION: Randomized controlled trials that involved administration of metformin to delay or prevent type 2 diabetes in individuals with impaired glucose tolerance or impaired fasting glucose were included. Development of diabetes was a required outcome measure; follow-up time of at least 6 months was required. Three studies met these criteria. SYNTHESIS: The 3 studies varied in ethnicity of the population studied, in the rates of conversion to diabetes from prediabetes, and in the dose of metformin used. In general the studies were well done, although 2 of the 3 did not do true intention-to-treat analyses. A sensitivity analysis was completed by converting all data to intention-to-treat data and assuming a worst-case scenario for the people who were lost to follow-up. CONCLUSION: Metformin decreases the rate of conversion from prediabetes to diabetes. This was true at higher dosage (850 mg twice daily) and lower dosage (250 mg twice or 3 times daily); in people of varied ethnicity; and even when a sensitivity analysis was applied to the data. The number needed to treat was between 7 and 14 for treatment over a 3-year period. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2 2 2 2 2,2	2	pubmed	train	87
Title: Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects. Abstract: Mutations in several genes encoding transcription factors of the hepatocyte nuclear factor (HNF) cascade are associated with maturity-onset diabetes of the young (MODY), a monogenic form of early-onset diabetes mellitus. The ability of the orphan nuclear receptor small heterodimer partner (SHP, NR0B2) to modulate the transcriptional activity of MODY1 protein, the nuclear receptor HNF-4alpha, suggested SHP as a candidate MODY gene. We screened 173 unrelated Japanese subjects with early-onset diabetes for mutations in this gene and found five different mutations (H53fsdel10, L98fsdel9insAC, R34X, A195S, and R213C) in 6 subjects as well as one apparent polymorphism (R216H), all present in the heterozygous state. Interestingly, all of the subjects with the mutations were mildly or moderately obese at onset of diabetes, and analysis of the lineages of these individuals indicated that the SHP mutations were associated with obesity rather than with diabetes. Therefore, an additional group of 101 unrelated nondiabetic subjects with early-onset obesity was screened for mutations in the SHP gene. Two of the previously observed mutations (R34X and A195S) and two additional mutations (R57W and G189E) were identified in 6 subjects, whereas no mutations were identified in 116 young nondiabetic lean controls (P = 0.0094). Functional studies of the mutant proteins show that the mutations result in the loss of SHP activity. These results suggest that genetic variation in the SHP gene contributes to increased body weight and reveal a pathway leading to this common metabolic disorder in Japanese. 1-hop neighbor's text information:Title: Phenotypic characteristics of early-onset autosomal-dominant type 2 diabetes unlinked to known maturity-onset diabetes of the young (MODY) genes. Abstract: OBJECTIVE: To investigate whether there are forms of early-onset autosomal-dominant type 2 diabetes that are distinct from typical maturity-onset diabetes of the young (MODY) and to characterize their phenotypic characteristics. RESEARCH DESIGN AND METHODS: The study included 220 affected subjects from 29 families in which early-onset type 2 diabetes occurred in multiple generations and was not linked to known MODY genes (MODY gene-negative families). All individuals underwent an oral glucose tolerance test and other clinical measurements aimed at investigating the underlying metabolic defect and the presence of diabetic complications. For comparison, 79 affected carriers of MODY3 (hepatocyte nuclear factor [HNF]-1 alpha) mutations were similarly examined. RESULTS: Subjects from MODY gene-negative pedigrees were diagnosed with diabetes at an older age (36 +/- 17 vs. 21 +/- 10 years, P = 0.0001) and were more frequently obese (52 vs. 18%, P = 0.0001) than MODY3 individuals. MODY gene-negative patients who were insulin treated required more exogenous insulin than did MODY3 subjects (0.7 +/- 0.4 vs. 0.45 +/- 0.2 U.kg-1.day-1, P = 0.04), despite similar C-peptide levels. Among subjects not treated with insulin, MODY gene-negative subjects had significantly higher serum insulin levels, both fasting (16.5 +/- 15 vs. 6.5 +/- 5 microU/ml, P = 0.027) and 2 h after a glucose load (53 +/- 44 vs. 11 +/- 10, P = 0.002). They also had higher serum triglycerides (P = 0.02), higher cholesterol levels (P = 0.02), more hypertension (P = 0.0001), and more nephropathy (P = 0.001). Differences persisted when families were matched for age at diagnosis. CONCLUSIONS: Our findings indicate the existence of forms of early-onset autosomal-dominant type 2 diabetes that are distinct from MODY and are frequently characterized by insulin resistance, similar to later-onset type 2 diabetes. Because of the Mendelian pattern of inheritance, the goal of identifying the genes involved in these forms of diabetes appears to be particularly feasible. 1-hop neighbor's text information:Title: Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3) Abstract: The disease non-insulin-dependent (type 2) diabetes mellitus (NIDDM) is characterized by abnormally high blood glucose resulting from a relative deficiency of insulin. It affects about 2% of the world's population and treatment of diabetes and its complications are an increasing health-care burden. Genetic factors are important in the aetiology of NIDDM, and linkage studies are starting to localize some of the genes that influence the development of this disorder. Maturity-onset diabetes of the young (MODY), a single-gene disorder responsible for 2-5% of NIDDM, is characterized by autosomal dominant inheritance and an age of onset of 25 years or younger. MODY genes have been localized to chromosomes 7, 12 and 20 (refs 5, 7, 8) and clinical studies indicate that mutations in these genes are associated with abnormal patterns of glucose-stimulated insulin secretion. The gene on chromosome 7 (MODY2) encodes the glycolytic enzyme glucokinases which plays a key role in generating the metabolic signal for insulin secretion and in integrating hepatic glucose uptake. Here we show that subjects with the MODY3-form of NIDDM have mutations in the gene encoding hepatocyte nuclear factor-1alpha (HNF-1alpha, which is encoded by the gene TCF1). HNF-1alpha is a transcription factor that helps in the tissue-specific regulation of the expression of several liver genes and also functions as a weak transactivator of the rat insulin-I gene. 1-hop neighbor's text information:Title: Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Abstract: The steady-state basal plasma glucose and insulin concentrations are determined by their interaction in a feedback loop. A computer-solved model has been used to predict the homeostatic concentrations which arise from varying degrees beta-cell deficiency and insulin resistance. Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment of the contributions of insulin resistance and deficient beta-cell function to the fasting hyperglycaemia (homeostasis model assessment, HOMA). The accuracy and precision of the estimate have been determined by comparison with independent measures of insulin resistance and beta-cell function using hyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate of insulin resistance obtained by homeostasis model assessment correlated with estimates obtained by use of the euglycaemic clamp (Rs = 0.88, p less than 0.0001), the fasting insulin concentration (Rs = 0.81, p less than 0.0001), and the hyperglycaemic clamp, (Rs = 0.69, p less than 0.01). There was no correlation with any aspect of insulin-receptor binding. The estimate of deficient beta-cell function obtained by homeostasis model assessment correlated with that derived using the hyperglycaemic clamp (Rs = 0.61, p less than 0.01) and with the estimate from the intravenous glucose tolerance test (Rs = 0.64, p less than 0.05). The low precision of the estimates from the model (coefficients of variation: 31% for insulin resistance and 32% for beta-cell deficit) limits its use, but the correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop. 2-hop neighbor's text information:Title: Management of type 2 diabetes mellitus. Role of thiazolidinediones. Abstract: OBJECTIVE: To review evidence supporting use of thiazolidinediones (TZDs) in management of type 2 diabetes mellitus (DM2). QUALITY OF EVIDENCE: A MEDLINE search found several randomized controlled trials (level I evidence). No systematic reviews of these trials were found in the Cochrane Library. MAIN MESSAGE: Thiazolidinediones lower hemoglobin AIc levels by as much as 1.0% to 1.5%. Effects can be seen in as little as 4 weeks, but full lowering takes 6 to 12 weeks. When used in combination with other diabetic agents, such as sulfonylureas and biguanides, TZDs' hypoglycemic effects appear to be complementary. Thiazolidinediones directly improve insulin sensitivity and recovery of pancreatic beta cell function. Nevertheless, there is no evidence indicating that TZDs are superior to other antidiabetic agents currently available or that TZDs reduce the long-term complications of DM2. CONCLUSION: Ongoing trials will further define the role of TZDs in management of diabetic patients. In current practice, cost is often a factor in the decision to prescribe TZDs. 2-hop neighbor's text information:Title: Adoptive transfer of syngeneic bone marrow-derived cells in mice with obesity-induced diabetes: selenoorganic antioxidant ebselen restores stem cell competence. Abstract: There are conflicting data regarding the effects of transplantation of bone marrow-derived cells (BMDCs) on the severity of diabetes. We therefore inquired whether the competence of BMDCs is preserved on adoptive transfer into diabetic (db/db) mice and how the adoptive transfer of BMDCs affects vascular and metabolic abnormalities in these mice. Recipient db/db mice received infusions of BMDCs prepared from either db/db or non-diabetic heterozygout mice (db/m) mice and effects on endothelium-dependent relaxation, insulin sensitivity, and renal function were evaluated. Recipients of BMDCs from db/m, but not db/db donors showed better glucose control, exhibited striking improvement in endothelium-dependent relaxation in response to acetylcholine, and had partially restored renal function. Improved glucose control was due to enhanced insulin sensitivity, most likely secondary to improved vascular function. Enhanced apoptosis of endothelial progenitor cells under oxidative stress, as well as decreased endothelial progenitor cell numbers were responsible for the apparent functional incompetence of BMDCs from db/db donors. Treatment of db/db mice with Ebselen restored the resistance of both BMDCs and endothelial progenitor cells to oxidative stress, improved acetylcholine-induced vasorelaxation, and reduced proteinuria in db/db recipients of BMDC transplantation. In conclusion, infusion of BMDCs obtained from db/m donors to db/db recipient mice benefited macrovascular function, insulin sensitivity, and nephropathy. BMDCs obtained from db/db mice were functionally incompetent secondary to the increased proportion of apoptotic cells on oxidative stress challenge; their competence was restored by Ebselen therapy. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2 2 2 2 2,2	2	pubmed	train	89
Title: Comparative trial between insulin glargine and NPH insulin in children and adolescents with type 1 diabetes mellitus. Abstract: The objective of this study was to compare the efficacy and safety of insulin glargine, a long-acting insulin analog, with NPH insulin in children and adolescents with type 1 diabetes mellitus (T1DM). In a multicenter, open-label, randomized, 6-month study, 349 patients with TIDM, aged 5-16 years, received insulin glargine once daily or NPH insulin either once or twice daily, based on their prior treatment regimen. Although there was no significant difference between the NPH insulin and insulin glargine treatment groups with respect to baseline to endpoint change in HbA1c levels, fasting blood glucose (FBG) levels decreased significantly more in the insulin glargine group (-1.29 mmol/l) than in the NPH insulin group (-0.68 mmol/L, p = 0.02). The percentage of symptomatic hypoglycemic events was similar between groups; however, fewer patients in the insulin glargine group reported severe hypoglycemia (23% vs 29%) and severe nocturnal hypoglycemia (13% vs 18%), although these differences were not statistically significant (p = 0.22 and p = 0.19, respectively). Fewer serious adverse events occurred in the insulin glargine group than in the NPH insulin group (p < 0.02). A once-daily subcutaneous dose of insulin glargine provides effective glycemic control and is well tolerated in children and adolescents with T1DM. 1-hop neighbor's text information:Title: Diabetes screening, diagnosis, and therapy in pediatric patients with type 2 diabetes. Abstract: The dramatic rise in the incidence and prevalence of type 2 diabetes mellitus in the pediatric and adolescent populations has been associated with the ongoing epidemic of overweight, obesity, insulin resistance, and metabolic syndrome seen in these age groups. Although the majority of pediatric patients diagnosed with diabetes are still classified as having type 1 diabetes, almost 50% of patients with diabetes in the pediatric age range (under 18 years) may have type 2 diabetes. Screening of high-risk patients for diabetes and prediabetes is important. Prompt diagnosis and accurate diabetes classification facilitate appropriate and timely treatment and may reduce the risk for complications. This is especially important in children because lifestyle interventions may be successful and the lifelong risk for complications is greatest. Treatment usually begins with dietary modification, weight loss, and a structured program of physical exercise. Oral antidiabetic agents are added when lifestyle intervention alone fails to maintain glycemic control. Given the natural history of type 2 diabetes, most if not all patients will eventually require insulin therapy. In those requiring insulin, improved glycemic control and reduced frequency of hypoglycemia can be achieved with insulin analogs. It is common to add insulin therapy to existing oral therapy only when oral agents no longer provide adequate glycemic control. 1-hop neighbor's text information:Title: Institution of basal-bolus therapy at diagnosis for children with type 1 diabetes mellitus. Abstract: OBJECTIVE: We studied whether the institution of basal-bolus therapy immediately after diagnosis improved glycemic control in the first year after diagnosis for children with newly diagnosed type 1 diabetes mellitus. METHODS: We reviewed the charts of 459 children > or =6 years of age who were diagnosed as having type 1 diabetes between July 1, 2002, and June 30, 2006 (212 treated with basal-bolus therapy and 247 treated with a more-conventional neutral protamine Hagedorn regimen). We abstracted data obtained at diagnosis and at quarterly clinic visits and compared groups by using repeated-measures, mixed-linear model analysis. We also reviewed the records of 198 children with preexisting type 1 diabetes mellitus of >1-year duration who changed from the neutral protamine Hagedorn regimen to a basal-bolus regimen during the review period. RESULTS: Glargine-treated subjects with newly diagnosed diabetes had lower hemoglobin A1c levels at 3, 6, 9, and 12 months after diagnosis than did neutral protamine Hagedorn-treated subjects (average hemoglobin A1c levels of 7.05% with glargine and 7.63% with neutral protamine Hagedorn, estimated across months 3, 6, 9, and 12, according to repeated-measures models adjusted for age at diagnosis and baseline hemoglobin A1c levels; treatment difference: 0.58%). Children with long-standing diabetes had no clinically important changes in their hemoglobin A1c levels in the first year after changing regimens. CONCLUSION: The institution of basal-bolus therapy with insulin glargine at the time of diagnosis of type 1 diabetes was associated with improved glycemic control, in comparison with more-conventional neutral protamine Hagedorn regimens, during the first year after diagnosis. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2 1,1	1	pubmed	train	90
Title: IL-1alpha, IL-1beta, and IFN-gamma mark beta cells for Fas-dependent destruction by diabetogenic CD4(+) T lymphocytes. Abstract: Cytokines such as IL-1alpha, IL-1beta, and IFN-gamma have long been implicated in the pathogenesis of autoimmune diabetes, but the mechanisms through which they promote diabetogenesis remain unclear. Here we show that CD4(+) T lymphocytes propagated from transgenic nonobese diabetic (NOD) mice expressing the highly diabetogenic, beta cell-specific 4.1-T-cell receptor (4.1-TCR) can kill IL-1alpha-, IL-1beta-, and IFN-gamma-treated beta cells from NOD mice. Untreated NOD beta cells and cytokine-treated beta cells from Fas-deficient NOD.lpr mice are not targeted by these T cells. Killing of islet cells in vitro was associated with cytokine-induced upregulation of Fas on islet cells and was independent of MHC class II expression. Abrogation of Fas expression in 4.1-TCR-transgenic NOD mice afforded nearly complete protection from diabetes and did not interfere with the development of the transgenic CD4(+) T cells or with their ability to cause insulitis. In contrast, abrogation of perforin expression did not affect beta cell-specific cytotoxicity or the diabetogenic potential of these T cells. These data demonstrate a novel mechanism of action of IL-1alpha, IL-1beta, and IFN-gamma in autoimmune diabetes, whereby these cytokines mark beta cells for Fas-dependent lysis by autoreactive CD4(+) T cells. 1-hop neighbor's text information:Title: Induction of type I diabetes by interferon-alpha in transgenic mice. Abstract: Type I diabetes is an autoimmune disease involving an interaction between an epigenetic event (possibly a viral infection), the pancreatic beta cells, and the immune system in a genetically susceptible host. The possibility that the type I interferons could mediate this interaction was tested with transgenic mice in which the insulin-producing beta cells expressed an interferon-alpha. These mice developed a hypoinsulinemic diabetes associated with a mixed inflammation centered on the islets. The inflammation and the diabetes were prevented with a neutralizing antibody to the interferon-alpha. Thus, the expression of interferon-alpha by the beta cells could be causal in the development of type I diabetes, which suggests a therapeutic approach to this disease. 1-hop neighbor's text information:Title: The role of Fas in autoimmune diabetes. Abstract: Immunologically privileged sites express Fas ligand (FasL), which protects them from attack by activated T cells that express Fas and die upon contact with FasL. In an attempt to protect nonobese diabetic mice (NOD) from autoimmune diabetes, we made FasL transgenic NOD mice using the beta cell-specific rat insulin-1 promoter. Surprisingly, these transgenic mice showed heightened sensitivity to diabetogenic T cells, which was due to self-destruction of beta cells upon T cell-mediated induction of Fas. Fas-negative NOD(lpr/lpr) animals were resistant to diabetogenic T cells and to spontaneous diabetes. Thus, induction of Fas expression on beta cells and their subsequent destruction constitutes the main pathogenic mechanism in autoimmune diabetes. 1-hop neighbor's text information:Title: Exclusive expression of MHC class II proteins on CD45+ cells in pancreatic islets of NOD mice. Abstract: The expression of MHC class II molecules on beta-cells of the pancreatic islet has been proposed to play a role in the genesis of insulin-dependent diabetes mellitus in the NOD mouse. We investigated this by immunofluorescent double labeling of islet cells with anti-MHC and anti-CD45 to identify cells of hematopoietic origin. MHC class I expression increased with age on CD45- islet cells. MHC class II expression was not observed on CD45- islet cells at any age; the only cells in the islet that were MHC class II positive were also CD45+. This indicates that all MHC class II-positive cells in the islet are lymphoid cells that infiltrate the islet, whereas the islet endocrine cells express no MHC class II molecules. However, an increase in MHC class I expression occurred on beta-cells, and this may play a role in immunopathogenesis. 2-hop neighbor's text information:Title: Protection from autoimmune diabetes and T-cell lymphoproliferation induced by FasL mutation are differentially regulated and can be uncoupled pharmacologically. Abstract: Spontaneous mutation of Fas (lpr) or FasL (gld) completely protects nonobese diabetic mice from autoimmune diabetes but also causes massive double-negative T-cell lymphoproliferation. In this study, we used bone marrow chimeras and adoptive transfer analysis to investigate further the role of FasL in the pathogenesis of autoimmune diabetes and to determine whether gld-induced tolerance and double-negative T-cell lymphoproliferation can be uncoupled from each other. We show that FasL expressed on hematopoietic and nonhematopoietic compartments plays nonredundant roles in the pathogenesis of autoimmune diabetes. Mutation of FasL in either compartment interferes with the autoimmune process and prevents onset of diabetes, but FasL expressed in the hematopoietic compartment is the dominant regulator of T-cell homeostasis. Furthermore, pathogenesis of diabetes is dependent on normal FasL expression in both compartments, whereas only minimal FasL function is required to maintain T-cell homeostasis. Consequently, partial disruption of FasL protects from autoimmune diabetes without causing T-cell lymphoproliferation. This is demonstrated genetically in nonobese diabetic-gld/+ mice and pharmacologically by using FasL-neutralizing antibody. These results have important implications for understanding the role of the Fas pathway in pathogenesis of autoimmune diseases and for designing novel FasL-modulating therapies. 2-hop neighbor's text information:Title: Major histocompatibility complex class I-restricted T cells are required for all but the end stages of diabetes development in nonobese diabetic mice and use a prevalent T cell receptor alpha chain gene rearrangement. Abstract: Nonobese diabetic (NOD) mice develop insulin-dependent diabetes mellitus due to autoimmune T lymphocyte-mediated destruction of pancreatic beta cells. Although both major histocompatibility complex class I-restricted CD8(+) and class II-restricted CD4(+) T cell subsets are required, the specific role each subset plays in the pathogenic process is still unclear. Here we show that class I-dependent T cells are required for all but the terminal stages of autoimmune diabetes development. To characterize the diabetogenic CD8(+) T cells responsible, we isolated and propagated in vitro CD8(+) T cells from the earliest insulitic lesions of NOD mice. They were cytotoxic to NOD islet cells, restricted to H-2Kd, and showed a diverse T cell receptor beta chain repertoire. In contrast, their alpha chain repertoire was more restricted, with a recurrent amino acid sequence motif in the complementarity-determining region 3 loop and a prevalence of Valpha17 family members frequently joined to the Jalpha42 gene segment. These results suggest that a number of the CD8(+) T cells participating in the initial phase of autoimmune beta cell destruction recognize a common structural component of Kd/peptide complexes on pancreatic beta cells, possibly a single peptide. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1 0 1 1,1	2	pubmed	train	93
Title: Administering glutamic acid decarboxylase to NOD mice prevents diabetes. Abstract: Type 1 diabetes is the result of an ongoing autoimmune response to specific proteins expressed by the insulin producing beta cells. Recently, a number of beta cell autoantigens have been identified. However, their role in mediating the diabetogenic response is not known. Here we assess the relative importance of a panel of beta cell autoantigens in the disease process. The approach was to inhibit T cell proliferation to a given autoantigen by either i.t. or i.v. injections, and then determine the effect this had on the diabetogenic response. We show that administering murine glutamic acid decarboxylase (GAD) to 3-week-old NOD females can reduce the frequency of insulitis and prevent the onset of diabetes. In contrast, carboxypeptidase H or peripherin do not induce a similar protective effect, suggesting that GAD has a critical role in the diabetogenic response. These results also suggest that GAD may provide a useful target for antigen-specific immunotherapy. 1-hop neighbor's text information:Title: Modulation of diabetes in NOD mice by GAD65-specific monoclonal antibodies is epitope specific and accompanied by anti-idiotypic antibodies. Abstract: Type 1 diabetes is caused by the autoimmune destruction of pancreatic beta cells. Here we show that administration of a human monoclonal antibody (b96.11) specific to the 65-kDa isoform of glutamate decarboxylase (GAD65) to prediabetic non-obese diabetic (NOD) mice significantly delays the onset of autoimmune diabetes. We found this effect to be epitope-specific, as only b96.11 showed this therapeutic property, while a GAD65-specific human monoclonal control antibody (b78) derived from the same patient, but specific to a different determinant of GAD65, had no significant effect on the progression of disease. Administration of b96.11 or b78 to NOD mice was accompanied by the generation of anti-idiotypic antibodies. Importantly, the induced anti-idiotypic antibodies were specific for the immunizing antibody and blocked the binding of GAD65 by the respective antibody. These findings suggest a potential role for the internal image of the GAD65 determinant recognized by b96.11 in the anti-idiotypic antibody, supporting an immunomodulatory role for GAD65-specific autoantibodies, as originally postulated by Jerne. 1-hop neighbor's text information:Title: Autoreactive human T-cell receptor initiates insulitis and impaired glucose tolerance in HLA DR4 transgenic mice. Abstract: A human T-cell receptor (TcR) derived from an autoreactive T-cell specific for GAD65, from a subject at high risk for autoimmune diabetes, was introduced into HLA-DR4 transgenic mice. The source of TcR was a CD4(+) T(H)1(+) T-cell clone which responded to an immunodominant epitope of the human islet protein GAD65, an epitope shared with both GAD65 and GAD67 in the mouse. The resulting HLA-DR4/GAD-TcR transgenic mice on a Rag2(o/o)/I-Ab(o/o)/B6 background exhibited a CD4(+) infiltrate into pancreatic islets that correlated with a loss of insulin in infiltrated islets. These mice also exhibited a subclinical impaired tolerance to exogenously fed glucose as assayed by an intraperitoneal glucose tolerance test. T cells containing the GAD65/67 (555-567) responsive TcR undergo strong negative selection as evidenced by a 10-fold lower thymocyte cellularity compared to non-TcR transgenic mice, and clonotype peripheral T cells represented approximately 1% of CD4(+) T cells in Rag2 sufficient mice. Upon in vitro stimulation, GAD65/67 555-567 responsive T cells secrete interferon-gamma, minimal interleukin (IL)-2 and tumor necrosis factor-alpha, and no IL-4, IL-5, IL-10, or IL-17, consistent with a T(H)1 profile. These data demonstrate that CD4(+) T cells specific for a naturally processed epitope within GAD can specifically home to pancreatic islets and lead to impaired islet beta-cell function in diabetes-associated HLA-DR4 transgenic mice on the relatively non-autoimmune C57BL/6 background. The relatively slow progression and patchy insulitis are reminiscent of the chronic pre-clinical phase similar to a majority of human at-risk subjects, and models these indolent features of human T1D. 1-hop neighbor's text information:Title: Absence of significant Th2 response in diabetes-prone non-obese diabetic (NOD) mice. Abstract: Accumulating evidence suggests that Th1 T cells play a pivotal role in the development of autoimmune diabetes. Conversely, promoting a Th2 response inhibits disease progression. However, it has not been determined whether Th2 cells are regulatory T cells that fail at the time of diabetes development in naive non-diabetic NOD mice. Therefore, in order to evaluate cytokine secretion by spleen and islet infiltrating T cells in NOD mice at different stages of the autoimmune process, we developed an ELISPOT assay that detects IL-2, IL-4, and interferon-gamma (IFN-gamma) secretion in vitro at the single-cell level. We showed that, whatever the age considered, IFN-gamma is predominantly secreted, and that no IL-4-secreting cells are detected in the islets of male and female NOD mice. Spleen cells from 8-week-old female NOD mice, which include regulatory suppressor T cells, do not secrete IL-4, either upon presentation of islet cell antigens in vitro, or after transfer in vivo, but do secrete IFN-gamma. IFN-gamma secretion by T cells from diabetic mice results from CD4 but not CD8 T cells in transfer experiments into NOD/severe combined immunodeficient (SCID) recipients. These results suggest that (i) detection of regulatory CD4 T cells in NOD mice is not paralleled by a Th2 response; (ii) beta cell destruction does not depend on a switch from a Th2 to a Th1-type response; and (iii) CD8 T cells do not participate in induction of diabetes by secreting IFN-gamma. 2-hop neighbor's text information:Title: Prevention of type I diabetes transfer by glutamic acid decarboxylase 65 peptide 206-220-specific T cells. Abstract: Glutamic acid decarboxylase (GAD) 65 is one of the major pancreatic antigens targeted by self-reactive T cells in type I diabetes mellitus. T cells specific for GAD65 are among the first to enter inflamed islets and may be important for the initiation of autoimmune diabetes. However, we previously reported that nonobese diabetic (NOD) mice transgenic for a T cell antigen receptor (TCR) specific for one of the immunodominant epitopes of GAD65, peptide 286-300 (G286), are protected from insulitis and diabetes. To examine whether other GAD65-reactive T cells share this phenotype, we have generated TCR transgenic NOD mice for a second immunodominant epitope of GAD65, peptide 206-220 (G206). As in G286 mice, G206 mice do not develop islet inflammation or diabetes. When adoptively transferred along with diabetogenic T cells, activated G206 T cells significantly delayed the onset of diabetes in NOD.scid recipients. Both G206 and G286 T cells produce immunoregulatory cytokines IFN-gamma and IL-10 at low levels when activated by cognate antigens. These data suggest that GAD65-specific T cells may play a protective role in diabetes pathogenesis by regulating pathogenic T cell responses. A better understanding of the functions of autoreactive T cells in type I diabetes will be necessary for choosing desirable targets for immunotherapy. 2-hop neighbor's text information:Title: Plasmid DNAs encoding insulin and glutamic acid decarboxylase 65 have distinct effects on the progression of autoimmune diabetes in nonobese diabetic mice. Abstract: We previously demonstrated that administration of plasmid DNAs (pDNAs) encoding IL-4 and a fragment of glutamic acid decarboxylase 65 (GAD65) fused to IgGFc induces GAD65-specific Th2 cells and prevents insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice. To assess the general applicability of pDNA vaccination to mediate Ag-specific immune deviation, we examined the immunotherapeutic efficacy of recombinants encoding murine insulin A and B chains fused to IgGFc. Insulin was chosen based on studies demonstrating that administration of insulin or insulin B chain by a variety of strategies prevents IDDM in NOD mice. Surprisingly, young NOD mice receiving i.m. injections of pDNA encoding insulin B chain-IgGFc with or without IL-4 exhibited an accelerated progression of insulitis and developed early diabetes. Exacerbation of IDDM correlated with an increased frequency of IFN-gamma-secreting CD4(+) and CD8(+) T cells in response to insulin B chain-specific peptides compared with untreated mice. In contrast, treatment with pDNAs encoding insulin A chain-IgGFc and IL-4 elicited a low frequency of IL-4-secreting Th cells and had no effect on the progression of IDDM. Vaccination with pDNAs encoding GAD65-IgGFc and IL-4, however, prevented IDDM. These results demonstrate that insulin- and GAD65-specific T cell reactivity induced by pDNA vaccination has distinct effects on the progression of IDDM. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1 1 1 1,1	2	pubmed	train	95
Title: Accelerated diabetes in non-obese diabetic (NOD) mice differing in incidence of spontaneous disease. Abstract: The NOD mouse is an established model of autoimmune diabetes mellitus. Various lines of NOD mice differ in their incidence of spontaneous diabetes, e.g. 93% of female NOD/Lt mice compared with 46% of female NOD/Wehi mice develop diabetes by 250 days. These two lines were studied under conditions which greatly accelerate the onset of hyperglycaemia. It was hoped that their responses to these manipulations would reveal characteristic differences which would increase our understanding of diabetes resistance in the low incidence NOD/Wehi line. One dose of 300 mg/kg of cyclophosphamide (CP) produced hyperglycaemia in 50% of NOD mice within 2 weeks in both lines. They were also equally susceptible to diabetes induced by splenocyte transfer at 21 days of age from prediabetic 150-day-old NOD/Lt or NOD/Wehi females. Five daily 40 mg/kg doses of streptozotocin (STZ) resulted in a severity of diabetes in the NOD mice greater than in C57BL or SJL/mice. While the incidence and severity of diabetes induced in the two NOD lines were similar, this appeared to be principally due to sensitivity to the toxic effects of STZ rather than its ability to exacerbate autoimmune beta cell destruction. It has previously been shown that it is possible to prevent diabetes in susceptible NOD mice with simple, relatively benign therapies and here we show that it is possible to induce diabetes in resistant animals at a rate indistinguishable from fully predisposed individuals. It therefore appears that the prediabetic NOD mouse is poised in an immunologically precarious state with the onset of disease being highly dependent on factors which exacerbate or moderate autoimmune destruction. 1-hop neighbor's text information:Title: Transfer of autoimmune diabetes mellitus with splenocytes from nonobese diabetic (NOD) mice. Abstract: The nonobese diabetic (NOD) mouse, a model of human type I diabetes, develops insulitis beginning at 4-6 wk of age. By 30 wk of age, 72% of females and 39% of males develop spontaneous diabetes, apparently because of an overwhelming autoimmune response to the insulin-producing beta-cells within the islets. To identify the immune mechanism responsible for destruction of beta-cells in the NOD mouse, we developed an adoptive transfer protocol that induces diabetes in NOD mice at an age when spontaneous diabetes is rarely observed. Splenocytes from overtly diabetic NOD mice were unable to transfer diabetes to very young (less than or equal to 6 wk) irradiated NOD mice but effectively transferred diabetes to irradiated NOD mice greater than 6 wk of age. In such transfers, overt diabetes was induced within 12-22 days in greater than 95% (79/82) of the recipients. Thus, transfer of splenocytes to young mice induces them to become diabetic at a higher frequency and at a younger age than their untreated littermates. Equally successful transfers with as few as 5 X 10(6) spleen cells have been performed in male and female NOD mice, even though males display a lower spontaneous incidence of diabetes than females. Splenocytes obtained from diabetic mice maintained on insulin for up to 2 mo also transferred diabetes. Because NOD mice display increasing levels of insulitis with age, spleen cells obtained from nondiabetic NOD mice of different ages were tested for their ability to transfer diabetes.(ABSTRACT TRUNCATED AT 250 WORDS) 1-hop neighbor's text information:Title: Raised temperature reduces the incidence of diabetes in the NOD mouse. Abstract: An association between the incidence of childhood Type 1 (insulin-dependent) diabetes mellitus and the average yearly temperature in different countries has been reported, the incidence being higher in countries with a lower mean temperature. We have studied the effect of environmental temperature on the incidence of diabetes in an animal model of Type 1 diabetes, the non-obese diabetic (NOD) mouse. Female NOD mice were divided at weaning, with one group placed at a higher temperature (mean 23.7 +/- 1.7 degrees C) and the other at a lower temperature (21.0 +/- 1.8 degrees C). At 20 weeks of age 6 of 16 mice at lower temperature and 1 of 17 mice at higher temperature had developed diabetes (p less than 0.02); at 30 weeks 10 of 16 and 5 of 17 mice had developed diabetes (p less than 0.05). Non-diabetic animals in the low temperature group had a higher food intake than those in the high temperature group between 13-15 weeks of age (28.0 +/- 1.2 g/week vs 24.8 +/- 0.7 g/week, p less than 0.05). In a parallel experiment, histological examination showed that there were similar degrees of insulitis in the high and low temperature groups at seven weeks of age. We conclude that environmental temperature can affect the incidence of diabetes in the NOD mouse and that this may be related to alterations in food intake. 1-hop neighbor's text information:Title: Syngeneic transfer of autoimmune diabetes from diabetic NOD mice to healthy neonates. Requirement for both L3T4+ and Lyt-2+ T cells. Abstract: We have developed a model of syngeneic adoptive transfer for type I diabetes mellitus of NOD mice. This model consists in injecting spleen cells from diabetic adult mice into newborn NOD recipients. 50% of recipients inoculated with 20 X 10(6) cells develop diabetes within the first 10 wk of life, at a time when none of the control littermates have yet become diabetic. The earliest successful transfers are observed at 3 wk of age, at a time when controls do not even exhibit histological changes in their pancreas. In addition we have shown that: (a) both males and females can be adoptively transferred, despite the fact that males rarely develop spontaneous diabetes in our colony; (b) diabetes transfer is a dose-dependent phenomenon that provides an in vivo assay for comparing the autoimmune potential of spleen cells from mice at various stages of their natural history; (c) the susceptibility of the recipients to the transfer is limited in time and declines after 3 wk; and (d) both L3T4+ and Lyt-2+ T cell subsets are necessary for the successful transfer. The neonatal syngeneic transfer provides an effective model for studies of the cellular events involved at regulatory and effector stages of autoimmune type I diabetes. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	0 0 0,0	1	pubmed	train	97
Title: Effect of source of dietary carbohydrate on plasma glucose and insulin responses to mixed meals in subjects with NIDDM. Abstract: It has been demonstrated that carbohydrate-rich foods result in different plasma glucose responses when eaten alone by normal subjects and patients with non-insulin-dependent diabetes mellitus (NIDDM). This study was designed to test if the glycemic response to mixed meals can be altered by selecting carbohydrate-rich foods based on their glycemic potency. Consequently, three test meals were developed that should have yielded high-, intermediate-, and low-glycemic responses based on the published glycemic index of all the carbohydrate foods in the meals. The test meals were consumed by normal individuals and patients with NIDDM, and the resultant plasma glucose and insulin responses were determined. The results indicated that the plasma glucose responses after the meals did not vary as a function of their glycemic potency in either the normal or NIDDM subjects. There were no significant differences in the plasma insulin responses for either group. These results indicate that the plasma glucose response to mixed meals did not vary as a function of the calculated glycemic potencies. Therefore, the glycemic response to a mixed meal was not predicted on the basis of the published values of the glycemic index of the individual carbohydrate foods included in the meal. 1-hop neighbor's text information:Title: Change in food choices following a glycemic load intervention in adults with type 2 diabetes. Abstract: The glycemic index (GI) reflects the postprandial glucose response of carbohydrate-containing foods, and adoption of a lower-GI diet may be beneficial in diabetes management. The purpose of this study was to evaluate change in food-group intake by participants after completing an intervention that included instruction about carbohydrate and the GI using a quasi-experimental design. Recruitment occurred from February to August 2005 and September to December 2006. Individuals 40 to 70 years old with type 2 diabetes for 1 year or longer were randomly assigned to an immediate (n=55) or delayed (n=48) treatment group. A 9-week group-based intervention regarding the quantity and type of carbohydrate for diabetes management was provided. Three sets of 24-hour dietary recalls were used to assess food-group intake. Foods were divided into nine main food groups and 166 subgroups based on the Dietary Guidelines for Americans 2005 and the United States Department of Agriculture's Food Guide Pyramid. Analysis of variance was used to examine between-group differences and paired t test compared maintenance of change for the immediate group. Change in dietary GI was significantly different between groups upon completion of the intervention by the immediate group (P<0.05). Participants consumed significantly more servings of whole fruit and nonfat dairy products following the intervention and fewer servings of vegetable fats (all P<0.05). Only whole-fruit consumption significantly declined in the immediate group during the maintenance period (P<0.05). Nutrition education can facilitate adoption of a lower-GI diet among free-living people with diabetes. Maintaining dietary change likely requires further intervention and support. 2-hop neighbor's text information:Title: A flexible, low-glycemic index mexican-style diet in overweight and obese subjects with type 2 diabetes improves metabolic parameters during a 6-week treatment period. Abstract: OBJECTIVE: The aim of this study was to compare the effects of a flexible lower- and higher-glycemic index (GI) Mexican-style diet on biochemical data and BMI during a 6-week treatment period. RESEARCH DESIGN AND METHODS: This study was a randomized, crossover design of two 6-week periods with a 6-week washout period between treatments. Subjects with type 2 diabetes (n = 36) with a BMI >25 kg/m(2) were selected. Fourteen subjects completed the study with eligible dietary records. Dietary instruction was provided on flexible diets with both a high and low GI. Fasting venous blood samples were taken at the start and finish of each dietary period, and biochemical data were analyzed. Multi- and univariate one-factor repeated-measures ANOVA were used to compare biochemical data. RESULTS: Glycemic load and GI were lower during the low-GI diet, and dietary fiber was lower during the high-GI diet. The participants in the low-GI period consumed significantly fewer carbohydrates, such as white-wheat bread, white long-grain rice, potatoes, high-GI fruits, and carrots, and more carbohydrates, such as pinto beans, whole-meal wheat bread, and low-GI fruits than did participants in the high-GI period. There were no differences in the amount of carbohydrates consumed, such as corn tortillas and dairy products. At the end of the study periods, A1c was improved on the low- compared with the high-GI diet (P < 0.008). CONCLUSIONS: We conclude that a low-GI diet, containing Mexican-style foods, may help to improve the metabolic control in type 2 obese diabetic subjects during a 6-week period. 2-hop neighbor's text information:Title: Glycemic index in the diet of European outpatients with type 1 diabetes: relations to glycated hemoglobin and serum lipids. Abstract: BACKGROUND: Little is known about the variation of the glycemic index (GI) in the diet of European outpatients with type 1 diabetes and how the GI of a commonly consumed diet is associated with metabolic control. OBJECTIVE: The present study examined the calculated dietary GI of European outpatients with type 1 diabetes for possible relations to glycated hemoglobin (Hb A(1c)) and serum lipid concentrations. DESIGN: The relation of the GI (calculated from a 3-d dietary record) to Hb A(1c), serum cholesterol (total, LDL, and HDL), and fasting triacylglycerol was analyzed in 2810 people with type 1 diabetes from the EURODIAB Complications Study. RESULTS: The GI was independently related to Hb A(1c) (P = 0.0001). Compared with the highest GI quartile (median GI: 89), adjusted Hb A(1c) in the lowest GI quartile (median GI: 75) was 11% lower in patients from southern European centers and 6% lower in patients from northern, western, and eastern European centers. Of the serum lipids, only the HDL cholesterol in patients from these European centers was independently related to the GI (P = 0.002). In southern European centers, the consumption of pasta, temperate-climate fruit, white bread, and potatoes largely determined the patients' dietary GI, whereas in the northern, western, and eastern European centers, consumption of bread, potatoes, and temperate-climate fruit was most relevant. CONCLUSIONS: This study in European patients with type 1 diabetes showed that a lower dietary GI is related to lower Hb A(1c) concentrations, independently of fiber intake. The consumption of bread and pasta had the biggest effect on the overall dietary GI of European outpatients. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2 2 1,2	2	pubmed	train	98
Title: HLA and insulin gene associations with IDDM. Abstract: The HLA DR genotype frequencies in insulin-dependent diabetes mellitus (IDDM) patients and the frequencies of DR alleles transmitted from affected parent to affected child both indicate that the DR3-associated predisposition is more "recessive" and the DR4-associated predisposition more "dominant" in inheritance after allowing for the DR3/DR4 synergistic effect. B locus distributions on patient haplotypes indicate that only subsets of both DR3 and DR4 are predisposing. Heterogeneity is detected for both the DR3 and DR4 predisposing haplotypes based on DR genotypic class. With appropriate use of the family structure of the data a control population of "unaffected" alleles can be defined. Application of this method confirms the predisposing effect associated with the class 1 allele of the polymorphic region 5' to the insulin gene. 1-hop neighbor's text information:Title: T-cell receptor genes and insulin-dependent diabetes mellitus (IDDM): no evidence for linkage from affected sib pairs. Abstract: Several investigators have reported an association between insulin-dependent diabetes mellitus (IDDM) and an RFLP detected with a probe for the constant region of the beta chain (C beta) of the human T-cell receptor (TCR). A likely hypothesis is that the closely linked TCR variable (V beta) region genes contribute to IDDM susceptibility and that the association with the TCR C beta locus reflects this contribution, via linkage disequilibrium between V beta and C beta. The products of the beta-chain genes might be expected to be involved in the etiology of IDDM because of the autoimmune aspects of IDDM, the known involvement of HLA, and the necessity for TCR and HLA molecules to interact in an immune response. In order to investigate the hypothesis, we tested for linkage between IDDM and V genes encoded at either the TCR beta locus on chromosome 7 or the TCR alpha locus on chromosome 14, using 36 families with multiple affected sibs. No excess sharing of haplotypes defined by V alpha or V beta gene RFLPs was observed in affected sib pairs from IDDM families. We also studied unrelated IDDM patients (N = 73) and controls (N = 45) with the C beta RFLP but were unable to confirm the reported association even when the sample was stratified by HLA-DR type. Our results are incompatible with close linkage, in the majority of families, between either the TCR alpha or TCR beta locus and a gene making a major contribution to susceptibility to IDDM. 1-hop neighbor's text information:Title: The role of HLA class II genes in insulin-dependent diabetes mellitus: molecular analysis of 180 Caucasian, multiplex families. Abstract: We report here our analysis of HLA class II alleles in 180 Caucasian nuclear families with at least two children with insulin-dependent diabetes mellitus (IDDM). DRB1, DQA1, DQB1, and DPB1 genotypes were determined with PCR/sequence-specific oligonucleotide probe typing methods. The data allowed unambiguous determination of four-locus haplotypes in all but three of the families. Consistent with other studies, our data indicate an increase in DR3/DR4, DR3/DR3, and DR4/DR4 genotypes in patients compared to controls. In addition, we found an increase in DR1/DR4, DR1/DR3, and DR4/DR8 genotypes. While the frequency of DQB10302 on DR4 haplotypes is dramatically increased in DR3/DR4 patients, DR4 haplotypes in DR1/DR4 patients exhibit frequencies of DQB10302 and DQB10301 more closely resembling those in control populations. The protective effect of DR2 is evident in this data set and is limited to the common DRB11501-DQB10602 haplotype. Most DR2+ patients carry the less common DR2 haplotype DRB11601-DQB10502, which is not decreased in patients relative to controls. DPB1 also appears to play a role in disease susceptibility. DPB10301 is increased in patients (P < .001) and may contribute to the disease risk of a number of different DR-DQ haplotypes. DPB10101, found almost exclusively on DR3 haplotypes in patients, is slightly increased, and maternal transmissions of DRB10301-DPB10101 haplotypes to affected children occur twice as frequently as do paternal transmissions. Transmissions of DR3 haplotypes carrying other DPB1 alleles occur at approximately equal maternal and paternal frequencies. The complex, multigenic nature of HLA class II-associated IDDM susceptibility is evident from these data. 1-hop neighbor's text information:Title: The aggregation of the 5' insulin gene polymorphism in insulin dependent (type I) diabetes mellitus families. Abstract: Population studies have suggested an increased frequency of small DNA insertions (class I alleles) 5' to the insulin gene in insulin dependent (type I) diabetes mellitus (IDDM). The present study examined this relationship within families. Forty-one families with at least one diabetic offspring were studied. Analysis of the insulin gene polymorphism was performed by digestion of DNA with Bg1I, SstI, RsaI, or PvuII and hybridisation with an insulin gene probe or polymorphic region specific probes. An increased frequency of class I alleles was found among the parents of diabetics (p = 0.02), as well as a trend towards increased frequency of parents homozygous for class I alleles and matings of two homozygous subjects. This increased homozygosity for class I alleles was present in non-diabetic sibs as well (p = 0.01). These results show that ascertainment through an offspring with IDDM selects for families with high frequencies of homozygosity for the class I allele and thus suggests that the insulin gene polymorphism is indeed providing part of the genetic predisposition to IDDM. When the major portion of genetic predisposition is provided by other genes (estimates are that HLA accounts for 30 to 70% in IDDM), identification of additional susceptibility genes becomes difficult. Even when formal linkage analysis is uninformative, our studies indicate that analysis for aggregation of specific alleles within families is a useful approach to this problem. 2-hop neighbor's text information:Title: Implication of specific DQB1 alleles in genetic susceptibility and resistance by identification of IDDM siblings with novel HLA-DQB1 allele and unusual DR2 and DR1 haplotypes. Abstract: Genetic susceptibility to insulin-dependent diabetes mellitus (IDDM) is associated with the HLA-DR3 and DR4 haplotypes. The HLA-DR2 haplotype is negatively associated with IDDM, an association that has been interpreted as dominant protection. Here, we describe the molecular analysis of the HLA class II genes in an unusual family with three HLA-DR1/2 siblings, all of whom have IDDM. With polymerase chain reaction amplification and sequence analysis to characterize the class II alleles, we identified a novel DQB1 allele on the DR1 haplotype and an unusual DQB1 allele on the DR2 haplotype. However, the DRB1 alleles on these DR1 and DR2 haplotypes are the conventional alleles (0101 and 1501, respectively). These results suggest that it is the conventional DQB1 allele (0602) not the DRB1 allele (1501) on the protective DR2 haplotype that confers protection in the general population and, furthermore, that these unusual DQB1 alleles may confer susceptibility to IDDM in this family. The unusual DQB1 allele on this DR2 haplotype encodes Asp at position 57, indicating that it is the allele DQB10602 and not simply the presence of this residue that is responsible for the protective effect. 2-hop neighbor's text information:Title: Measuring the genetic contribution of a single locus to a multilocus disease. Abstract: An increasing number of diseases are being demonstrated to be due to determinants at more than one genetic locus. It thus becomes of interest to determine the genetic contribution of a specific single locus. A method of estimating a "coefficient of genetic contribution" is described herein, based on a comparison of monozygotic twin concordance data for a specific disease, the empirical sibling recurrence risks, and the sharing of identical by descent genes at the specific locus of interest by pairs of siblings who are both affected. The value of the method is that it requires relatively few assumptions, and does not require knowledge of the mode of inheritance of disease susceptibility at the gene locus of interest. If there are major environmental determinants, this method will give a lower bound for the single locus of interest. To illustrate the method, it is applied to two specific diseases, insulin dependent diabetes mellitus (IDDM) and gluten-sensitive enteropathy (GSE), and a specific locus, the HLA gene complex. The best estimates would appear to be that the HLA "genes" provide a coefficient of 60% for IDDM susceptibilty, but only 30% for GSE. A possible reason for these differences is the markedly increased disease susceptibility of the DR3/DR4 heterozygote for IDDM. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1 1 1 1,1	2	pubmed	train	99
Title: Globalization, coca-colonization and the chronic disease epidemic: can the Doomsday scenario be averted? Abstract: There are at present approximately 110 million people with diabetes in the world but this number will reach over 220 million by the year 2010, the majority of them with type 2 diabetes. Thus there is an urgent need for strategies to prevent the emerging global epidemic of type 2 diabetes to be implemented. Tackling diabetes must be part of an integrated program that addresses lifestyle related disorders. The prevention and control of type 2 diabetes and the other major noncommunicable diseases (NCDs) can be cost- and health-effective through an integrated (i.e. horizontal) approach to noncommunicable diseases disease prevention and control. With the re-emergence of devastating communicable diseases including AIDS, the Ebola virus and tuberculosis, the pressure is on international and regional agencies to see that the noncommunicable disease epidemic is addressed. The international diabetes and public health communities need to adopt a more pragmatic view of the epidemic of type 2 diabetes and other noncommunicable diseases. The current situation is a symptom of globalization with respect to its social, cultural, economic and political significance. Type 2 diabetes will not be prevented by traditional medical approaches; what is required are major and dramatic changes in the socio-economic and cultural status of people in developing countries and the disadvantaged, minority groups in developed nations. The international diabetes and public health communities must lobby and mobilize politicians, other international agencies such as UNDP, UNICEF, and the World Bank as well as other international nongovernmental agencies dealing with the noncommunicable diseases to address the socio-economic, behavioural, nutritional and public health issues that have led to the type 2 diabetes and noncommunicable diseases epidemic. A multidisciplinary Task Force representing all parties which can contribute to a reversal of the underlying socio-economic causes of the problem is an urgent priority. 1-hop neighbor's text information:Title: Duration of breast-feeding and the incidence of type 2 diabetes mellitus in the Shanghai Women's Health Study. Abstract: AIMS/HYPOTHESIS: The aim of this study was to examine the association between lifetime breast-feeding and the incidence of type 2 diabetes mellitus in a large population-based cohort study of middle-aged women. METHODS: This was a prospective study of 62,095 middle-aged parous women in Shanghai, China, who had no prior history of type 2 diabetes mellitus, cancer or cardiovascular disease at study recruitment. Breast-feeding history, dietary intake, physical activity and anthropometric measurements were assessed by in-person interviews. The Cox regression model was employed to evaluate the association between breast-feeding and the risk of type 2 diabetes mellitus. RESULTS: After 4.6 years of follow-up, 1,561 women were diagnosed with type 2 diabetes mellitus. Women who had breastfed their children tended to have a lower risk of diabetes mellitus than those who had never breastfed [relative risk (RR)=0.88; 95% CI, 0.76-1.02; p=0.08]. Increasing duration of breast-feeding was associated with a reduced risk of type 2 diabetes mellitus. The fully adjusted RRs for lifetime breast-feeding duration were 1.00, 0.88, 0.89, 0.88, 0.75 and 0.68 (p trend=0.01) for 0, >0 to 0.99, >0.99 to 1.99, >1.99 to 2.99, >2.99 to 3.99 and >or=4 years in analyses adjusted for age, daily energy intake, BMI, WHR, smoking, alcohol intake, physical activity, occupation, income level, education level, number of live births and presence of hypertension at baseline. CONCLUSIONS/INTERPRETATION: Breast-feeding may protect parous women from developing type 2 diabetes mellitus later in life. 1-hop neighbor's text information:Title: Legume and soy food intake and the incidence of type 2 diabetes in the Shanghai Women's Health Study. Abstract: BACKGROUND: It has been postulated that a diet high in legumes may be beneficial for the prevention of type 2 diabetes mellitus (type 2 DM). However, data linking type 2 DM risk and legume intake are limited. OBJECTIVE: The objective of the study was to examine the association between legume and soy food consumption and self-reported type 2 DM. DESIGN: The study was conducted in a population-based prospective cohort of middle-aged Chinese women. We followed 64,227 women with no history of type 2 DM, cancer, or cardiovascular disease at study recruitment for an average of 4.6 y. Participants completed in-person interviews that collected information on diabetes risk factors, including dietary intake and physical activity in adulthood. Anthropometric measurements were taken. Dietary intake was assessed with a validated food-frequency questionnaire at the baseline survey and at the first follow-up survey administered 2-3 y after study recruitment. RESULTS: We observed an inverse association between quintiles of total legume intake and 3 mutually exclusive legume groups (peanuts, soybeans, and other legumes) and type 2 DM incidence. The multivariate-adjusted relative risk of type 2 DM for the upper quintile compared with the lower quintile was 0.62 (95% CI: 0.51, 0.74) for total legumes and 0.53 (95% CI: 0.45, 0.62) for soybeans. The association between soy products (other than soy milk) and soy protein consumption (protein derived from soy beans and their products) with type 2 DM was not significant. CONCLUSIONS: Consumption of legumes, soybeans in particular, was inversely associated with the risk type 2 DM. 1-hop neighbor's text information:Title: Exercise therapy in type 2 diabetes. Abstract: Structured exercise is considered an important cornerstone to achieve good glycemic control and improve cardiovascular risk profile in Type 2 diabetes. Current clinical guidelines acknowledge the therapeutic strength of exercise intervention. This paper reviews the wide pathophysiological problems associated with Type 2 diabetes and discusses the benefits of exercise therapy on phenotype characteristics, glycemic control and cardiovascular risk profile in Type 2 diabetes patients. Based on the currently available literature, it is concluded that Type 2 diabetes patients should be stimulated to participate in specifically designed exercise intervention programs. More attention should be paid to cardiovascular and musculoskeletal deconditioning as well as motivational factors to improve long-term treatment adherence and clinical efficacy. More clinical research is warranted to establish the efficacy of exercise intervention in a more differentiated approach for Type 2 diabetes subpopulations within different stages of the disease and various levels of co-morbidity. 2-hop neighbor's text information:Title: The cost-effectiveness of lifestyle modification or metformin in preventing type 2 diabetes in adults with impaired glucose tolerance. Abstract: BACKGROUND: The Diabetes Prevention Program (DPP) demonstrated that interventions can delay or prevent the development of type 2 diabetes. OBJECTIVE: To estimate the lifetime cost-utility of the DPP interventions. DESIGN: Markov simulation model to estimate progression of disease, costs, and quality of life. DATA SOURCES: The DPP and published reports. TARGET POPULATION: Members of the DPP cohort 25 years of age or older with impaired glucose tolerance. TIME HORIZON: Lifetime. PERSPECTIVES: Health system and societal. INTERVENTIONS: Intensive lifestyle, metformin, and placebo interventions as implemented in the DPP. OUTCOME MEASURES: Cumulative incidence of diabetes, microvascular and neuropathic complications, cardiovascular complications, survival, direct medical and direct nonmedical costs, quality-adjusted life-years (QALYs), and cost per QALY. RESULTS OF BASE-CASE ANALYSIS: Compared with the placebo intervention, the lifestyle and metformin interventions were estimated to delay the development of type 2 diabetes by 11 and 3 years, respectively, and to reduce the absolute incidence of diabetes by 20% and 8%, respectively. The cumulative incidence of microvascular, neuropathic, and cardiovascular complications were reduced and survival was improved by 0.5 and 0.2 years. Compared with the placebo intervention, the cost per QALY was approximately 1100 dollars for the lifestyle intervention and $31 300 for the metformin intervention. From a societal perspective, the interventions cost approximately 8800 dollars and 29,900 dollars per QALY, respectively. From both perspectives, the lifestyle intervention dominated the metformin intervention. RESULTS OF SENSITIVITY ANALYSIS: Cost-effectiveness improved when the interventions were implemented as they might be in routine clinical practice. The lifestyle intervention was cost-effective in all age groups. The metformin intervention did not represent good use of resources for persons older than 65 years of age. LIMITATIONS: Simulation results depend on the accuracy of the underlying assumptions, including participant adherence. CONCLUSIONS: Health policy should promote diabetes prevention in high-risk individuals. 2-hop neighbor's text information:Title: Barriers to physical activity in patients with diabetes. Abstract: PURPOSE: Two questions were addressed: (1) How much physical activity do patients with diabetes perform? (2) What are the perceived factors that prevent patients from doing more physical activity? RESEARCH DESIGN AND METHODS: Interview based questionnaires were distributed to consecutive patients attending the Diabetes Clinic, Ninewells Hospital, Dundee over a period of five months. Exclusion criteria were age below 20 years and inadequate understanding of English; 428 questionnaires were given out with 406 completed. RESULTS: Physical activity was undertaken by 34% of patients with diabetes and only 9% of these patients exercised sufficiently to achieve a large change in heart rate or breathing. The main reasons for inactivity included perceived difficulty taking part in exercise, feelings of tiredness, and being distracted by something good on television. Lack of time and lack of local facilities also contributed. CONCLUSIONS: Few patients with diabetes participate in physical activity, and in those who do the level of intensity is low. There are many modifiable factors distracting patients from exercise. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2 2 2 2 1,2	2	pubmed	train	103
Title: Relationships between angiotensin I converting enzyme gene polymorphism, plasma levels, and diabetic retinal and renal complications. Abstract: Insulin-dependent diabetes mellitus (IDDM), cardiovascular morbidity, and vital prognosis are linked to diabetic nephropathy, which is probably determined by renal hemodynamic abnormalities and by a genetic predisposition. Angiotensin I converting enzyme (ACE) regulates systemic and renal circulations through angiotensin II formation and kinins metabolism. Plasma and cellular ACE levels are genetically determined; an insertion/deletion polymorphism of the ACE gene is strongly associated with ACE levels, subjects homozygote for insertion (genotype II) having the lowest plasma values. We studied the relationship between the ACE gene polymorphism or plasma levels and microcirculatory disorders of IDDM through two independent studies: one involved 57 subjects with or without diabetic retinopathy, and the other compared 62 IDDM subjects with diabetic nephropathy to 62 diabetic control subjects with the same characteristics (including retinopathy severity) but with normal kidney function. The ACE genotype distribution was not different in diabetic subjects with or without retinopathy and in a healthy population. Conversely, an imbalance of ACE genotype distribution, with a low proportion of II subjects, was observed in IDDM subjects with diabetic nephropathy compared with their control subjects (P = 0.006). Plasma ACE levels were mildly elevated in all diabetic groups, independently of retinopathy, but they were higher in subjects with nephropathy than in those without nephropathy (P = 0.0022). The II genotype of ACE gene is a marker for reduced risk for diabetic nephropathy. 1-hop neighbor's text information:Title: Contribution of genetic polymorphism in the renin-angiotensin system to the development of renal complications in insulin-dependent diabetes: Genetique de la Nephropathie Diabetique (GENEDIAB) study group. Abstract: Diabetic nephropathy is a glomerular disease due to uncontrolled diabetes and genetic factors. It can be caused by glomerular hypertension produced by capillary vasodilation, due to diabetes, against constitutional glomerular resistance. As angiotensin II increases glomerular pressure, we studied the relationship between genetic polymorphisms in the renin-angiotensin system-angiotensin I converting enzyme (ACE), angiotensinogen (AGT), and angiotensin II, subtype 1, receptor-and the renal involvement of insulin-dependent diabetic subjects with proliferative retinopathy: those exposed to the risk of nephropathy due to diabetes. Of 494 subjects recruited in 17 centers in France and Belgium (GENEDIAB Study), 157 (32%) had no nephropathy, 104 (21%) incipient (microalbuminuria), 126 (25 %) established (proteinuria), and 107 (22%) advanced (plasma creatinine > or = 150 micromol/liter or renal replacement therapy) nephropathy. The severity of renal involvement was associated with ACE insertion/deletion (I/D) polymorphism: chi2 for trend 5.135, P = 0.023; adjusted odds ratio attributable to the D allele 1.889 (95% CI 1.209-2.952, P = 0.0052). Renal involvement was not directly linked to other polymorphisms. However, ACE I-D and AGT M235T polymorphisms interacted significantly (P = 0.0166): in subjects with ACE ID and DD genotypes, renal involvement increased from the AGT MM to TT genotypes. Thus, genetic determinants that affect renal angiotensin II and kinin productions are risk factors for the progression of glomerular disease in uncontrolled insulin-dependent diabetic patients. 1-hop neighbor's text information:Title: Role of glycaemic control in development of microalbuminuria in patients with insulin dependent diabetes. Abstract: OBJECTIVE: To ascertain which factors determine the progression from very low rates of albumin excretion to persistent microalbuminuria in patients with insulin dependent diabetes mellitus. DESIGN: A 10 year prospective study of a cohort of diabetic patients. SETTING: Outpatient department of the Portsmouth District Hospitals. SUBJECTS: 97 patients with insulin dependent diabetes mellitus who were initially free of microalbuminuria and hypertension. MAIN OUTCOME MEASURE: Urinary albumin: creatinine ratio. RESULTS: Eight of the 97 patients had developed microalbuminuria (urinary albumin:creatinine ratio > 3 mg/mmol in three consecutive early morning samples) by the 10 year follow up. The group who developed microalbuminuria had higher baseline log10 plasma glucose concentrations (mean (SD), 1.210 (0.122) v 0.984 (0.196) mmol/l, P < 0.001) and glycated haemoglobin concentrations (1.112% (0.069%) v 0.997% (0.076%), P < 0.001) and a younger age at onset of diabetes (10.0 (5.5) v 15.6 (7.8) years, P < 0.05). There was no difference in baseline duration of diabetes, smoking, sex, insulin dose, body mass index, serum creatinine concentration, or systolic, diastolic, or mean arterial blood pressure between the two groups. Multiple linear regression analysis showed that urinary albumin:creatinine ratio at 10 years was influenced by initial albumin:creatinine ratio (P = 0.006), initial glycated haemoglobin concentration (P = 0.002), and duration of diabetes (P = 0.045). Genotype for angiotensin converting enzyme was not related to the development of microalbuminuria nor, in a larger group of patients, the presence of any degree of diabetic nephropathy. CONCLUSION: In patients with insulin dependent diabetes mellitus the progression of minimal albuminuria and the development of microalbuminuria is determined primarily by poor long term glycaemic control. There is a weaker relation with longer duration of disease and younger age at onset of diabetes, but blood pressure does not seem to be implicated. Gene polymorphism for angiotensin converting enzyme is not linked to the development of microalbuminuria or established diabetic nephropathy. 1-hop neighbor's text information:Title: Prognostic value of the insertion/deletion polymorphism of the ACE gene in type 2 diabetic subjects: results from the Non-insulin-dependent Diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR), Diabete de type 2, Nephropathie et Genetique (DIAB2NEPHROGENE), and Survie, Diabete de type 2 et Genetique (SURDIAGENE) studies. Abstract: OBJECTIVE: We tested whether determination of the ACE insertion/deletion polymorphism is useful for renal and cardiovascular prognoses of type 2 diabetic subjects. RESEARCH DESIGN AND METHODS: The French participants (3,126 of 4,912) in the Non-Insulin-Dependent Diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR) trial were studied for their prognosis over 4 years according to their ACE insertion/deletion polymorphism. We used two cohorts of French type 2 diabetic patients for replication: a 3-year follow-up study (n = 917; Survie, Diabete de type 2 et Genetique [SURDIAGENE] study) and a case-control study on diabetic nephropathy (n = 1,277; Diabete de type 2, Nephropathie et Genetique [DIAB2NEPHROGENE] study). We investigated the effect of the insertion/deletion polymorphism on the primary outcome in the DIABHYCAR trial (defined as the first of the following events to occur: cardiovascular death, nonfatal myocardial infarction, stroke, heart failure leading to hospital admission, or end-stage renal failure) and its components. RESULTS: In DIABHYCAR, the primary outcome and most of its components were not affected by the ACE insertion/deletion genotype. Only renal outcome was favored by the I allele (P = 0.03). The risk of myocardial infarction was not affected by ACE genotype, but the probability of fatal outcome increased with the number of D alleles (P < 0.03). In SURDIAGENE, the association between the ACE I allele and renal outcome was not replicated. In DIAB2NEPHROGENE, no association was found with nephropathy. CONCLUSIONS: We were not able to demonstrate the manifest usefulness of the ACE insertion/deletion polymorphism for the prognosis of type 2 diabetic subjects. 2-hop neighbor's text information:Title: Familial factors determine the development of diabetic nephropathy in patients with IDDM. Abstract: To evaluate familial factors in the development of diabetic nephropathy in insulin-dependent diabetes mellitus (IDDM) we examined concordance for diabetic nephropathy in families with multiple IDDM siblings. Families (n = 110) were identified through Joslin Clinic patients (probands) with a sibling having IDDM. To be eligible, the probands' and siblings' ages at IDDM diagnosis were less than 21 years, and IDDM duration was more than 15 years for probands and more than 10 years for siblings. Mean post-pubertal diabetes duration was 23 years for probands (n = 110) and 21 years for siblings (n = 125). Nephropathy history was determined by medical record review for deceased patients and those with persistent proteinuria or end-stage renal disease to ascertain the date of onset of persistent proteinuria. For patients without documented nephropathy, the albumin/creatinin ratio was measured in multiple urine samples. The cumulative incidence of persistent proteinuria according to post-pubertal duration of IDDM was determined by life-table analysis. For probands and siblings combined, the cumulative incidence of advanced diabetic nephropathy after 30 years of IDDM was 35%, but the risk in siblings varied according to the proband's renal status. The cumulative risk in siblings after 25 years of IDDM (post-puberty) was 71.5% if the proband had persistent proteinuria but only 25.4% if the proband did not (p < 0.001). A difference of nearly 50% in the risk to IDDM siblings, depending upon the IDDM proband's renal status, is consistent with a major gene effect that predisposes an individual with IDDM to develop advanced diabetic nephropathy. 2-hop neighbor's text information:Title: The DIAB-HYCAR Study. Abstract: Microalbuminuria and proteinuria are strong independent predictors for increased cardiovascular mortality in non-insulin-dependent diabetic (NIDDM) patients. In such patients, angiotensin converting enzyme (ACE) inhibition improves the evolution of diabetic nephropathy; however, no data are currently available on the effects of such intervention on cardiovascular morbidity and mortality. The aim of the Diab-Hycar study is to test the hypothesis that ACE inhibition with a low daily dose of 1.25 mg ramipril, which has no significant effect on blood pressure, may reduce cardiovascular morbidity and/or mortality in normotensive or hypertensive NIDDM patients with persistent albuminuria. Selected and followed by general practitioners, 4000 patients will receive their usual oral antidiabetic treatment and if necessary antihypertensive treatment (ACE inhibitors excluded). In addition in a randomized, double-blind trial they will be given either a placebo or 1.25 mg ramipril daily. The follow-up is currently scheduled to last 3 years. The efficacy of ACE-inhibition will be assessed by the following major end-points: cardiovascular death, sudden death, myocardial infarction, stroke, renal replacement therapy. The Diab-Hycar study started on 3 February 1995. By 1 September 1995, 11,000 urine samples were tested. The prevalence of persistent albuminuria was 23%, 964 patients were initially included in the study, with 619 eligible patients included soon after. Different strategies have been developed to record cardiovascular events correctly and to minimize the number of patients lost to follow-up. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1 2 1 2,1	2	pubmed	train	105
Title: IL-1alpha, IL-1beta, and IFN-gamma mark beta cells for Fas-dependent destruction by diabetogenic CD4(+) T lymphocytes. Abstract: Cytokines such as IL-1alpha, IL-1beta, and IFN-gamma have long been implicated in the pathogenesis of autoimmune diabetes, but the mechanisms through which they promote diabetogenesis remain unclear. Here we show that CD4(+) T lymphocytes propagated from transgenic nonobese diabetic (NOD) mice expressing the highly diabetogenic, beta cell-specific 4.1-T-cell receptor (4.1-TCR) can kill IL-1alpha-, IL-1beta-, and IFN-gamma-treated beta cells from NOD mice. Untreated NOD beta cells and cytokine-treated beta cells from Fas-deficient NOD.lpr mice are not targeted by these T cells. Killing of islet cells in vitro was associated with cytokine-induced upregulation of Fas on islet cells and was independent of MHC class II expression. Abrogation of Fas expression in 4.1-TCR-transgenic NOD mice afforded nearly complete protection from diabetes and did not interfere with the development of the transgenic CD4(+) T cells or with their ability to cause insulitis. In contrast, abrogation of perforin expression did not affect beta cell-specific cytotoxicity or the diabetogenic potential of these T cells. These data demonstrate a novel mechanism of action of IL-1alpha, IL-1beta, and IFN-gamma in autoimmune diabetes, whereby these cytokines mark beta cells for Fas-dependent lysis by autoreactive CD4(+) T cells. 1-hop neighbor's text information:Title: Adenovirus early region 3 transgenes expressed in beta cells prevent autoimmune diabetes in nonobese diabetic mice: effects of deleting the adenovirus death protein 11.6K. Abstract: The incidence of type 1 diabetes (T1D) is decreased in nonobese diabetic mice expressing the complete cassette of adenovirus early region 3 (E3) immunomodulating genes in pancreatic beta cells. Embedded among the antiapoptotic E3 genes is one encoding an adenovirus death protein (ADP), which contributes to release of virion particles by promoting cell lysis. Because removal of this proapoptotic protein might have further enhanced the ability of E3 proteins to prevent T1D, an ADP-inactivated E3 construct was tested. Significantly, deletion of ADP did not improve the diabetes-protective effect of an E3 gene cassette. 1-hop neighbor's text information:Title: CD4 T cells, lymphopenia, and IL-7 in a multistep pathway to autoimmunity. Abstract: There are many inhibitory mechanisms that function at the cellular and molecular levels to maintain tolerance. Despite this, self-reactive clones escape regulatory mechanisms and cause autoimmunity in certain circumstances. We hypothesized that the same mechanisms that permit T cells to expand during homeostatic proliferation may inadvertently promote autoimmunity under certain conditions. One major homeostatic cytokine is IL-7, and studies have linked it or its receptor to the development of multiple sclerosis and other autoimmune diseases. We show in a model of beta-islet cell self-reactivity that the transfer of activated autoreactive CD4 T cells can prime and expand endogenous autoreactive CD8 T cells in a CD28- and CD40-dependent manner through the licensing of dendritic cells. Despite this, mice do not develop diabetes. However, the provision of exogenous IL-7 or the physiological production of IL-7 associated with lymphopenia was able to profoundly promote the expansion of self-reactive clones even in the presence of regulatory T cells. Autoimmune diabetes rapidly ensued with CD4 help and the subsequent activation of CD8 T cells, which contributed to disease progression. With the advent of many biologicals targeting TNFalpha, IL-6, and IL-1 and their effective use in the treatment of autoimmune diseases, we propose that IL-7 and its receptor may be promising targets for biological agents in the treatment of autoimmunity. 1-hop neighbor's text information:Title: Reduced incidence and delayed onset of diabetes in perforin-deficient nonobese diabetic mice. Abstract: To investigate the role of T cell-mediated, perforin-dependent cytotoxicity in autoimmune diabetes, perforin-deficient mice were backcrossed with the nonobese diabetes mouse strain. It was found that the incidence of spontaneous diabetes over a 1 yr period was reduced from 77% in perforin +/+ control to 16% in perforin-deficient mice. Also, the disease onset was markedly delayed (median onset of 39.5 versus 19 wk) in the latter. Insulitis with infiltration of CD4(+) and CD8(+) T cells occurred similarly in both groups of animals. Lower incidence and delayed disease onset were also evident in perforin-deficient mice when diabetes was induced by cyclophosphamide injection. Thus, perforin-dependent cytotoxicity is a crucial effector mechanism for beta cell elimination by cytotoxic T cells in autoimmune diabetes. However, in the absence of perforin chronic inflammation of the islets can lead to diabetogenic beta cell loss by less efficient secondary effector mechanisms. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1 1,1	1	pubmed	train	106
Title: Extracellular matrix protein-coated scaffolds promote the reversal of diabetes after extrahepatic islet transplantation. Abstract: BACKGROUND: The survival and function of transplanted pancreatic islets is limited, owing in part to disruption of islet-matrix attachments during the isolation procedure. Using polymer scaffolds as a platform for islet transplantation, we investigated the hypothesis that replacement of key extracellular matrix components known to surround islets in vivo would improve graft function at an extrahepatic implantation site. METHODS: Microporous polymer scaffolds fabricated from copolymers of lactide and glycolide were adsorbed with collagen IV, fibronectin, laminin-332 or serum proteins before seeding with 125 mouse islets. Islet-seeded scaffolds were then implanted onto the epididymal fat pad of syngeneic mice with streptozotocin-induced diabetes. Nonfasting glucose levels, weight gain, response to glucose challenges, and histology were used to assess graft function for 10 months after transplantation. RESULTS: Mice transplanted with islets seeded onto scaffolds adsorbed with collagen IV achieved euglycemia fastest and their response to glucose challenge was similar to normal mice. Fibronectin and laminin similarly promoted euglycemia, yet required more time than collagen IV and less time than serum. Histopathological assessment of retrieved grafts demonstrated that coating scaffolds with specific extracellular matrix proteins increased total islet area in the sections and vessel density within the transplanted islets, relative to controls. CONCLUSIONS: Extracellular matrix proteins adsorbed to microporous scaffolds can enhance the function of transplanted islets, with collagen IV maximizing graft function relative to the other proteins tested. These scaffolds enable the creation of well-defined microenvironments that promote graft efficacy at extrahepatic sites. 1-hop neighbor's text information:Title: Five-year follow-up after clinical islet transplantation. Abstract: Islet transplantation can restore endogenous beta-cell function to subjects with type 1 diabetes. Sixty-five patients received an islet transplant in Edmonton as of 1 November 2004. Their mean age was 42.9 +/- 1.2 years, their mean duration of diabetes was 27.1 +/- 1.3 years, and 57% were women. The main indication was problematic hypoglycemia. Forty-four patients completed the islet transplant as defined by insulin independence, and three further patients received >16,000 islet equivalents (IE)/kg but remained on insulin and are deemed complete. Those who became insulin independent received a total of 799,912 +/- 30,220 IE (11,910 +/- 469 IE/kg). Five subjects became insulin independent after one transplant. Fifty-two patients had two transplants, and 11 subjects had three transplants. In the completed patients, 5-year follow-up reveals that the majority ( approximately 80%) have C-peptide present post-islet transplant, but only a minority ( approximately 10%) maintain insulin independence. The median duration of insulin independence was 15 months (interquartile range 6.2-25.5). The HbA(1c) (A1C) level was well controlled in those off insulin (6.4% [6.1-6.7]) and in those back on insulin but C-peptide positive (6.7% [5.9-7.5]) and higher in those who lost all graft function (9.0% [6.7-9.3]) (P < 0.05). Those who resumed insulin therapy did not appear more insulin resistant compared with those off insulin and required half their pretransplant daily dose of insulin but had a lower increment of C-peptide to a standard meal challenge (0.44 +/- 0.06 vs. 0.76 +/- 0.06 nmol/l, P < 0.001). The Hypoglycemic score and lability index both improved significantly posttransplant. In the 128 procedures performed, bleeding occurred in 15 and branch portal vein thrombosis in 5 subjects. Complications of immunosuppressive therapy included mouth ulcers, diarrhea, anemia, and ovarian cysts. Of the 47 completed patients, 4 required retinal laser photocoagulation or vitrectomy and 5 patients with microalbuminuria developed macroproteinuria. The need for multiple antihypertensive medications increased from 6% pretransplant to 42% posttransplant, while the use of statin therapy increased from 23 to 83% posttransplant. There was no change in the neurothesiometer scores pre- versus posttransplant. In conclusion, islet transplantation can relieve glucose instability and problems with hypoglycemia. C-peptide secretion was maintained in the majority of subjects for up to 5 years, although most reverted to using some insulin. The results, though promising, still point to the need for further progress in the availability of transplantable islets, improving islet engraftment, preserving islet function, and reducing toxic immunosuppression. 1-hop neighbor's text information:Title: Reversal of diabetes by pancreatic islet transplantation into a subcutaneous, neovascularized device. Abstract: BACKGROUND: Transplantation of pancreatic islets for the treatment of type 1 diabetes allows for physiologic glycemic control and insulin-independence when sufficient islets are implanted via the portal vein into the liver. Intrahepatic islet implantation requires specific infrastructure and expertise, and risks inherent to the procedure include bleeding, thrombosis, and elevation of portal pressure. Additionally, the relatively higher drug metabolite concentrations in the liver may contribute to the delayed loss of graft function of recent clinical trials. Identification of alternative implantation sites using biocompatible devices may be of assistance improving graft outcome. A desirable bioartificial pancreas should be easy to implant, biopsy, and retrieve, while allowing for sustained graft function. The subcutaneous (SC) site may require a minimally invasive procedure performed under local anesthesia, but its use has been hampered so far by lack of early vascularization, induction of local inflammation, and mechanical stress on the graft. METHODS: Chemically diabetic rats received syngeneic islets into the liver or SC into a novel biocompatible device consisting of a cylindrical stainless-steel mesh. The device was implanted 40 days prior to islet transplantation to allow embedding by connective tissue and neovascularization. Reversal of diabetes and glycemic control was monitored after islet transplantation. RESULTS: Syngeneic islets transplanted into a SC, neovascularized device restored euglycemia and sustained function long-term. Removal of graft-bearing devices resulted in hyperglycemia. Explanted grafts showed preserved islets and intense vascular networks. CONCLUSIONS: Ease of implantation, biocompatibility, and ability to maintain long-term graft function support the potential of our implantable device for cellular-based reparative therapies. 1-hop neighbor's text information:Title: Management of insulin-dependent diabetes mellitus. Abstract: Insulin therapy has been lifesaving for patients with insulin-dependent diabetes mellitus. Unfortunately, longer lifespan has unmasked microvascular, neurological and macrovascular complications that result in profound morbidity and increased mortality. Driven by the conviction that better physiological control of glycaemic levels will prevent and/or ameliorate long term complications, and by the desire to make diabetes care as user-friendly as possible, clinical research efforts have led to the development of new treatment methods with the aim of achieving near normal metabolic control. Such methods include the use of self monitoring, multiple daily insulin injection regimens, external and implantable insulin pumps, and whole organ pancreas and isolated islet cell transplantation. In addition, dietary manipulation, including the use of alpha-glucosidase inhibitors, has played a role in controlling glycaemia. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 0 1,0	1	pubmed	train	107
Title: Advanced glycation end products cause increased CCN family and extracellular matrix gene expression in the diabetic rodent retina. Abstract: AIMS/HYPOTHESIS: Referred to as CCN, the family of growth factors consisting of cystein-rich protein 61 (CYR61, also known as CCN1), connective tissue growth factor (CTGF, also known as CCN2), nephroblastoma overexpressed gene (NOV, also known as CCN3) and WNT1-inducible signalling pathway proteins 1, 2 and 3 (WISP1, -2 and -3; also known as CCN4, -5 and -6) affects cellular growth, differentiation, adhesion and locomotion in wound repair, fibrotic disorders, inflammation and angiogenesis. AGEs formed in the diabetic milieu affect the same processes, leading to diabetic complications including diabetic retinopathy. We hypothesised that pathological effects of AGEs in the diabetic retina are a consequence of AGE-induced alterations in CCN family expression. MATERIALS AND METHODS: CCN gene expression levels were studied at the mRNA and protein level in retinas of control and diabetic rats using real-time quantitative PCR, western blotting and immunohistochemistry at 6 and 12 weeks of streptozotocin-induced diabetes in the presence or absence of aminoguanidine, an AGE inhibitor. In addition, C57BL/6 mice were repeatedly injected with exogenously formed AGE to establish whether AGE modulate retinal CCN growth factors in vivo. RESULTS: After 6 weeks of diabetes, Cyr61 expression levels were increased more than threefold. At 12 weeks of diabetes, Ctgf expression levels were increased twofold. Treatment with aminoguanidine inhibited Cyr61 and Ctgf expression in diabetic rats, with reductions of 31 and 36%, respectively, compared with untreated animals. Western blotting showed a twofold increase in CTGF production, which was prevented by aminoguanidine treatment. In mice infused with exogenous AGE, Cyr61 expression increased fourfold and Ctgf expression increased twofold in the retina. CONCLUSIONS/INTERPRETATION: CTGF and CYR61 are downstream effectors of AGE in the diabetic retina, implicating them as possible targets for future intervention strategies against the development of diabetic retinopathy. 1-hop neighbor's text information:Title: Exercise-induced expression of angiogenic growth factors in skeletal muscle and in capillaries of healthy and diabetic mice. Abstract: BACKGROUND: Diabetes has negative, and exercise training positive, effects on the skeletal muscle vasculature, but the mechanisms are not yet fully understood. In the present experiment the effects of running exercise on the mRNA expression of pro- and antiangiogenic factors were studied in healthy and diabetic skeletal muscle. The responses in capillaries and muscle fibers, collected from the muscle with laser capture microdissection, were also studied separately. METHODS: Healthy and streptozotocin-induced diabetic mice were divided into sedentary and exercise groups. Exercise was a single bout of 1 h running on a treadmill. Gastrocnemius muscles were harvested 3 h and 6 h post exercise, and angiogenesis-related gene expressions were analyzed with real-time PCR. In addition to muscle homogenates, capillaries and muscle fibers were collected from the muscle with laser capture microdissection method and analyzed for vascular endothelial growth factor-A (VEGF-A) and thrombospondin-1 (TSP-1) mRNA expression. RESULTS: Of the proangiogenic factors, VEGF-A and VEGF receptor-2 (VEGFR-2) mRNA expression increased significantly (P < 0.05) in healthy skeletal muscle 6 h post exercise. VEGF-B also showed a similar trend (P = 0.08). No significant change was observed post exercise in diabetic muscles in the expression of VEGF-A, VEGFR-2 or VEGF-B. The expression of angiogenesis inhibitor TSP-1 and angiogenic extracellular matrix protein Cyr61 were significantly increased in diabetic muscles (P < 0.05-0.01). Capillary mRNA expression resembled that in the muscle homogenates, however, the responses were greater in capillaries compared to muscle homogenates and pure muscle fibers. CONCLUSION: The present study is the first to report the effects of a single bout of exercise on the expression of pro- and antiangiogenic factors in diabetic skeletal muscle, and it provides novel data about the separate responses in capillaries and muscle fibers to exercise and diabetes. Diabetic mice seem to have lower angiogenic responses to exercise compared to healthy mice, and they show markedly increased expression of angiogenesis inhibitor TSP-1. Furthermore, exercise-induced VEGF-A expression was shown to be greater in capillaries than in muscle fibers. 1-hop neighbor's text information:Title: Renal connective tissue growth factor induction in experimental diabetes is prevented by aminoguanidine. Abstract: The aim of this study was to determine whether aminoguanidine (AG), an inhibitor of advanced glycation, prevents expression of the profibrotic cytokine, connective tissue growth factor (CTGF), as well as accumulation of the previously reported CTGF-dependent matrix protein, fibronectin, in a model of experimental diabetic nephropathy. Diabetic animals were randomly allocated into groups receiving 32 wk of AG or vehicle. Diabetic rats showed increases in CTGF mRNA and protein expression as well as in advanced glycation end-product (AGE) and fibronectin immunostaining, compared with nondiabetic rats. In the diabetic kidney, the increase in CTGF gene and protein expression as well as expression of the extracellular matrix protein fibronectin were prevented by AG. To further explore the relationship between AGEs and mesangial CTGF and fibronectin production, cultured human mesangial cells were exposed in vitro to soluble AGE-BSA and carboxymethyl lysine-BSA, and this led to induction of both CTGF and fibronectin. On the basis of our in vitro findings in mesangial cells linking AGEs to CTGF expression, the known prosclerotic effects of CTGF, and the ability of AG to attenuate mesangial expansion, it is postulated that the antifibrotic effects of AG in this animal model may be partially mediated by CTGF. 1-hop neighbor's text information:Title: Connective tissue growth factor is necessary for retinal capillary basal lamina thickening in diabetic mice. Abstract: Experimental prevention of basal lamina (BL) thickening of retinal capillaries ameliorates early vascular changes caused by diabetes. Connective tissue growth factor (CTGF) is upregulated early in diabetes in the human retina and is a potent inducer of expression of BL components. We hypothesize that CTGF is causally involved in diabetes-induced BL thickening of retinal capillaries. To test this hypothesis, we compared the effects of streptozotocin (STZ)-induced diabetes on retinal capillary BL thickness between wild-type mice (CTGF+/+) and mice lacking one functional CTGF allele (CTGF+/-). Differences in BL thickness were calculated by quantitative analysis of electron microscopic images of transversally sectioned capillaries in and around the inner nuclear layer of the retina. We show that BL thickening was significant in diabetic CTGF+/+ mice compared with control CTGF+/+ mice, whereas diabetes did not significantly induce BL thickening in CTGF+/- mice. We conclude that CTGF expression is necessary for diabetes-induced BL thickening and suggest that reduction of CTGF levels may be protective against the development of diabetic retinopathy. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	0 0 0,0	1	pubmed	train	108
Title: Accelerated diabetes in non-obese diabetic (NOD) mice differing in incidence of spontaneous disease. Abstract: The NOD mouse is an established model of autoimmune diabetes mellitus. Various lines of NOD mice differ in their incidence of spontaneous diabetes, e.g. 93% of female NOD/Lt mice compared with 46% of female NOD/Wehi mice develop diabetes by 250 days. These two lines were studied under conditions which greatly accelerate the onset of hyperglycaemia. It was hoped that their responses to these manipulations would reveal characteristic differences which would increase our understanding of diabetes resistance in the low incidence NOD/Wehi line. One dose of 300 mg/kg of cyclophosphamide (CP) produced hyperglycaemia in 50% of NOD mice within 2 weeks in both lines. They were also equally susceptible to diabetes induced by splenocyte transfer at 21 days of age from prediabetic 150-day-old NOD/Lt or NOD/Wehi females. Five daily 40 mg/kg doses of streptozotocin (STZ) resulted in a severity of diabetes in the NOD mice greater than in C57BL or SJL/mice. While the incidence and severity of diabetes induced in the two NOD lines were similar, this appeared to be principally due to sensitivity to the toxic effects of STZ rather than its ability to exacerbate autoimmune beta cell destruction. It has previously been shown that it is possible to prevent diabetes in susceptible NOD mice with simple, relatively benign therapies and here we show that it is possible to induce diabetes in resistant animals at a rate indistinguishable from fully predisposed individuals. It therefore appears that the prediabetic NOD mouse is poised in an immunologically precarious state with the onset of disease being highly dependent on factors which exacerbate or moderate autoimmune destruction. 1-hop neighbor's text information:Title: Comparison of high- and low-diabetes-incidence NOD mouse strains. Abstract: The nonobese diabetic (NOD) mouse is a model of insulin-dependent diabetes mellitus. These mice develop insulinopenia and hyperglycemia secondary to beta-cell destruction, which is associated with insulitis and autoantibody production. We have two strains of NOD mice: a low-incidence strain (NOD/Wehi), in which less than 10% females and less than 1% males develop diabetes by 150 days despite intense insulitis, and a high-incidence strain (NOD/Lt), in which most females and many males develop diabetes by 150 days. This phenotypic difference has been maintained for 24 mo despite identical housing in our specific pathogen-free unit. Reciprocal skin grafting and allozyme electrophoresis have not identified a difference between the strains. Mixed-lymphocyte cultures were performed with splenic T-lymphocytes cultured with equal numbers of irradiated stimulator splenocytes for 3-6 days. NOD/Wehi mice demonstrated a heightened syngeneic mixed-lymphocyte response (SMLR), averaging 19% of the allogeneic response to CBA/CaHWehi cells. The response to NOD/Lt stimulator cells was not significantly different from the syngeneic response. In contrast, NOD/Lt mice had an SMLR similar to that of BALB/cAnBradleyWehi control mice, averaging 5% of the allogeneic response. NOD/Lt cells also responded similarly to NOD/Wehi stimulator cells and briskly to allogeneic cells. The heightened SMLR in NOD/Wehi mice may reflect active generation of suppressor function, and this may account for the low incidence of diabetes. 1-hop neighbor's text information:Title: Multiple low-dose streptozotocin-induced hyperglycemia and insulitis in C57BL mice: influence of inbred background, sex, and thymus. Abstract: Insulin-dependent diabetes induced in susceptible strains of mice by multiple, low-dose streptozotocin treatment has been proposed to entail a thymus-dependent, autoimmune destruction of beta cells. In this study, thymectomized and genetically athymic mice have been tested for susceptibility to streptozotocin. Thymectomy was performed on newborn (day 1) to 3-day-old C57BL/KsJ mice. At 8 wk of age, thymectomized and sham-operated mice of both sexes were tested for susceptibility to diabetes induction by multiple, low-dose streptozotocin treatment (35 mg/kg of body weight per day for 6 consecutive days). Thymectomy failed to block susceptibility of males to induction of severe hyperglycemia. Beta cell necrosis and inflammatory cell infiltrates (insulitis) were consistent histopathological features. In general, females-both thymus-intact and thymectomized-were less susceptible than males to streptozotocin-induced hyperglycemia, and females exhibited an equally severe insulitis by experimental day 14; thus, the detection of an underlying insulitis did not predict the development of a more severe hyperglycemia because most streptozotocin-treated females at experimental day 35 continued to show only a modest hyperglycemia (about 200 mg/dl) compared to males (>400 mg/dl). That streptozotocin-induced hyperglycemia could occur in the absence of an intact thymus was further demonstrated in genetically athymic C57BL/6J NIcrOu nu/nu males and thymus-intact +/? littermate controls. C57BL/6J mice were resistant to streptozotocin-induced insulitis. This study shows that the presence of insulitis does not necessarily presage onset of severe hyperglycemia (e.g., C57BL/KsJ females), and conversely, the presence of severe hyperglycemia after low-dose streptozotocin treatment is not necessarily diagnostic of an underlying insulitis (e.g., C57BL/6J +/? and nu/nu males). These data stress the need for caution in the interpretation of studies of streptozotocin-insulitis sensitivities of nude mice. 1-hop neighbor's text information:Title: The presence of splenic T cells specific for islet cell antigens in nonobese diabetic mice. Abstract: Nonobese diabetic (NOD) mice display a syndrome with dramatic clinical and pathological features similar to Type 1 diabetes in man. Mononuclear cells intensively infiltrate the pancreas (insulitis), mostly T cells taking part. However, the functional role and specificity of these cells are currently uncertain. We investigated the response of splenic T cells from NOD mice to islet cells, using interleukin 2 (IL-2) production and cell proliferation. Splenic T cells from NOD mice responded with IL-2 production and proliferation when both islet cell antigens from NOD mice and mitomycin C-treated spleen cells (source of antigen-presenting cells) from NOD mice or major histocompatibility complex (MHC)-compatible ILI mice were present. Splenic T cells could produce IL-2 in response to islet cells from sources other than the NOD mouse, but could not produce significantly this lymphokine in response to submandibular gland, gastric mucosal, liver, spleen, and ovarian cells from NOD mice. NOD T cells produced this antigen-specific response first when the mice were 8 weeks old, the response grew stronger until 20 weeks of age and then tapered off. The present study indicates the presence of T cells specific for islet cell antigens in the spleen of NOD mice and suggests that the antigen-specific T cell response increases in parallel with the development of insulitis. 2-hop neighbor's text information:Title: Insulin-dependent diabetes mellitus induced by subdiabetogenic doses of streptozotocin: obligatory role of cell-mediated autoimmune processes. Abstract: The role of thymic functions in the development of insulin-dependent diabetes was investigated in athymic nude (nu/nu) mice and euthymic heterozygous (+/nu) littermates of BALB/c origin treated with streptozotocin. The injection of a single high dose of streptozotocin (200 mg/kg body weight) induced rapid and permanent hyperglycemia in both nu/nu and +/nu mice. In contrast, the injection of the same total dose divided into multiple "subdiabetogenic" doses (40 mg/kg per day for 5 consecutive days) caused the development of delayed but progressive hyperglycemia only in the thymus-competent +/nu mice. Female mice of either genotype were significantly less susceptible to streptozotocin at both doses. Restoration of thymic immunity in nu/nu mice by thymus grafts also restored the susceptibility to the hyperglycemic effects of multiple low doses of streptozotocin. Moreover, splenic lymphocytes from +/nu mice previously made diabetic with the multiple low-dose injections of streptozotocin induced transient glucose intolerance in nu/nu mice. The ability of the diabetic spleen cells to transfer the diabetic state was abolished when the splenic lymphocytes were depleted of the T cells but not when they were depleted of B cells. These results provide direct proof that thymus-dependent functions play an obligatory etiologic role in the development of diabetes in mice treated with repeated subdiabetogenic doses of streptozotocin. These observations also add to the growing evidence that autoimmune amplification mechanisms may be critically involved in the etiology of juvenile-onset diabetes mellitus in humans. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	0 0 0 0,0	2	pubmed	train	109
Title: Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects. Abstract: Mutations in several genes encoding transcription factors of the hepatocyte nuclear factor (HNF) cascade are associated with maturity-onset diabetes of the young (MODY), a monogenic form of early-onset diabetes mellitus. The ability of the orphan nuclear receptor small heterodimer partner (SHP, NR0B2) to modulate the transcriptional activity of MODY1 protein, the nuclear receptor HNF-4alpha, suggested SHP as a candidate MODY gene. We screened 173 unrelated Japanese subjects with early-onset diabetes for mutations in this gene and found five different mutations (H53fsdel10, L98fsdel9insAC, R34X, A195S, and R213C) in 6 subjects as well as one apparent polymorphism (R216H), all present in the heterozygous state. Interestingly, all of the subjects with the mutations were mildly or moderately obese at onset of diabetes, and analysis of the lineages of these individuals indicated that the SHP mutations were associated with obesity rather than with diabetes. Therefore, an additional group of 101 unrelated nondiabetic subjects with early-onset obesity was screened for mutations in the SHP gene. Two of the previously observed mutations (R34X and A195S) and two additional mutations (R57W and G189E) were identified in 6 subjects, whereas no mutations were identified in 116 young nondiabetic lean controls (P = 0.0094). Functional studies of the mutant proteins show that the mutations result in the loss of SHP activity. These results suggest that genetic variation in the SHP gene contributes to increased body weight and reveal a pathway leading to this common metabolic disorder in Japanese. 1-hop neighbor's text information:Title: Phenotypic characteristics of early-onset autosomal-dominant type 2 diabetes unlinked to known maturity-onset diabetes of the young (MODY) genes. Abstract: OBJECTIVE: To investigate whether there are forms of early-onset autosomal-dominant type 2 diabetes that are distinct from typical maturity-onset diabetes of the young (MODY) and to characterize their phenotypic characteristics. RESEARCH DESIGN AND METHODS: The study included 220 affected subjects from 29 families in which early-onset type 2 diabetes occurred in multiple generations and was not linked to known MODY genes (MODY gene-negative families). All individuals underwent an oral glucose tolerance test and other clinical measurements aimed at investigating the underlying metabolic defect and the presence of diabetic complications. For comparison, 79 affected carriers of MODY3 (hepatocyte nuclear factor [HNF]-1 alpha) mutations were similarly examined. RESULTS: Subjects from MODY gene-negative pedigrees were diagnosed with diabetes at an older age (36 +/- 17 vs. 21 +/- 10 years, P = 0.0001) and were more frequently obese (52 vs. 18%, P = 0.0001) than MODY3 individuals. MODY gene-negative patients who were insulin treated required more exogenous insulin than did MODY3 subjects (0.7 +/- 0.4 vs. 0.45 +/- 0.2 U.kg-1.day-1, P = 0.04), despite similar C-peptide levels. Among subjects not treated with insulin, MODY gene-negative subjects had significantly higher serum insulin levels, both fasting (16.5 +/- 15 vs. 6.5 +/- 5 microU/ml, P = 0.027) and 2 h after a glucose load (53 +/- 44 vs. 11 +/- 10, P = 0.002). They also had higher serum triglycerides (P = 0.02), higher cholesterol levels (P = 0.02), more hypertension (P = 0.0001), and more nephropathy (P = 0.001). Differences persisted when families were matched for age at diagnosis. CONCLUSIONS: Our findings indicate the existence of forms of early-onset autosomal-dominant type 2 diabetes that are distinct from MODY and are frequently characterized by insulin resistance, similar to later-onset type 2 diabetes. Because of the Mendelian pattern of inheritance, the goal of identifying the genes involved in these forms of diabetes appears to be particularly feasible. 1-hop neighbor's text information:Title: Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3) Abstract: The disease non-insulin-dependent (type 2) diabetes mellitus (NIDDM) is characterized by abnormally high blood glucose resulting from a relative deficiency of insulin. It affects about 2% of the world's population and treatment of diabetes and its complications are an increasing health-care burden. Genetic factors are important in the aetiology of NIDDM, and linkage studies are starting to localize some of the genes that influence the development of this disorder. Maturity-onset diabetes of the young (MODY), a single-gene disorder responsible for 2-5% of NIDDM, is characterized by autosomal dominant inheritance and an age of onset of 25 years or younger. MODY genes have been localized to chromosomes 7, 12 and 20 (refs 5, 7, 8) and clinical studies indicate that mutations in these genes are associated with abnormal patterns of glucose-stimulated insulin secretion. The gene on chromosome 7 (MODY2) encodes the glycolytic enzyme glucokinases which plays a key role in generating the metabolic signal for insulin secretion and in integrating hepatic glucose uptake. Here we show that subjects with the MODY3-form of NIDDM have mutations in the gene encoding hepatocyte nuclear factor-1alpha (HNF-1alpha, which is encoded by the gene TCF1). HNF-1alpha is a transcription factor that helps in the tissue-specific regulation of the expression of several liver genes and also functions as a weak transactivator of the rat insulin-I gene. 1-hop neighbor's text information:Title: Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Abstract: The steady-state basal plasma glucose and insulin concentrations are determined by their interaction in a feedback loop. A computer-solved model has been used to predict the homeostatic concentrations which arise from varying degrees beta-cell deficiency and insulin resistance. Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment of the contributions of insulin resistance and deficient beta-cell function to the fasting hyperglycaemia (homeostasis model assessment, HOMA). The accuracy and precision of the estimate have been determined by comparison with independent measures of insulin resistance and beta-cell function using hyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate of insulin resistance obtained by homeostasis model assessment correlated with estimates obtained by use of the euglycaemic clamp (Rs = 0.88, p less than 0.0001), the fasting insulin concentration (Rs = 0.81, p less than 0.0001), and the hyperglycaemic clamp, (Rs = 0.69, p less than 0.01). There was no correlation with any aspect of insulin-receptor binding. The estimate of deficient beta-cell function obtained by homeostasis model assessment correlated with that derived using the hyperglycaemic clamp (Rs = 0.61, p less than 0.01) and with the estimate from the intravenous glucose tolerance test (Rs = 0.64, p less than 0.05). The low precision of the estimates from the model (coefficients of variation: 31% for insulin resistance and 32% for beta-cell deficit) limits its use, but the correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop. 2-hop neighbor's text information:Title: Rosiglitazone RECORD study: glucose control outcomes at 18 months. Abstract: AIMS: To compare glucose control over 18 months between rosiglitazone oral combination therapy and combination metformin and sulphonylurea in people with Type 2 diabetes. METHODS: RECORD, a multicentre, parallel-group study of cardiovascular outcomes, enrolled people with an HbA(1c) of 7.1-9.0% on maximum doses of metformin or sulphonylurea. If on metformin they were randomized to add-on rosiglitazone or sulphonylurea (open label) and if on sulphonylurea to rosiglitazone or metformin. HbA(1c) was managed to < or = 7.0% by dose titration. A prospectively defined analysis of glycaemic control on the first 1122 participants is reported here, with a primary outcome assessed against a non-inferiority margin for HbA(1c) of 0.4%. RESULTS: At 18 months, HbA(1c) reduction on background metformin was similar with rosiglitazone and sulphonylurea [difference 0.07 (95% CI -0.09, 0.23)%], as was the change when rosiglitazone or metformin was added to sulphonylurea [0.06 (-0.09, 0.20)%]. At 6 months, the effect on HbA(1c) was greater with add-on sulphonylurea, but was similar whether sulphonylurea was added to rosiglitazone or metformin. Differences in fasting plasma glucose were not statistically significant at 18 months [rosiglitazone vs. sulphonylurea -0.36 (-0.74, 0.02) mmol/l, rosiglitazone vs. metformin -0.34 (-0.73, 0.05) mmol/l]. Increased homeostasis model assessment insulin sensitivity and reduced C-reactive protein were greater with rosiglitazone than metformin or sulphonylurea (all P < or = 0.001). Body weight was significantly increased with rosiglitazone compared with sulphonylurea [difference 1.2 (0.4, 2.0) kg, P = 0.003] and metformin [difference 4.3 (3.6, 5.1) kg, P < 0.001]. CONCLUSIONS: In people with diabetes, rosiglitazone in combination with metformin or sulphonylurea was demonstrated to be non-inferior to the standard combination of metformin + sulphonylurea in lowering HbA(1c) over 18 months, and produces greater improvements in C-reactive protein and basal insulin sensitivity but is also associated with greater weight gain. 2-hop neighbor's text information:Title: Pharmacokinetics and pharmacodynamics of gliclazide in Caucasians and Australian Aborigines with type 2 diabetes. Abstract: AIMS: Gliclazide pharmacokinetics and pharmacodynamics were assessed in 9 Caucasians and 10 Australian Aborigines with uncomplicated type 2 diabetes. METHODS: Subjects were on a stable dose of 80 mg gliclazide twice daily, took 160 mg on the morning of study and had a standard breakfast. No further gliclazide was given over the next 48 h. Regular blood samples were drawn for serum glucose, insulin and gliclazide assay. Gliclazide was measured using h.p.l.c. Noncompartmental analysis was used to describe primary data. A multicompartment model incorporating entero-hepatic recirculation was fitted to group mean serum gliclazide profiles. RESULTS: The Caucasians were older than the Aborigines (mean +/- s.d. age 53.4 +/- 12.2 vs 40.3 +/- 6.9 years, P < 0.05) but had similar diabetes duration, body mass index and glycated haemoglobin. Noncompartmental analysis revealed no between-group differences in gliclazide kinetics. Post-breakfast serum glucose and insulin responses were also similar apart from a longer time to maximum concentration (tmax) for glucose amongst the Aborigines (2.6 +/- 0.4 vs 2.2 +/- 0. 3 h in Caucasians; P = 0.024). Gliclazide tmax exhibited a skewed unimodal distribution and was not associated with gliclazide maximum concentration, or glucose or insulin responses. Most patients had a serum gliclazide profile suggestive of enterohepatic recirculation and/or biphasic absorption. Model-derived estimates of the extent of putative enterohepatic recirculation were 30% and 20% of dose in Caucasians and Aborigines, respectively. CONCLUSIONS: Gliclazide is equally effective in Caucasian and Aboriginal diabetic patients. The pharmacokinetics of oral gliclazide appear more complex than previously thought. Gliclazide pharmacodynamics are unrelated to rate and extent of absorption, consistent with a threshold concentration for hypoglycaemic effect. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2 2 2 2 2,2	2	pubmed	train	110
Title: Functioning and well-being of patients with type 2 diabetes or angina pectoris, compared with the general population. Abstract: This study compares the health-related quality of life (HRQOL) of patients with type 2 diabetes mellitus or angina pectoris with that of a standard population sample (SPS). The HRQOL was assessed by the Swedish Health-Related Quality of Life Survey (SWED-QUAL), a generic HRQOL questionnaire adapted from the Medical Outcomes Study (MOS), with twelve scales tapping aspects of physical, mental, social and general health. Subjects between 45 and 84 years of age who answered the questionnaire were included, i.e. 266 patients with type 2 diabetes, 758 patients with mild angina pectoris (Canadian Classes I and II) and 908 with severe angina (Canadian Classes III and IV). As controls, we used 1126 subjects from the SPS. Patients with type 2 diabetes, mild angina and severe angina showed an increasing degree of health disturbance, compared with the SPS. Diabetic patients with no heart disease showed only a minor impact on the HRQOL, while the presence of a heart disease showed a considerable impact. In angina patients, the presence of diabetes also to some extent added to the decrease in HRQOL. On comparing the impact of the heart disease and diabetes on the HRQOL, the heart disease showed a stronger effect on most aspects of the HRQOL than diabetes. It is concluded that coronary heart disease is an important predictor of the impact on the HRQOL of type 2 diabetes patients. 1-hop neighbor's text information:Title: Subjective quality of life of outpatients with diabetes: comparison with family caregivers' impressions and control group. Abstract: BACKGROUND: There is a paucity of studies on comparison of quality of life (QOL) of type-1 and type-2 diabetes patients, and the impact of family caregivers' impressions on the QOL of patients. OBJECTIVES: To assess the subjective QOL of Sudanese diabetics using the WHOQOL-Bref, compared with a general population sample; examine caregiver-patient concordance; and assess the variables that impact on QOL. METHOD: The responses of 105 outpatients with type-1 diabetes and 136 with type-2 diabetes were compared with their family caregivers' impressions and 139 general population subjects. RESULTS: Patients were predominantly dissatisfied with their life circumstances. Type-1 diabetics had significantly lowest QOL scores, while the control group had highest scores. Having additional medical problems; having diminished sexual desire; and being young, unemployed and single were associated with poor QOL, but illness duration was not. Type-2 diabetics had lesser concordance with caregivers. The only predictor of patients' QOL was the caregivers' impression of patients' QOL. CONCLUSIONS: Caregivers' impression of patients' QOL impacted on outcome. Caregiver education is, therefore, important. The factors associated with QOL indicate a group that needs focused attention. The good QOL for type-2 and nonsignificance of illness duration encourage therapeutic optimism. 2-hop neighbor's text information:Title: Erectile dysfunction and quality of life in type 2 diabetic patients: a serious problem too often overlooked. Abstract: OBJECTIVE: Within the context of a large, nationwide outcomes research program in type 2 diabetes, we assess the prevalence of self-reported erectile dysfunction and evaluate its impact on quality of life. RESEARCH DESIGN AND METHODS: The study involved 1,460 patients enrolled by 114 diabetes outpatient clinics and 112 general practitioners. Patients were asked to complete a questionnaire investigating their ability to achieve and maintain an erection. Various aspects of quality of life were also assessed depressive using the following instruments: SF-36 Health Survey, diabetes health distress, psychological adaptation to diabetes, depressive symptoms (CES-D scale), and quality of sexual life. RESULTS: Overall, 34% of the patients reported frequent erectile problems, 24% reported occasional problems, and 42% reported no erectile problems. After adjusting for patient characteristics, erectile dysfunction was associated with higher levels of diabetes-specific health distress and worse psychological adaptation to diabetes, which were, in turn, related to worse metabolic control. Erectile problems were also associated with a dramatic increase in the prevalence of severe depressive symptoms, lower scores in the mental components of the SF-36, and a less satisfactory sexual life. A total of 63% of the patients reported that their physicians had never investigated their sexual problems. CONCLUSIONS: Erectile dysfunction is extremely common among type 2 diabetic patients and is associated with poorer quality of life, as measured with generic and diabetes-specific instruments. Despite their relevance, sexual problems are seldom investigated by general practitioners and specialists. 2-hop neighbor's text information:Title: Personal and family factors associated with quality of life in adolescents with diabetes. Abstract: OBJECTIVE: Quality of life is an important criterion for assessing outcomes of treatment in chronic illness related to psychosocial well-being. The purpose of this study was to evaluate the factors that influence quality of life in adolescents with IDDM. RESEARCH DESIGN AND METHODS: Self-reports were obtained from 52 adolescents (age 13-20 years, mean 16.1 +/- 1.9 [mean +/- SD], diabetes duration 8.2 +/- 3.4 years, 49% female) using the following scales: Diabetes Quality of Life for Youths, Children's Depression Inventory, Issues in Coping with Diabetes, Diabetes Family Behavior Scale, Family Adaptability and Cohesion, Self-Efficacy for Diabetes, and the Adolescent Coping Orientation. Metabolic control was measured by HbA1c. RESULTS: Teenagers whose diabetes had the greater impact (R2 = 0.48) and were less satisfied (R2 = 0.45) felt that management was more difficult (r = 0.56) and that diabetes was more upsetting (r = 0.63). They also used fewer rebellion strategies for coping (r = -0.44), had lower diabetes self-efficacy (r = -0.36), and had more depressive symptoms (r = 0.61). Higher impact was also associated with higher family warmth and caring (r = -0.54) and lower family adaptability (r = -0.42). Teenagers who were more worried (R2 = 0.37) about their diabetes felt that management was more difficult (r = 0.40) and that diabetes was more upsetting (r = 0.58), and they used less rebellion (r = -0.49) and more ventilation (r = 0.42) to cope, had lower diabetes (r = -0.40) and medical (r = -0.30) self-efficacy, were more depressed (r = 0.55), and their families were less warm and caring (r = -0.33). HbA1c levels were not associated with quality of life or any other psychosocial factors except in teenagers who perceived their families as providing more guidance and control. These teenagers had lower HbA1c values than those whose families were less involved. CONCLUSIONS: Even teenagers who are successfully achieving HbA1c goals of therapy may perceive diabetes as having a negative impact on their lives, be depressed, and find diabetes difficult to manage. Diabetes treatment teams need to pay equal attention to the psychosocial needs to the quiet, nonrebellious teen with well-controlled diabetes from a supportive family as they do to the rebellious adolescent with poorly controlled diabetes. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 2 1,2	2	pubmed	train	111
Title: Prevalence and risk factors for urinary incontinence in women with type 2 diabetes and impaired fasting glucose: findings from the National Health and Nutrition Examination Survey (NHANES) 2001-2002. Abstract: OBJECTIVE: Diabetes is associated with increased risk of urinary incontinence. It is unknown whether women with pre-diabetes, or impaired fasting glucose (IFG), have increased prevalence of incontinence. We determined the prevalence of, and risk factors for, incontinence among U.S. women with diabetes and IFG. RESEARCH DESIGN AND METHODS: The 2001-2002 National Health and Nutrition Examination Survey measured fasting plasma glucose and obtained information about diabetes and urinary incontinence among 1,461 nonpregnant adult women. Self-reported weekly or more frequent incontinence, both overall and by type (urge and stress), was our outcome. RESULTS: Of the 1,461 women, 17% had diabetes and 11% met criteria for IFG. Prevalence of weekly incontinence was similar among women in these two groups (35.4 and 33.4%, respectively) and significantly higher than among women with normal fasting glucose (16.8%); both urge and stress incontinence were increased. In addition to well-recognized risk factors including age, weight, and oral estrogen use, two microvascular complications caused by diabetes, specifically macroalbuminuria and peripheral neuropathic pain, were associated with incontinence. CONCLUSIONS: Physicians should be alert for incontinence, an often unrecognized and therefore undertreated disorder, among women with diabetes and IFG, in particular those with microvascular complications. The additional prospect of improvements in their incontinence may help motivate some high-risk women to undertake difficult lifestyle changes to reduce their more serious risk of diabetes and its sequelae. 1-hop neighbor's text information:Title: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Abstract: BACKGROUND: Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial. METHODS: 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48-60 years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6.1-15.0 mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. In the conventional group, the aim was the best achievable FPG with diet alone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy. FINDINGS: Over 10 years, haemoglobin A1c (HbA1c) was 7.0% (6.2-8.2) in the intensive group compared with 7.9% (6.9-8.8) in the conventional group--an 11% reduction. There was no difference in HbA1c among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-related endpoint; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40, p=0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints between the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p<0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg). INTERPRETATION: Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes.(ABSTRACT TRUNCATED) 1-hop neighbor's text information:Title: Type 2 diabetes mellitus and risk of developing urinary incontinence. Abstract: OBJECTIVES: To evaluate the association between type 2 diabetes mellitus (DM) and development of urinary incontinence in women. DESIGN: Prospective, observational study. SETTING: The Nurses' Health Study cohort. PARTICIPANTS: Eighty-one thousand eight hundred forty-five women who reported information on urinary function in 1996. MEASUREMENTS: Self-reported, physician-diagnosed DM was ascertained using questionnaire from 1976 to 1996 and confirmed using standard criteria. Self-reported urinary incontinence, defined as leakage at least weekly, was ascertained in 1996 and 2000. Logistic regression models were used to calculate multivariate-adjusted relative risks (RRs) and 95% confidence intervals (CIs) for the relationship between DM (as of 1996) and prevalent and incident incontinence. RESULTS: The risk of prevalent incontinence (multivariate RR=1.28, 95% CI=1.18-1.39) and incident incontinence (multivariate RR=1.21, 95% CI=1.02-1.43) was significantly greater in women with DM than women without. Using a validated severity index, risk of developing severe incontinence was even more substantial in women with DM than in those without (multivariate RR=1.40, 95% CI=1.15-1.71 for leakage enough to wet the underwear; RR=1.97, 95% CI=1.24-3.12 for leakage enough to wet the outer clothing). In addition, risk of incontinence increased with duration of DM (P-trend=.03 for prevalent incontinence; P=.001 for incident incontinence). CONCLUSION: DM independently increases risk of urinary incontinence in women. Because risk of incontinence appeared associated with longer duration of DM, even delaying the onset of DM could have important public health implications. 1-hop neighbor's text information:Title: Urinary incontinence among women with type 1 diabetes--how common is it? Abstract: PURPOSE: We compared the prevalence, level of bother and effect on daily activities of urinary incontinence among women with type 1 diabetes enrolled in the Epidemiology of Diabetes Interventions and Complications study to a population based sample of women with normal glucose. MATERIALS AND METHODS: We performed a cross-sectional analysis of women with type 1 diabetes and normal glucose tolerance using 2 study populations. The Diabetes Control and Complications Trial cohort followup, Epidemiology of Diabetes Interventions and Complications, began in 1994. In 2004 women participants (550) completed a self-administered questionnaire on urinary incontinence. Our primary outcome was weekly or greater incontinence, overall and by type. Prevalence of urinary incontinence was compared to a subgroup of women with normal glucose in the 2001 to 2002 National Health and Nutrition Examination Survey (NHANES). RESULTS: Overall 65% of women with type 1 diabetes reported any urinary incontinence (17% reported weekly incontinence). Nearly 40% of these women were greatly bothered by their incontinence and 9% believed it affected their day-to-day activities. Women with type 1 diabetes had a nearly 2-fold greater prevalence of weekly urge incontinence compared to those without diabetes in the NHANES cohort (8.8% vs 4.5%, p = 0.01). CONCLUSIONS: Urinary incontinence is common in women with type 1 diabetes and the prevalence of weekly urge incontinence is far greater compared to that in women with normal glucose levels. Moreover, the prevalence of urinary incontinence in women with type 1 diabetes was greater than that of neuropathy, retinopathy and nephropathy. These findings highlight the importance of screening for urinary incontinence among women with type 1 diabetes. Studies examining factors associated with urinary incontinence in women with type 1 diabetes are warranted. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2 2 1,2	1	pubmed	train	112
Title: Involvement of endothelial cells in relaxation and contraction responses of the aorta to isoproterenol in naive and streptozotocin-induced diabetic rats. Abstract: Experiments were designed to investigate the importance of the endothelium in the relaxation of isolated rat aorta caused by a beta adrenoceptor agonist. Mechanical removal of the endothelium attenuated the relaxation induced by isoproterenol (ISO) and did not affect the relaxation produced by forskolin and by sodium nitroprusside. High concentrations of ISO produced an increase in the resting tension of aortic strips with and without endothelium in a concentration-dependent manner. Mechanical removal of the endothelium or treatment with methylene blue enhanced the maximal contraction induced by ISO. Phentolamine antagonized the contractile responses induced by ISO. In the case of streptozotocin-induced diabetic rats, both aortic strips with and without endothelium generated concentration-response curves for ISO-induced relaxation that were shifted to the right. The relaxant responses to forskolin and sodium nitroprusside were not significantly different between vessels from diabetic and age-matched control rats. In both aortic strips with and without endothelium, the maximal contraction in response to high concentrations of ISO was significantly enhanced in strips from diabetic rats. These results suggest that ISO-induced relaxation of aortic strips with endothelium is mediated by beta adrenoceptors on both the endothelium and the smooth muscle, and high concentrations of ISO produce an increase in the resting tension through alpha adrenoceptors. It is further suggested that the decreased relaxant response of the aorta to ISO in diabetes may be due to decreased density or affinity of beta adrenoceptors on the smooth muscle. 1-hop neighbor's text information:Title: Changes in superoxide dismutase mRNA expression by streptozotocin-induced diabetes. Abstract: 1. Experiments were designed to investigate the involvement of superoxide anions in the attenuated endothelium-dependent relaxation of the rat aorta from streptozotocin (STZ)-induced diabetic rats. 2. The endothelium-dependent relaxation responses to acetylcholine (ACh, 10(-7) M) in helical strips of the aorta precontracted with noradrenaline (NA, 5 x 10(-3) approximately 3 x 10(-7) M) were significantly decreased in STZ-induced diabetic rats. The recovery phase of the relaxation after single administration of ACh in the STZ-induced diabetic rats was more rapid than those in control vessels. 3. Preincubation of aortic strips with superoxide dismutase (SOD, 60 u ml-1) normalized the recovery phase of the relaxation of diabetic aorta after single administration of ACh, whereas catalase (150 u ml-1) or indomethacin (10(-5) M) had no effects on the relaxation. 4. SOD (180 u ml-1) caused relaxation in NA precontracted aortic strips and the degree of the SOD-induced relaxation was significantly greater in diabetic aorta as compared with age-matched control vessels. 5. When the changes in mRNA expressions of Mn-SOD or Cu-Zn-SOD were observed, Mn-SOD mRNA expression was markedly decreased, and Cu-Zn-SOD was slightly decreased in diabetic aorta. 6. These results suggest that the rapid destruction of NO by superoxide anions may occur in the STZ-induced diabetic rats, and this may be due to a decrease in mRNA expression of Mn-SOD or Cu-Zn-SOD. 1-hop neighbor's text information:Title: Attenuated responses to endothelin-1, KCl and CaCl2, but not noradrenaline, of aortae from rats with streptozotocin-induced diabetes mellitus. Abstract: 1. This study investigated the responsiveness to vasoconstrictor agents (including endothelin-1, ET-1) of aortic rings from rats with two-week streptozotocin (STZ, 60 mg kg-1, i.v.)-induced diabetes and vehicle-treated control rats. The basal tension was 10 g, which was estimated to be more physiological than the tension of 1-2 g that has been previously used for most studies of aortic rings from diabetic rats. 2. Maximum responses to ET-1 (0.13-18 nM), KCl (2-20 mM) or CaCl2 (10 microM-10 mM) were reduced in aortae from STZ-treated rats compared to those from control rats. Such reductions were still evident after removal of the endothelium. 3. Responses to noradrenaline (NA, 0.1 nM-26 microM) of aortae from STZ-treated rats were not significantly different from responses of aortae of control rats. 4. Removal of endothelium resulted in a significant reduction in the EC50 values for NA of rings from both STZ-treated rats (6.90 +/- 0.13 and 8.17 +/- 0.35 (-log M) with and without endothelium, respectively, n = 5) and control rats (6.90 +/- 0.15 and 8.37 +/- 0.44 (-log M) with and without endothelium, respectively, n = 5). 5. In calcium-free medium (with 1 mM EGTA), responses to NA and ET-1 were reduced compared with those in normal Krebs solution and maximum responses were less in rings from STZ-treated compared with control rats. 6. Indomethacin (5 microM) did not prevent the reduced maximum responsiveness to ET-1 in rings from STZ-treated rats compared with those from controls.7. This study indicates that changes in vascular responsiveness to ET-1, KCI and CaCl2 (but not NA) occur in aortae of two-week STZ-treated rats. The endothelium does not appear to play a major role in mediating changes in responsiveness to ET-1. 2-hop neighbor's text information:Title: Increased alpha 2-adrenoreceptor mediated vascular contraction in diabetic rats. Abstract: Contractile responses of aortic ring preparations from control and diabetic rats to nonselective (noradrenaline) and selective alpha 1-(phenylephrine) and alpha 2-(clonidine) adrenoreceptor agonists were examined to determine the contribution of these receptor subtypes to the response. Aortae from diabetic rats were more responsive to noradrenaline compared to age-matched control rats. There was no difference between contractile responses of aortae from control and diabetic rats to phenylephrine, whereas clonidine-induced contractions were enhanced in aortae from diabetic rats. Dependence of clonidine-induced contractions on extracellular calcium availability was determined. Each of the methods used indicated increased dependency of aortae from diabetic rats on extracellular calcium availability for clonidine-induced contractile force generation. These data indicate that the increased noradrenaline-induced responsiveness of aortae from diabetic rats may be attributed to an increased alpha 2-adrenoreceptor component of the contractile response. It is also concluded that the alpha 2-adrenoreceptor mediated contraction is primarily dependent upon extracellular calcium. From this we suggest that the increased contractile responsiveness of aortae from diabetic rats to alpha 2-adrenoreceptor stimulating drugs may be related to an altered coupling mechanism between the alpha 2-adrenoreceptors and the calcium ion channels or due to a change in membrane permeability as a result of the disease process. 2-hop neighbor's text information:Title: Effects of experimental diabetes on the responsiveness of rat aorta. Abstract: 1. Vascular responsiveness was examined in aortic ring preparations, with or without endothelium, from rats with experimental diabetes induced by streptozotocin and from vehicle-treated (control) rats. 2. There were no significant differences between diabetic tissues and control tissues in the responsiveness to the vasoconstrictors noradrenaline, 5-hydroxytryptamine and KCl, and to the vasodilators sodium nitroprusside, isoprenaline and acetylcholine. 3. When maximum contractions to vasoconstrictors was expressed relative to tissue weight, maximum contractions were significantly greater in diabetic tissues. 4. When expressed in terms of the KCl contraction, there were no significant differences between diabetic and control tissues in the maximum contraction to vasoconstrictors. 5. These results demonstrate that diabetic-induced changes in vascular responsiveness, if any, do not occur at the receptor level. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	0 0 0 0,0	2	pubmed	train	113
Title: Accelerated diabetes in non-obese diabetic (NOD) mice differing in incidence of spontaneous disease. Abstract: The NOD mouse is an established model of autoimmune diabetes mellitus. Various lines of NOD mice differ in their incidence of spontaneous diabetes, e.g. 93% of female NOD/Lt mice compared with 46% of female NOD/Wehi mice develop diabetes by 250 days. These two lines were studied under conditions which greatly accelerate the onset of hyperglycaemia. It was hoped that their responses to these manipulations would reveal characteristic differences which would increase our understanding of diabetes resistance in the low incidence NOD/Wehi line. One dose of 300 mg/kg of cyclophosphamide (CP) produced hyperglycaemia in 50% of NOD mice within 2 weeks in both lines. They were also equally susceptible to diabetes induced by splenocyte transfer at 21 days of age from prediabetic 150-day-old NOD/Lt or NOD/Wehi females. Five daily 40 mg/kg doses of streptozotocin (STZ) resulted in a severity of diabetes in the NOD mice greater than in C57BL or SJL/mice. While the incidence and severity of diabetes induced in the two NOD lines were similar, this appeared to be principally due to sensitivity to the toxic effects of STZ rather than its ability to exacerbate autoimmune beta cell destruction. It has previously been shown that it is possible to prevent diabetes in susceptible NOD mice with simple, relatively benign therapies and here we show that it is possible to induce diabetes in resistant animals at a rate indistinguishable from fully predisposed individuals. It therefore appears that the prediabetic NOD mouse is poised in an immunologically precarious state with the onset of disease being highly dependent on factors which exacerbate or moderate autoimmune destruction. 1-hop neighbor's text information:Title: Transfer of autoimmune diabetes mellitus with splenocytes from nonobese diabetic (NOD) mice. Abstract: The nonobese diabetic (NOD) mouse, a model of human type I diabetes, develops insulitis beginning at 4-6 wk of age. By 30 wk of age, 72% of females and 39% of males develop spontaneous diabetes, apparently because of an overwhelming autoimmune response to the insulin-producing beta-cells within the islets. To identify the immune mechanism responsible for destruction of beta-cells in the NOD mouse, we developed an adoptive transfer protocol that induces diabetes in NOD mice at an age when spontaneous diabetes is rarely observed. Splenocytes from overtly diabetic NOD mice were unable to transfer diabetes to very young (less than or equal to 6 wk) irradiated NOD mice but effectively transferred diabetes to irradiated NOD mice greater than 6 wk of age. In such transfers, overt diabetes was induced within 12-22 days in greater than 95% (79/82) of the recipients. Thus, transfer of splenocytes to young mice induces them to become diabetic at a higher frequency and at a younger age than their untreated littermates. Equally successful transfers with as few as 5 X 10(6) spleen cells have been performed in male and female NOD mice, even though males display a lower spontaneous incidence of diabetes than females. Splenocytes obtained from diabetic mice maintained on insulin for up to 2 mo also transferred diabetes. Because NOD mice display increasing levels of insulitis with age, spleen cells obtained from nondiabetic NOD mice of different ages were tested for their ability to transfer diabetes.(ABSTRACT TRUNCATED AT 250 WORDS) 1-hop neighbor's text information:Title: Raised temperature reduces the incidence of diabetes in the NOD mouse. Abstract: An association between the incidence of childhood Type 1 (insulin-dependent) diabetes mellitus and the average yearly temperature in different countries has been reported, the incidence being higher in countries with a lower mean temperature. We have studied the effect of environmental temperature on the incidence of diabetes in an animal model of Type 1 diabetes, the non-obese diabetic (NOD) mouse. Female NOD mice were divided at weaning, with one group placed at a higher temperature (mean 23.7 +/- 1.7 degrees C) and the other at a lower temperature (21.0 +/- 1.8 degrees C). At 20 weeks of age 6 of 16 mice at lower temperature and 1 of 17 mice at higher temperature had developed diabetes (p less than 0.02); at 30 weeks 10 of 16 and 5 of 17 mice had developed diabetes (p less than 0.05). Non-diabetic animals in the low temperature group had a higher food intake than those in the high temperature group between 13-15 weeks of age (28.0 +/- 1.2 g/week vs 24.8 +/- 0.7 g/week, p less than 0.05). In a parallel experiment, histological examination showed that there were similar degrees of insulitis in the high and low temperature groups at seven weeks of age. We conclude that environmental temperature can affect the incidence of diabetes in the NOD mouse and that this may be related to alterations in food intake. 1-hop neighbor's text information:Title: Syngeneic transfer of autoimmune diabetes from diabetic NOD mice to healthy neonates. Requirement for both L3T4+ and Lyt-2+ T cells. Abstract: We have developed a model of syngeneic adoptive transfer for type I diabetes mellitus of NOD mice. This model consists in injecting spleen cells from diabetic adult mice into newborn NOD recipients. 50% of recipients inoculated with 20 X 10(6) cells develop diabetes within the first 10 wk of life, at a time when none of the control littermates have yet become diabetic. The earliest successful transfers are observed at 3 wk of age, at a time when controls do not even exhibit histological changes in their pancreas. In addition we have shown that: (a) both males and females can be adoptively transferred, despite the fact that males rarely develop spontaneous diabetes in our colony; (b) diabetes transfer is a dose-dependent phenomenon that provides an in vivo assay for comparing the autoimmune potential of spleen cells from mice at various stages of their natural history; (c) the susceptibility of the recipients to the transfer is limited in time and declines after 3 wk; and (d) both L3T4+ and Lyt-2+ T cell subsets are necessary for the successful transfer. The neonatal syngeneic transfer provides an effective model for studies of the cellular events involved at regulatory and effector stages of autoimmune type I diabetes. 2-hop neighbor's text information:Title: Checkpoints in the progression of autoimmune disease: lessons from diabetes models. Abstract: In the last few years, data from experiments employing transgenic models of autoimmune disease have strengthened a particular concept of autoimmunity: disease results not so much from cracks in tolerance induction systems, leading to the generation of anti-self repertoire, as from the breakdown of secondary systems that keep these cells in check. T cells with anti-self specificities are readily found in disease-free individuals but ignore target tissues. This is also the case in some transgenic models, in spite of overwhelming numbers of autoreactive cells. In other instances, local infiltration and inflammation result, but they are well tolerated for long periods of time and do not terminally destroy target tissue. We review the possible molecular and cellular mechanisms that underlie these situations, with a particular emphasis on the destruction of pancreatic beta cells in transgenic models of insulin-dependent disease. 2-hop neighbor's text information:Title: Effect of cyclosporin A treatment on the production of antibody in insulin-dependent (type I) diabetic patients. Abstract: Anti-islet cell and anti-insulin antibody production was studies over a 12-mo period in 82 recently diagnosed diabetics randomly receiving either cyclosporin or placebo. Cyclosporin had only minimal effects on the production of anti-islet cell antibodies whether directed to islet cytoplasmic (immunofluorescence) or membrane (cytotoxicity assay) antigens even in patients undergoing remission. These data suggest that these antibodies do not play a major role in the pathogenesis of the disease particularly since their (irregular) presence is not predictive of the clinical response to cyclosporin. Conversely, cyclosporin completely suppressed the synthesis of antibodies elicited by exogenous insulin irrespective of the insulin doses received, and decreased the autoantibody production against thyroid antigens, indicating that cyclosporin has variable effects on antibody production against various antigens. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	0 0 0 1 1,0	2	pubmed	train	114
Title: Distal neuropathy in experimental diabetes mellitus. Abstract: Although nerve conduction slowing is a well-accepted abnormality in rats with acute experimental diabetes, reports of neuropathological changes in diabetic rat nerves have been inconsistent. To examine this further, we studied electrophysiological and morphological features of posterior tibial nerves and their distal branches from four-week streptozotocin-induced diabetic rats and matched controls. Diabetic rat posterior tibial motor conduction was slowed (mean +/- 1 SD, 34.8 +/- 3.1 m/sec; controls, 41.2 +/- 2.5 m/sec), and evoked muscle response amplitudes were only half of control values. Using quantitative techniques, we documented a diminution in number of the largest myelinated fibers in otherwise normal mid posterior tibial nerves, with an increase in the smaller sizes, indicating either a degree of axonal atrophy or impaired fiber growth during development. The principal pathological finding was active breakdown of myelinated fibers in the most distal motor twigs of hindfoot muscles supplied by posterior tibial branches, with preservation of fibers in more proximal segments of these nerves. This anatomical lesion in diabetic nerves could account for both oberved conduction slowing and lowered muscle response amplitudes. A consistent feature in both diabetic and control mid lateral plantar nerves was a zone of demyelination that apparently occurs at this natural site of nerve entrapment in rats. Taken together, the pathological abnormalities of peripheral nerve in acute experimental diabetes are best explained as resulting from a distal axonopathy. 1-hop neighbor's text information:Title: Neurotrophic modulation of myelinated cutaneous innervation and mechanical sensory loss in diabetic mice. Abstract: Human diabetic patients often lose touch and vibratory sensations, but to date, most studies on diabetes-induced sensory nerve degeneration have focused on epidermal C-fibers. Here, we explored the effects of diabetes on cutaneous myelinated fibers in relation to the behavioral responses to tactile stimuli from diabetic mice. Weekly behavioral testing began prior to streptozotocin (STZ) administration and continued until 8 weeks, at which time myelinated fiber innervation was examined in the footpad by immunohistochemistry using antiserum to neurofilament heavy chain (NF-H) and myelin basic protein (MBP). Diabetic mice developed reduced behavioral responses to non-noxious (monofilaments) and noxious (pinprick) stimuli. In addition, diabetic mice displayed a 50% reduction in NF-H-positive myelinated innervation of the dermal footpad compared with non-diabetic mice. To test whether two neurotrophins nerve growth factor (NGF) and/or neurotrophin-3 (NT-3) known to support myelinated cutaneous fibers could influence myelinated innervation, diabetic mice were treated intrathecally for 2 weeks with NGF, NT-3, NGF and NT-3. Neurotrophin-treated mice were then compared with diabetic mice treated with insulin for 2 weeks. NGF and insulin treatment both increased paw withdrawal to mechanical stimulation in diabetic mice, whereas NT-3 or a combination of NGF and NT-3 failed to alter paw withdrawal responses. Surprisingly, all treatments significantly increased myelinated innervation compared with control-treated diabetic mice, demonstrating that myelinated cutaneous fibers damaged by hyperglycemia respond to intrathecal administration of neurotrophins. Moreover, NT-3 treatment increased epidermal Merkel cell numbers associated with nerve fibers, consistent with increased numbers of NT-3-responsive slowly adapting A-fibers. These studies suggest that myelinated fiber loss may contribute as significantly as unmyelinated epidermal loss in diabetic neuropathy, and the contradiction between neurotrophin-induced increases in dermal innervation and behavior emphasizes the need for multiple approaches to accurately assess sensory improvements in diabetic neuropathy. 1-hop neighbor's text information:Title: Structural abnormalities do not explain the early functional abnormalities in the peripheral nerves of the streptozotocin diabetic rat. Abstract: The streptozotocin (STZ)-diabetic rat, the most commonly employed model of experimental diabetic neuropathy, is characterised by a reduction in nerve conduction velocity, pain threshold and blood flow. Whether or not structural abnormalities underlie these functional abnormalities is unclear. 10 adult male Sprague-Dawley STZ-diabetic rats (diabetes duration 27 d) and 10 age-matched (23 wk) control animals were studied. Motor nerve conduction velocity (m s(-1)) was significantly reduced in diabetic (41.31 +/- 0.8) compared with control (46.15 +/- 1.5) animals (P < 0.001). The concentration of sciatic nerve glucose (P < 0.001), fructose (P < 0.001) and sorbitol (P < 0.001) was elevated, and myoinositol (P < 0.001) was reduced in diabetic compared with control animals. Detailed morphometric studies demonstrated no significant difference in fascicular area, myelinated fibre density, fibre and axon areas as well as unmyelinated fibre density and diameter. Endoneurial capillary density, basement membrane area and endothelial cell profile number did not differ between diabetic and control animals. However, luminal area (P < 0.03) was increased and endothelial cell area (P < 0.08) was decreased in the diabetic rats. We conclude there is no detectable structural basis for the reduction in nerve conduction velocity, pain threshold or blood flow, observed in the streptozotocin diabetic rat. 1-hop neighbor's text information:Title: Transport of myo-inositol into endoneurial preparations of sciatic nerve from normal and streptozotocin-diabetic rats. Abstract: myo-Inositol transport by a viable rat sciatic-nerve preparation is described. Such 'endoneurial' nerve preparations accumulated myo-inositol by an energy-dependent saturable system. Streptozotocin-diabetes reduced myo-inositol transport into sciatic nerve by approx. 40%. Elevated medium glucose concentration reduced myo-inositol transport into control nerves to a similar extent. Fructose and sorbitol did not inhibit myo-inositol transport. Inclusion of an aldose reductase inhibitor in the medium counteracted the reduced myo-inositol transport caused by elevated glucose concentration. The importance of these results to the problem of diabetic neuropathy is discussed. 2-hop neighbor's text information:Title: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. Abstract: BACKGROUND: Long-term microvascular and neurologic complications cause major morbidity and mortality in patients with insulin-dependent diabetes mellitus (IDDM). We examined whether intensive treatment with the goal of maintaining blood glucose concentrations close to the normal range could decrease the frequency and severity of these complications. METHODS: A total of 1441 patients with IDDM--726 with no retinopathy at base line (the primary-prevention cohort) and 715 with mild retinopathy (the secondary-intervention cohort) were randomly assigned to intensive therapy administered either with an external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin injections. The patients were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly. RESULTS: In the primary-prevention cohort, intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76 percent (95 percent confidence interval, 62 to 85 percent), as compared with conventional therapy. In the secondary-intervention cohort, intensive therapy slowed the progression of retinopathy by 54 percent (95 percent confidence interval, 39 to 66 percent) and reduced the development of proliferative or severe nonproliferative retinopathy by 47 percent (95 percent confidence interval, 14 to 67 percent). In the two cohorts combined, intensive therapy reduced the occurrence of microalbuminuria (urinary albumin excretion of > or = 40 mg per 24 hours) by 39 percent (95 percent confidence interval, 21 to 52 percent), that of albuminuria (urinary albumin excretion of > or = 300 mg per 24 hours) by 54 percent (95 percent confidence interval 19 to 74 percent), and that of clinical neuropathy by 60 percent (95 percent confidence interval, 38 to 74 percent). The chief adverse event associated with intensive therapy was a two-to-threefold increase in severe hypoglycemia. CONCLUSIONS: Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM. 2-hop neighbor's text information:Title: Histopathological heterogeneity of neuropathy in insulin-dependent and non-insulin-dependent diabetes, and demonstration of axo-glial dysjunction in human diabetic neuropathy. Abstract: Altered sorbitol and myo-inositol metabolism, (Na,K)-ATPase function, electrochemical sodium gradients, axonal swelling, and distortion and disruption of the node of Ranvier ("axo-glial dysjunction") directly implicate hyperglycemia in the pathogenesis of neuropathy in diabetic rats, but the relevance of this sequence to clinical neuropathy in heterogeneous groups of diabetic patients remains to be established. Fascicular sural nerve morphometry in 11 patients with neuropathy complicating insulin-dependent diabetes revealed a pattern of interrelated structural changes strikingly similar to that of the diabetic rat when compared to age-matched controls. 17 older non-insulin-dependent diabetic patients with comparable duration and severity of hyperglycemia and severity of neuropathy, displayed similar nerve fiber loss, paranodal demyelination, paranodal remyelination and segmental demyelination compared to age-matched controls, but axo-glial dysjunction was replaced by Wallerian degeneration as the primary manifestation of fiber damage, and fiber loss occurred in a spatial pattern consistent with an ischemic component. The mechanistic model developed from the diabetic rat does indeed appear to apply to human diabetic neuropathy, but superimposed hormonal, metabolic, vascular, and/or age-related effects alter the morphologic expression of the neuropathy in non-insulin dependent diabetes. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	0 0 0 1 1,0	2	pubmed	train	115
Title: Administering glutamic acid decarboxylase to NOD mice prevents diabetes. Abstract: Type 1 diabetes is the result of an ongoing autoimmune response to specific proteins expressed by the insulin producing beta cells. Recently, a number of beta cell autoantigens have been identified. However, their role in mediating the diabetogenic response is not known. Here we assess the relative importance of a panel of beta cell autoantigens in the disease process. The approach was to inhibit T cell proliferation to a given autoantigen by either i.t. or i.v. injections, and then determine the effect this had on the diabetogenic response. We show that administering murine glutamic acid decarboxylase (GAD) to 3-week-old NOD females can reduce the frequency of insulitis and prevent the onset of diabetes. In contrast, carboxypeptidase H or peripherin do not induce a similar protective effect, suggesting that GAD has a critical role in the diabetogenic response. These results also suggest that GAD may provide a useful target for antigen-specific immunotherapy. 1-hop neighbor's text information:Title: Modulation of diabetes in NOD mice by GAD65-specific monoclonal antibodies is epitope specific and accompanied by anti-idiotypic antibodies. Abstract: Type 1 diabetes is caused by the autoimmune destruction of pancreatic beta cells. Here we show that administration of a human monoclonal antibody (b96.11) specific to the 65-kDa isoform of glutamate decarboxylase (GAD65) to prediabetic non-obese diabetic (NOD) mice significantly delays the onset of autoimmune diabetes. We found this effect to be epitope-specific, as only b96.11 showed this therapeutic property, while a GAD65-specific human monoclonal control antibody (b78) derived from the same patient, but specific to a different determinant of GAD65, had no significant effect on the progression of disease. Administration of b96.11 or b78 to NOD mice was accompanied by the generation of anti-idiotypic antibodies. Importantly, the induced anti-idiotypic antibodies were specific for the immunizing antibody and blocked the binding of GAD65 by the respective antibody. These findings suggest a potential role for the internal image of the GAD65 determinant recognized by b96.11 in the anti-idiotypic antibody, supporting an immunomodulatory role for GAD65-specific autoantibodies, as originally postulated by Jerne. 1-hop neighbor's text information:Title: Autoreactive human T-cell receptor initiates insulitis and impaired glucose tolerance in HLA DR4 transgenic mice. Abstract: A human T-cell receptor (TcR) derived from an autoreactive T-cell specific for GAD65, from a subject at high risk for autoimmune diabetes, was introduced into HLA-DR4 transgenic mice. The source of TcR was a CD4(+) T(H)1(+) T-cell clone which responded to an immunodominant epitope of the human islet protein GAD65, an epitope shared with both GAD65 and GAD67 in the mouse. The resulting HLA-DR4/GAD-TcR transgenic mice on a Rag2(o/o)/I-Ab(o/o)/B6 background exhibited a CD4(+) infiltrate into pancreatic islets that correlated with a loss of insulin in infiltrated islets. These mice also exhibited a subclinical impaired tolerance to exogenously fed glucose as assayed by an intraperitoneal glucose tolerance test. T cells containing the GAD65/67 (555-567) responsive TcR undergo strong negative selection as evidenced by a 10-fold lower thymocyte cellularity compared to non-TcR transgenic mice, and clonotype peripheral T cells represented approximately 1% of CD4(+) T cells in Rag2 sufficient mice. Upon in vitro stimulation, GAD65/67 555-567 responsive T cells secrete interferon-gamma, minimal interleukin (IL)-2 and tumor necrosis factor-alpha, and no IL-4, IL-5, IL-10, or IL-17, consistent with a T(H)1 profile. These data demonstrate that CD4(+) T cells specific for a naturally processed epitope within GAD can specifically home to pancreatic islets and lead to impaired islet beta-cell function in diabetes-associated HLA-DR4 transgenic mice on the relatively non-autoimmune C57BL/6 background. The relatively slow progression and patchy insulitis are reminiscent of the chronic pre-clinical phase similar to a majority of human at-risk subjects, and models these indolent features of human T1D. 1-hop neighbor's text information:Title: Absence of significant Th2 response in diabetes-prone non-obese diabetic (NOD) mice. Abstract: Accumulating evidence suggests that Th1 T cells play a pivotal role in the development of autoimmune diabetes. Conversely, promoting a Th2 response inhibits disease progression. However, it has not been determined whether Th2 cells are regulatory T cells that fail at the time of diabetes development in naive non-diabetic NOD mice. Therefore, in order to evaluate cytokine secretion by spleen and islet infiltrating T cells in NOD mice at different stages of the autoimmune process, we developed an ELISPOT assay that detects IL-2, IL-4, and interferon-gamma (IFN-gamma) secretion in vitro at the single-cell level. We showed that, whatever the age considered, IFN-gamma is predominantly secreted, and that no IL-4-secreting cells are detected in the islets of male and female NOD mice. Spleen cells from 8-week-old female NOD mice, which include regulatory suppressor T cells, do not secrete IL-4, either upon presentation of islet cell antigens in vitro, or after transfer in vivo, but do secrete IFN-gamma. IFN-gamma secretion by T cells from diabetic mice results from CD4 but not CD8 T cells in transfer experiments into NOD/severe combined immunodeficient (SCID) recipients. These results suggest that (i) detection of regulatory CD4 T cells in NOD mice is not paralleled by a Th2 response; (ii) beta cell destruction does not depend on a switch from a Th2 to a Th1-type response; and (iii) CD8 T cells do not participate in induction of diabetes by secreting IFN-gamma. 2-hop neighbor's text information:Title: Induction of glutamic acid decarboxylase 65-specific Th2 cells and suppression of autoimmune diabetes at late stages of disease is epitope dependent. Abstract: Peptide-based immunotherapy is one strategy by which to selectively suppress the T cell-mediated destruction of beta cells and treat insulin-dependent diabetes mellitus (IDDM). Here, we investigated whether a panel of T cell epitopes derived from the beta cell autoantigen glutamic acid decarboxylase 65 (GAD65) differ in their capacity to induce Th2 cell function in nonobese diabetic (NOD) mice and in turn prevent overt IDDM at different preclinical stages of disease development. The panel consists of GAD65-specific peptides spanning aa 217-236 (p217), 247-265 (p247), 290-309 (p290), and 524-543 (p524). Our studies revealed that all of the peptides effectively prevented insulitis and diabetes when administered to NOD mice before the onset of insulitis. In contrast, only a mixture of p217 and p290 prevented progression of insulitis and overt IDDM in NOD mice exhibiting extensive beta cell autoimmunity. Immunization with the GAD65-specific peptides did not block IDDM development in NOD mice deficient in IL-4 expression. These findings demonstrate that GAD65-specific peptide immunotherapy effectively suppresses progression to overt IDDM, requires the production of IL-4, and is dependent on the epitope targeted and the extent of preexisting beta cell autoimmunity in the recipient. 2-hop neighbor's text information:Title: The thymus as a site for evaluating the potency of candidate beta cell autoantigens in NOD mice. Abstract: Intrathymic (i.t.) injection of islet cells or whole islets retards development of insulin dependent diabetes mellitus (IDDM) in spontaneous animal models of the disease. Protection of 4-week-old prediabetic NOD/Lt female mice from subsequent IDDM development was specific for the it route of administration since intraperitoneal injection of an equal number of syngeneic islets failed to retard IDDM. The protective effect of i.t. injection of islet cells was compared with the effect of i.t. injection of syngeneic peritoneal exudate cells, NIT-1 cells, bovine serum albumin (BSA), ABBOS peptide, a 52 kDa islet cell membrane protein, various synthetic peptides from human glutamic acid decarboxylase (GAD) and a Coxsackievirus B4-derived peptide with homology to GAD. Interestingly, only a GAD-derived peptide containing sequence homology to Coxsackie-virus B4, and the corresponding Coxsackievirus B4-derived peptide, delayed IDDM onset. To establish the immunological mechanism underlying the reduced IDDM incidence following i.t. injection of islet cells, adoptive transfer of splenic leukocytes into NOD-scid/scid mice was performed. Splenic leukocytes from i.t.-injected non-diabetic females transferred IDDM into NOD-scid/scid recipients, but more slowly than splenocytes from unmanipulated, diabetic (control) donors. Co-transfer of 1:1 mixtures of splenic leukocytes from it islet-injected (and diabetes-free) NOD/Lt females and from untreated NOD/Lt diabetic donors produced IDDM as rapidly as splenocytes from diabetic donors injected alone. Hence, any peripheral suppression generated in i.t.-protected females was not sufficiently strong to prevent IDDM transfer by committed T-effector cells from the diabetic donors.(ABSTRACT TRUNCATED AT 250 WORDS) I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1 1 1 1,1	2	pubmed	train	118
Title: Serum ferritin levels in poorly- and well-controlled diabetes mellitus. Abstract: Serum ferritin level is related to body iron stores and is influenced by several diseases. We aimed to evaluate the association between serum ferritin concentration and the complications and nature of diabetes mellitus (DM). We examined association of ferritin concentration, fasting and post-prandial glucose levels and glycated hemoglobin in 329 patients with type 2 diabetes mellitus and 269 healthy controls. In the present study, 41 of 150 poorly controlled diabetic patients and 31 of 119 cases had hyperferritinemia. We confirmed that serum ferritin was increased in diabetic patients as long as glycemic control is not achieved. There was also a correlation between ferritin level and diabetic retinopathy. In conclusion, this study showed an independent positive association between serum ferritin concentration and markers of glucose homeostasis. 1-hop neighbor's text information:Title: The metal chelators, trientine and citrate, inhibit the development of cardiac pathology in the Zucker diabetic rat. Abstract: PURPOSE: The objective of this study was to determine the efficacy of dietary supplementation with the metal chelators, trientine or citric acid, in preventing the development of cardiomyopathy in the Zucker diabetic rat. HYPOTHESIS: We hypothesized that dietary chelators would attenuate metal-catalyzed oxidative stress and damage in tissues and protect against pathological changes in ventricular structure and function in type II diabetes. METHODS: Animals (10 weeks old) included lean control (LC, fa/+), untreated Zucker diabetic fatty (ZDF, fa/fa), and ZDF rats treated with either trientine (triethylenetetramine) or citrate at 20 mg/d in drinking water, starting when rats were frankly diabetic. Cardiac functional assessment was determined using a Millar pressure/volume catheter placed in the left ventricle at 32 weeks of age. RESULTS: End diastolic volume for the ZDF animals increased by 36% indicating LV dilatation (P < .05) and was accompanied by a 30% increase in the end diastolic pressure (P <or= .05). Both trientine and citric acid prevented the increases in EDV and EDP (P < .05). Ejection fraction and myocardial relaxation were also significantly improved with chelator treatment. CONCLUSION: Dietary supplementation with trientine and citric acid significantly prevented structural and functional changes in the diabetic heart, supporting the merits of mild chelators for prevention of cardiovascular disease in diabetes. 2-hop neighbor's text information:Title: Effect of antioxidant treatment of streptozotocin-induced diabetic rats on endoneurial blood flow, motor nerve conduction velocity, and vascular reactivity of epineurial arterioles of the sciatic nerve. Abstract: We have shown that diabetes-induced reduction in endoneurial blood flow (EBF) and impaired endothelium-dependent vascular relaxation precede slowing of motor nerve conduction velocity (MNCV) and decreased sciatic nerve Na(+)/K(+) ATPase activity. Furthermore, vascular dysfunction was accompanied by an accumulation of superoxide in arterioles that provide circulation to the sciatic nerve. In the present study, we examined the effect that treatment of streptozotocin-induced diabetic rats with antioxidants has on vascular and neural function. Diabetic rats were treated with 0.5% alpha-lipoic acid as a diet supplement or with hydroxyethyl starch deferoxamine (HES-DFO) by weekly intravenous injections at a dose of 75 mg/kg. The treatments significantly improved diabetes-induced decrease in EBF, acetylcholine-mediated vascular relaxation in arterioles that provide circulation to the region of the sciatic nerve, and MNCV. The treatments also reduced the production of superoxide by the aorta and superoxide and peroxynitrite by arterioles that provide circulation to the region of the sciatic nerve. Treating diabetic rats with alpha-lipoic acid prevented the diabetes-induced increase in thiobarbituric acid-reactive substances in serum and significantly improved lens glutathione levels. In contrast, treating diabetic rats with HES-DFO did not prevent diabetes-induced changes of either of these markers of oxidative stress. Diabetes-induced increase in sciatic nerve conjugated diene levels was not improved by treatment with either alpha-lipoic acid or HES-DFO. Treating diabetic rats with alpha-lipoic acid but not HES-DFO partially improved sciatic nerve Na(+)/K(+) ATPase activity and myo-inositol content. The increase in sciatic nerve sorbitol levels in diabetic rats was unchanged by either treatment. These studies suggest that diabetes-induced oxidative stress and the generation of superoxide may be partially responsible for the development of diabetic vascular and neural complications. 2-hop neighbor's text information:Title: Inhibitors of the Maillard reaction and AGE breakers as therapeutics for multiple diseases. Abstract: The Maillard reaction is a complex series of reactions that involve reducing-sugars and proteins, giving a multitude of end-products that are known as advanced glycation end-products (AGEs). AGEs can contribute to the pathogenesis of diabetes and neurological diseases such as Alzheimer's disease. AGEs also play a major role in vascular stiffening, atherosclerosis, osteoarthritis, inflammatory arthritis and cataracts. Thus, AGE inhibitors and AGE breakers offer a potential strategy as therapeutics for diverse diseases. Various AGE inhibitors have been developed in recent years, and their underlying mechanism is based on the attenuation of glycoxidation and/or oxidative stress by the sequestration of metal ions, reactive 1,2-dicarbonyl compounds, and reactive oxygen and reactive nitrogen species. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2 0 2,2	2	pubmed	train	121
Title: IL-1alpha, IL-1beta, and IFN-gamma mark beta cells for Fas-dependent destruction by diabetogenic CD4(+) T lymphocytes. Abstract: Cytokines such as IL-1alpha, IL-1beta, and IFN-gamma have long been implicated in the pathogenesis of autoimmune diabetes, but the mechanisms through which they promote diabetogenesis remain unclear. Here we show that CD4(+) T lymphocytes propagated from transgenic nonobese diabetic (NOD) mice expressing the highly diabetogenic, beta cell-specific 4.1-T-cell receptor (4.1-TCR) can kill IL-1alpha-, IL-1beta-, and IFN-gamma-treated beta cells from NOD mice. Untreated NOD beta cells and cytokine-treated beta cells from Fas-deficient NOD.lpr mice are not targeted by these T cells. Killing of islet cells in vitro was associated with cytokine-induced upregulation of Fas on islet cells and was independent of MHC class II expression. Abrogation of Fas expression in 4.1-TCR-transgenic NOD mice afforded nearly complete protection from diabetes and did not interfere with the development of the transgenic CD4(+) T cells or with their ability to cause insulitis. In contrast, abrogation of perforin expression did not affect beta cell-specific cytotoxicity or the diabetogenic potential of these T cells. These data demonstrate a novel mechanism of action of IL-1alpha, IL-1beta, and IFN-gamma in autoimmune diabetes, whereby these cytokines mark beta cells for Fas-dependent lysis by autoreactive CD4(+) T cells. 1-hop neighbor's text information:Title: Spontaneous autoimmune diabetes in monoclonal T cell nonobese diabetic mice. Abstract: It has been established that insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice results from a CD4+ and CD8+ T cell-dependent autoimmune process directed against the pancreatic beta cells. The precise roles that beta cell-reactive CD8+ and CD4+ T cells play in the disease process, however, remain ill defined. Here we have investigated whether naive beta cell-specific CD8+ and CD4+ T cells can spontaneously accumulate in pancreatic islets, differentiate into effector cells, and destroy beta cells in the absence of other T cell specificities. This was done by introducing Kd- or I-Ag7-restricted beta cell-specific T cell receptor (TCR) transgenes that are highly diabetogenic in NOD mice (8.3- and 4.1-TCR, respectively), into recombination-activating gene (RAG)-2-deficient NOD mice, which cannot rearrange endogenous TCR genes and thus bear monoclonal TCR repertoires. We show that while RAG-2(-/-) 4.1-NOD mice, which only bear beta cell-specific CD4+ T cells, develop diabetes as early and as frequently as RAG-2+ 4.1-NOD mice, RAG-2(-/-) 8.3-NOD mice, which only bear beta cell-specific CD8+ T cells, develop diabetes less frequently and significantly later than RAG-2(+) 8.3-NOD mice. The monoclonal CD8+ T cells of RAG-2(-/-) 8.3-NOD mice mature properly, proliferate vigorously in response to antigenic stimulation in vitro, and can differentiate into beta cell-cytotoxic T cells in vivo, but do not efficiently accumulate in islets in the absence of a CD4+ T cell-derived signal, which can be provided by splenic CD4+ T cells from nontransgenic NOD mice. These results demonstrate that naive beta cell- specific CD8+ and CD4+ T cells can trigger diabetes in the absence of other T or B cell specificities, but suggest that efficient recruitment of naive diabetogenic beta cell-reactive CD8+ T cells to islets requires the assistance of beta cell-reactive CD4+ T cells. 1-hop neighbor's text information:Title: Contribution of Fas to diabetes development. Abstract: Fas (Tnfrsf6, Apo-1, CD95) is a death receptor involved in apoptosis induced in many cell types. Fas have been shown to be expressed by insulin-producing beta cells in mice and humans. However, the importance of Fas in the development of autoimmune diabetes remains controversial. To further evaluate the importance of Fas in pathogenesis of diabetes, we generated NOD mice (nonobese diabetic mice developing spontaneous autoimmune diabetes) with beta cell-specific expression of a dominant-negative point mutation in a death domain of Fas, known as lpr(cg) or Fas(cg). Spontaneous diabetes was significantly delayed in NOD mice expressing Fas(cg), and the effect depended on the expression level of the transgene. However, Fas(cg)-bearing mice were still sensitive to diabetes transferred by splenocytes from overtly diabetic NOD mice. At the same time, Fas(cg) expression did neutralize the accelerating effect of transgenic Fas-ligand expressed by the same beta cells. Thus, both Fas-dependent and -independent mechanisms are involved in beta cell destruction, but interference with the Fas pathway early in disease development may retard or prevent diabetes progression. 2-hop neighbor's text information:Title: The role of CD8+ T cells in the initiation of insulin-dependent diabetes mellitus. Abstract: While it is generally accepted that T cells are critical for the development of diabetes in the non-obese diabetic (NOD) mouse, the precise functions of the CD4+ and CD8+ subsets remain ill-defined. Transfer experiments have provided evidence that CD4+ cells are the disease initiators, provoking massive mononuclear leukocyte infiltration into the pancreatic islets, while CD8+ cells play an effector role, responsible for the final destruction of islet beta cells. It was surprising, then, to find that NOD mice carrying a null mutation at the beta 2-microglobulin (beta 2-mu) locus, and thereby lacking major histocompatibility complex class I molecules and CD8+ T cells, developed neither insulitis nor diabetes. Here, we argue that the absence of insulitis in these animals results from their lack of CD8+ cells because islet infiltration is also absent when NOD mice are treated with an anti-CD8 monoclonal antibody (mAb) at a young age. Interestingly, the anti-CD8 effect is only observed when the mAb is injected during a discrete age window--2 to 5 weeks after birth. Transfer experiments indicate that the lack of CD8+ cells during this period somehow alters the phenotype of CD4+ cells, preventing them from expressing their insulitis potential. This is not because they are generally immuno-incompetent nor because they are generally more prone to differentiating into cells with Th2 characteristics. Given that neither the beta 2-mu mutation nor anti-CD8 treatment affect insulitis in a T cell receptor transgenic (tg) mouse strain with a CD4+ T cell repertoire highly skewed for an anti-islet cell reactivity, the most straight-forward interpretation of these observations is that CD8+ cells are required for effective priming and expansion of autoreactive CD4+ cells. 2-hop neighbor's text information:Title: Proinsulin: a unique autoantigen triggering autoimmune diabetes. Abstract: In healthy individuals the immune system does not react aggressively toward host cells, a phenomenon defined as self tolerance. If self tolerance is broken autoimmune disease can develop, during which autoreactive lymphocytes are directed to a variety of autoantigenic epitopes. However, researchers have yet to determine whether immune responses to multiple autoantigens develop independently of each other or are the result of the response "spreading" from one autoantigen to another. In a study of NOD mice in this issue of the JCI, Krishnamurthy et al. show that the autoreactive T cell response to the autoantigen proinsulin lies upstream of that to islet-specific glucose-6-phosphatase catalytic subunit-related protein, suggesting that the pathogenic autoimmune response to proinsulin subsequently spreads to other antigens (see the related article beginning on page 3258). These data support the current view that this pancreatic beta cell hormone is the first autoantigen targeted by the immune response in autoimmune diabetes. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1 1 1,1	2	pubmed	train	122
Title: Effects of varying carbohydrate content of diet in patients with non-insulin-dependent diabetes mellitus. Abstract: OBJECTIVE: To study effects of variation in carbohydrate content of diet on glycemia and plasma lipoproteins in patients with non-insulin-dependent diabetes mellitus (NIDDM). DESIGN: A four-center randomized crossover trial. SETTING: Outpatient and inpatient evaluation in metabolic units. PATIENTS: Forty-two NIDDM patients receiving glipizide therapy. INTERVENTIONS: A high-carbohydrate diet containing 55% of the total energy as carbohydrates and 30% as fats was compared with a high-monounsaturated-fat diet containing 40% carbohydrates and 45% fats. The amounts of saturated fats, polyunsaturated fats, cholesterol, sucrose, and protein were similar. The study diets, prepared in metabolic kitchens, were provided as the sole nutrients to subjects for 6 weeks each. To assess longer-term effects, a subgroup of 21 patients continued the diet they received second for an additional 8 weeks. MAIN OUTCOME MEASURES: Fasting plasma glucose, insulin, lipoproteins, and glycosylated hemoglobin concentrations. Twenty-four-hour profiles of glucose, insulin, and triglyceride levels. RESULTS: The site of study as well as the diet order did not affect the results. Compared with the high-monounsaturated-fat diet, the high-carbohydrate diet increased fasting plasma triglyceride levels and very low-density lipoprotein cholesterol levels by 24% (P < .0001) and 23% (P = .0001), respectively, and increased daylong plasma triglyceride, glucose, and insulin values by 10% (P = .03), 12% (P < .0001), and 9% (P = .02), respectively. Plasma total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels remained unchanged. The effects of both diets on plasma glucose, insulin, and triglyceride levels persisted for 14 weeks. CONCLUSIONS: In NIDDM patients, high-carbohydrate diets compared with high-monounsaturated-fat diets caused persistent deterioration of glycemic control and accentuation of hyperinsulinemia, as well as increased plasma triglyceride and very-low-density lipoprotein cholesterol levels, which may not be desirable. 1-hop neighbor's text information:Title: Association of diet with glycated hemoglobin during intensive treatment of type 1 diabetes in the Diabetes Control and Complications Trial. Abstract: BACKGROUND: Persons with type 1 diabetes have received widely varying dietary advice based on putative effects on glycemic control. OBJECTIVE: The objective was to determine whether diet composition was associated with subsequent glycated hemoglobin (Hb A1c) concentrations during intensive therapy for type 1 diabetes. DESIGN: We examined associations between quantiles of dietary intake and Hb A1c adjusted for age and sex in 532 intensively treated participants in the Diabetes Control and Complications Trial (DCCT) who had complete dietary data through 5 y of follow-up. Multivariate macronutrient density linear regression models tested the association of Hb A1c at year 5 with macronutrient composition and were adjusted for age, sex, exercise, triglyceride concentration, body mass index (BMI), baseline Hb A1c, and concurrent insulin dose. RESULTS: Higher insulin dose, lower carbohydrate intake, and higher saturated, monounsaturated, and total fat intakes were associated with higher Hb A1c concentrations at year 5. In age- and sex-adjusted multivariate macronutrient models, substitution of fat for carbohydrate was associated with higher Hb A1c concentrations (P = 0.01); this relation remained significant after adjustment for exercise level, serum triglycerides, and BMI (P = 0.02) but was no longer significant (P = 0.1) after adjustment for baseline Hb A1c and concurrent insulin dose. CONCLUSION: Among intensively treated patients with type 1 diabetes, diets higher in fat and saturated fat and lower in carbohydrate are associated with worse glycemic control, independent of exercise and BMI. 1-hop neighbor's text information:Title: Modifications of coronary risk factors. Abstract: In addition to the revascularization and glycemic management interventions assigned at random, the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) design includes the uniform control of major coronary artery disease risk factors, including dyslipidemia, hypertension, smoking, central obesity, and sedentary lifestyle. Target levels for risk factors were adjusted throughout the trial to comply with changes in recommended clinical practice guidelines. At present, the goals are low-density lipoprotein cholesterol <2.59 mmol/L (<100 mg/dL) with an optional goal of <1.81 mmol/L (<70 mg/dL); plasma triglyceride level <1.70 mmol/L (<150 mg/dL); blood pressure level <130 mm Hg systolic and <80 mm Hg diastolic; and smoking cessation treatment for all active smokers. Algorithms were developed for the pharmacologic management of dyslipidemia and hypertension. Dietary prescriptions for the management of glycemia, plasma lipid profiles, and blood pressure levels were adapted from existing clinical practice guidelines. Patients with a body mass index >25 were prescribed moderate caloric restriction; after the trial was under way, a lifestyle weight-management program was instituted. All patients were formally prescribed both endurance and resistance/flexibility exercises, individually adapted to their level of disability and fitness. Pedometers were distributed as a biofeedback strategy. Strategies to achieve the goals for risk factors were designed by BARI 2D working groups (lipid, cardiovascular and hypertension, and nonpharmacologic intervention) and the ongoing implementation of the strategies is monitored by lipid, hypertension, and lifestyle intervention management centers. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1,2	1	pubmed	train	123
Title: Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects. Abstract: Mutations in several genes encoding transcription factors of the hepatocyte nuclear factor (HNF) cascade are associated with maturity-onset diabetes of the young (MODY), a monogenic form of early-onset diabetes mellitus. The ability of the orphan nuclear receptor small heterodimer partner (SHP, NR0B2) to modulate the transcriptional activity of MODY1 protein, the nuclear receptor HNF-4alpha, suggested SHP as a candidate MODY gene. We screened 173 unrelated Japanese subjects with early-onset diabetes for mutations in this gene and found five different mutations (H53fsdel10, L98fsdel9insAC, R34X, A195S, and R213C) in 6 subjects as well as one apparent polymorphism (R216H), all present in the heterozygous state. Interestingly, all of the subjects with the mutations were mildly or moderately obese at onset of diabetes, and analysis of the lineages of these individuals indicated that the SHP mutations were associated with obesity rather than with diabetes. Therefore, an additional group of 101 unrelated nondiabetic subjects with early-onset obesity was screened for mutations in the SHP gene. Two of the previously observed mutations (R34X and A195S) and two additional mutations (R57W and G189E) were identified in 6 subjects, whereas no mutations were identified in 116 young nondiabetic lean controls (P = 0.0094). Functional studies of the mutant proteins show that the mutations result in the loss of SHP activity. These results suggest that genetic variation in the SHP gene contributes to increased body weight and reveal a pathway leading to this common metabolic disorder in Japanese. 1-hop neighbor's text information:Title: Maturity-onset diabetes of the young (MODY). Abstract: This review summarized aspects of the widening scope, phenotypic expression, natural history, recognition, pathogeneses, and heterogenous nature of maturity-onset diabetes of the young (MODY), an autosomal dominant inherited subtype of NIDDM, which can be recognized at a young age. There are differences in metabolic, hormonal, and vascular abnormalities in different ethnic groups and even among Caucasian pedigrees. In MODY patients with low insulin responses, there is a delayed and decreased insulin and C-peptide secretory response to glucose from childhood or adolescence, even before glucose intolerance appears; it may represent the basic genetic defect. The nondiabetic siblings have had normal insulin responses for decades. The fasting hyperglycemia of some MODY has been treated successfully with sulfonylureas for more than 30 years. In a few, after years or decades of diabetes, the insulin and C-peptide responses to glucose are so low that they may resemble those of early Type I diabetes. The rate of progression of the insulin secretory defect over time does distinguish between these two types of diabetes. In contrast are patients from families who have very high insulin responses to glucose despite glucose intolerance and fasting hyperglycemia similar to those seen in patients with low insulin responses. In many of these patients, there is in vivo and in vitro evidence of insulin resistance. Whatever its mechanism, the compensatory insulin responses to nutrients must be insufficient to maintain normal carbohydrate tolerance. This suggests that diabetes occurs only in those patients who have an additional islet cell defect, i.e., insufficient beta cell reserve and secretory capacity. In a few MODY pedigrees with high insulin responses to glucose and lack of evidence of insulin resistance, an insulin is secreted which is a structurally abnormal, mutant insulin molecule that is biologically ineffective. No associations have been found between specific HLA antigens and MODY in Caucasian, black, and Asian pedigrees. Linkage studies of the insulin gene, the insulin receptor gene, the erythrocyte/Hep G2 glucose transporter locus, and the apolipoprotein B locus have shown no association with MODY. Vascular disease may be as prevalent as in conventional NIDDM. Because of autosomal dominant transmission and penetrance at a young age, MODY is a good model for further investigations of etiologic and pathogenetic factors in NIDDM, including the use of genetic linkage strategies to identify diabetogenic genes. 1-hop neighbor's text information:Title: Altered insulin secretory responses to glucose in diabetic and nondiabetic subjects with mutations in the diabetes susceptibility gene MODY3 on chromosome 12. Abstract: One form of maturity-onset diabetes of the young (MODY) results from mutations in a gene, designated MODY3, located on chromosome 12 in band q24. The present study was undertaken to define the interactions between glucose and insulin secretion rate (ISR) in subjects with mutations in MODY3. Of the 13 MODY3 subjects, six subjects with normal fasting glucose and glycosylated hemoglobin and seven overtly diabetic subjects were studied as were six nondiabetic control subjects. Each subject received graded intravenous glucose infusions on two occasions separated by a 42-h continuous intravenous glucose infusion designed to prime the beta-cell to secrete more insulin in response to glucose. ISRs were derived by deconvolution of peripheral C-peptide levels. Basal glucose levels were higher and insulin levels were lower in MODY3 subjects with diabetes compared with nondiabetic subjects or with normal healthy control subjects. In response to the graded glucose infusion, ISRs were significantly lower in the diabetic subjects over a broad range of glucose concentrations. ISRs in the nondiabetic MODY3 subjects were not significantly different from those of the control subjects at plasma glucose levels <8 mmol/l. As glucose rose above this level, however, the increase in insulin secretion in these subjects was significantly reduced. Administration of glucose by intravenous infusion for 42 h resulted in a significant increase in the amount of insulin secreted over the 5-9 mmol/l glucose concentration range in the control subjects and nondiabetic MODY3 subjects (by 38 and 35%, respectively), but no significant change was observed in the diabetic MODY3 subjects. In conclusion, in nondiabetic MODY3 subjects insulin secretion demonstrates a diminished ability to respond when blood glucose exceeds 8 mmol/l. The priming effect of glucose on insulin secretion is preserved. Thus, beta-cell dysfunction is present before the onset of overt hyperglycemia in this form of MODY. The defect in insulin secretion in the nondiabetic MODY3 subjects differs from that reported previously in nondiabetic MODY1 or mildly diabetic MODY2 subjects. 1-hop neighbor's text information:Title: Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1) Abstract: The disease maturity-onset diabetes of the young (MODY) is a genetically heterogeneous monogenic form of non-insulin-dependent (type 2) diabetes mellitus (NIDDM), characterized by early onset, usually before 25 years of age and often in adolescence or childhood, and by autosomal dominant inheritance. It has been estimated that 2-5% of patients with NIDDM may have this form of diabetes mellitus. Clinical studies have shown that prediabetic MODY subjects have normal insulin sensitivity but suffer from a defect in glucose-stimulated insulin secretion, suggesting that pancreatic beta-cell dysfunction rather than insulin resistance is the primary defect in this disorder. Linkage studies have localized the genes that are mutated in MODY on human chromosomes 20 (MODY1), 7 (MODY2) and 12 (MODY3), with MODY2 and MODY3 being allelic with the genes encoding glucokinase, a key regulator of insulin secretion, and hepatocyte nuclear factor-1alpha (HNF-1alpha), a transcription factor involved in tissue-specific regulation of liver genes but also expressed in pancreatic islets, insulinoma cells and other tissues. Here we show that MODY1 is the gene encoding HNF-4alpha (gene symbol, TCF14), a member of the steroid/thyroid hormone receptor superfamily and an upstream regulator of HNF-1alpha expression. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2 2 2,2	1	pubmed	train	124
Title: Prevalence and risk factors for urinary incontinence in women with type 2 diabetes and impaired fasting glucose: findings from the National Health and Nutrition Examination Survey (NHANES) 2001-2002. Abstract: OBJECTIVE: Diabetes is associated with increased risk of urinary incontinence. It is unknown whether women with pre-diabetes, or impaired fasting glucose (IFG), have increased prevalence of incontinence. We determined the prevalence of, and risk factors for, incontinence among U.S. women with diabetes and IFG. RESEARCH DESIGN AND METHODS: The 2001-2002 National Health and Nutrition Examination Survey measured fasting plasma glucose and obtained information about diabetes and urinary incontinence among 1,461 nonpregnant adult women. Self-reported weekly or more frequent incontinence, both overall and by type (urge and stress), was our outcome. RESULTS: Of the 1,461 women, 17% had diabetes and 11% met criteria for IFG. Prevalence of weekly incontinence was similar among women in these two groups (35.4 and 33.4%, respectively) and significantly higher than among women with normal fasting glucose (16.8%); both urge and stress incontinence were increased. In addition to well-recognized risk factors including age, weight, and oral estrogen use, two microvascular complications caused by diabetes, specifically macroalbuminuria and peripheral neuropathic pain, were associated with incontinence. CONCLUSIONS: Physicians should be alert for incontinence, an often unrecognized and therefore undertreated disorder, among women with diabetes and IFG, in particular those with microvascular complications. The additional prospect of improvements in their incontinence may help motivate some high-risk women to undertake difficult lifestyle changes to reduce their more serious risk of diabetes and its sequelae. 1-hop neighbor's text information:Title: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Abstract: BACKGROUND: Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial. METHODS: 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48-60 years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6.1-15.0 mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. In the conventional group, the aim was the best achievable FPG with diet alone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy. FINDINGS: Over 10 years, haemoglobin A1c (HbA1c) was 7.0% (6.2-8.2) in the intensive group compared with 7.9% (6.9-8.8) in the conventional group--an 11% reduction. There was no difference in HbA1c among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-related endpoint; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40, p=0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints between the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p<0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg). INTERPRETATION: Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes.(ABSTRACT TRUNCATED) 1-hop neighbor's text information:Title: Type 2 diabetes mellitus and risk of developing urinary incontinence. Abstract: OBJECTIVES: To evaluate the association between type 2 diabetes mellitus (DM) and development of urinary incontinence in women. DESIGN: Prospective, observational study. SETTING: The Nurses' Health Study cohort. PARTICIPANTS: Eighty-one thousand eight hundred forty-five women who reported information on urinary function in 1996. MEASUREMENTS: Self-reported, physician-diagnosed DM was ascertained using questionnaire from 1976 to 1996 and confirmed using standard criteria. Self-reported urinary incontinence, defined as leakage at least weekly, was ascertained in 1996 and 2000. Logistic regression models were used to calculate multivariate-adjusted relative risks (RRs) and 95% confidence intervals (CIs) for the relationship between DM (as of 1996) and prevalent and incident incontinence. RESULTS: The risk of prevalent incontinence (multivariate RR=1.28, 95% CI=1.18-1.39) and incident incontinence (multivariate RR=1.21, 95% CI=1.02-1.43) was significantly greater in women with DM than women without. Using a validated severity index, risk of developing severe incontinence was even more substantial in women with DM than in those without (multivariate RR=1.40, 95% CI=1.15-1.71 for leakage enough to wet the underwear; RR=1.97, 95% CI=1.24-3.12 for leakage enough to wet the outer clothing). In addition, risk of incontinence increased with duration of DM (P-trend=.03 for prevalent incontinence; P=.001 for incident incontinence). CONCLUSION: DM independently increases risk of urinary incontinence in women. Because risk of incontinence appeared associated with longer duration of DM, even delaying the onset of DM could have important public health implications. 1-hop neighbor's text information:Title: Urinary incontinence among women with type 1 diabetes--how common is it? Abstract: PURPOSE: We compared the prevalence, level of bother and effect on daily activities of urinary incontinence among women with type 1 diabetes enrolled in the Epidemiology of Diabetes Interventions and Complications study to a population based sample of women with normal glucose. MATERIALS AND METHODS: We performed a cross-sectional analysis of women with type 1 diabetes and normal glucose tolerance using 2 study populations. The Diabetes Control and Complications Trial cohort followup, Epidemiology of Diabetes Interventions and Complications, began in 1994. In 2004 women participants (550) completed a self-administered questionnaire on urinary incontinence. Our primary outcome was weekly or greater incontinence, overall and by type. Prevalence of urinary incontinence was compared to a subgroup of women with normal glucose in the 2001 to 2002 National Health and Nutrition Examination Survey (NHANES). RESULTS: Overall 65% of women with type 1 diabetes reported any urinary incontinence (17% reported weekly incontinence). Nearly 40% of these women were greatly bothered by their incontinence and 9% believed it affected their day-to-day activities. Women with type 1 diabetes had a nearly 2-fold greater prevalence of weekly urge incontinence compared to those without diabetes in the NHANES cohort (8.8% vs 4.5%, p = 0.01). CONCLUSIONS: Urinary incontinence is common in women with type 1 diabetes and the prevalence of weekly urge incontinence is far greater compared to that in women with normal glucose levels. Moreover, the prevalence of urinary incontinence in women with type 1 diabetes was greater than that of neuropathy, retinopathy and nephropathy. These findings highlight the importance of screening for urinary incontinence among women with type 1 diabetes. Studies examining factors associated with urinary incontinence in women with type 1 diabetes are warranted. 2-hop neighbor's text information:Title: Management of type 2 diabetes mellitus. Role of thiazolidinediones. Abstract: OBJECTIVE: To review evidence supporting use of thiazolidinediones (TZDs) in management of type 2 diabetes mellitus (DM2). QUALITY OF EVIDENCE: A MEDLINE search found several randomized controlled trials (level I evidence). No systematic reviews of these trials were found in the Cochrane Library. MAIN MESSAGE: Thiazolidinediones lower hemoglobin AIc levels by as much as 1.0% to 1.5%. Effects can be seen in as little as 4 weeks, but full lowering takes 6 to 12 weeks. When used in combination with other diabetic agents, such as sulfonylureas and biguanides, TZDs' hypoglycemic effects appear to be complementary. Thiazolidinediones directly improve insulin sensitivity and recovery of pancreatic beta cell function. Nevertheless, there is no evidence indicating that TZDs are superior to other antidiabetic agents currently available or that TZDs reduce the long-term complications of DM2. CONCLUSION: Ongoing trials will further define the role of TZDs in management of diabetic patients. In current practice, cost is often a factor in the decision to prescribe TZDs. 2-hop neighbor's text information:Title: Antihypertensive therapy, new-onset diabetes, and cardiovascular disease. Abstract: Type 2 diabetes mellitus is a worldwide epidemic with considerable health and economic consequences. Diabetes is an important risk factor for cardiovascular disease, which is the leading cause of death in diabetic patients, and decreasing the incidence of diabetes may potentially reduce the burden of cardiovascular disease. This article discusses the clinical trial evidence for modalities associated with a reduction in the risk of new-onset diabetes, with a focus on the role of antihypertensive agents that block the renin-angiotensin system. Lifestyle interventions and the use of antidiabetic, anti-obesity, and lipid-lowering drugs are also reviewed. An unresolved question is whether decreasing the incidence of new-onset diabetes with non-pharmacologic or pharmacologic intervention will also lower the risk of cardiovascular disease. A large ongoing study is investigating whether the treatment with an oral antidiabetic drug or an angiotensin-receptor blocker will reduce the incidence of new-onset diabetes and cardiovascular disease in patients at high risk for developing diabetes. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2 2 1 2 2,2	2	pubmed	train	127
Title: Prevalence and risk factors for urinary incontinence in women with type 2 diabetes and impaired fasting glucose: findings from the National Health and Nutrition Examination Survey (NHANES) 2001-2002. Abstract: OBJECTIVE: Diabetes is associated with increased risk of urinary incontinence. It is unknown whether women with pre-diabetes, or impaired fasting glucose (IFG), have increased prevalence of incontinence. We determined the prevalence of, and risk factors for, incontinence among U.S. women with diabetes and IFG. RESEARCH DESIGN AND METHODS: The 2001-2002 National Health and Nutrition Examination Survey measured fasting plasma glucose and obtained information about diabetes and urinary incontinence among 1,461 nonpregnant adult women. Self-reported weekly or more frequent incontinence, both overall and by type (urge and stress), was our outcome. RESULTS: Of the 1,461 women, 17% had diabetes and 11% met criteria for IFG. Prevalence of weekly incontinence was similar among women in these two groups (35.4 and 33.4%, respectively) and significantly higher than among women with normal fasting glucose (16.8%); both urge and stress incontinence were increased. In addition to well-recognized risk factors including age, weight, and oral estrogen use, two microvascular complications caused by diabetes, specifically macroalbuminuria and peripheral neuropathic pain, were associated with incontinence. CONCLUSIONS: Physicians should be alert for incontinence, an often unrecognized and therefore undertreated disorder, among women with diabetes and IFG, in particular those with microvascular complications. The additional prospect of improvements in their incontinence may help motivate some high-risk women to undertake difficult lifestyle changes to reduce their more serious risk of diabetes and its sequelae. 1-hop neighbor's text information:Title: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. Abstract: OBJECTIVE: To determine whether tight control of blood pressure prevents macrovascular and microvascular complications in patients with type 2 diabetes. DESIGN: Randomised controlled trial comparing tight control of blood pressure aiming at a blood pressure of <150/85 mm Hg (with the use of an angiotensin converting enzyme inhibitor captopril or a beta blocker atenolol as main treatment) with less tight control aiming at a blood pressure of <180/105 mm Hg. SETTING: 20 hospital based clinics in England, Scotland, and Northern Ireland. SUBJECTS: 1148 hypertensive patients with type 2 diabetes (mean age 56, mean blood pressure at entry 160/94 mm Hg); 758 patients were allocated to tight control of blood pressure and 390 patients to less tight control with a median follow up of 8.4 years. MAIN OUTCOME MEASURES: Predefined clinical end points, fatal and non-fatal, related to diabetes, deaths related to diabetes, and all cause mortality. Surrogate measures of microvascular disease included urinary albumin excretion and retinal photography. RESULTS: Mean blood pressure during follow up was significantly reduced in the group assigned tight blood pressure control (144/82 mm Hg) compared with the group assigned to less tight control (154/87 mm Hg) (P<0.0001). Reductions in risk in the group assigned to tight control compared with that assigned to less tight control were 24% in diabetes related end points (95% confidence interval 8% to 38%) (P=0.0046), 32% in deaths related to diabetes (6% to 51%) (P=0.019), 44% in strokes (11% to 65%) (P=0.013), and 37% in microvascular end points (11% to 56%) (P=0.0092), predominantly owing to a reduced risk of retinal photocoagulation. There was a non-significant reduction in all cause mortality. After nine years of follow up the group assigned to tight blood pressure control also had a 34% reduction in risk in the proportion of patients with deterioration of retinopathy by two steps (99% confidence interval 11% to 50%) (P=0.0004) and a 47% reduced risk (7% to 70%) (P=0.004) of deterioration in visual acuity by three lines of the early treatment of diabetic retinopathy study (ETDRS) chart. After nine years of follow up 29% of patients in the group assigned to tight control required three or more treatments to lower blood pressure to achieve target blood pressures. CONCLUSION: Tight blood pressure control in patients with hypertension and type 2 diabetes achieves a clinically important reduction in the risk of deaths related to diabetes, complications related to diabetes, progression of diabetic retinopathy, and deterioration in visual acuity. 1-hop neighbor's text information:Title: Cardiovascular risk factors in confirmed prediabetic individuals. Does the clock for coronary heart disease start ticking before the onset of clinical diabetes? Abstract: Although type II diabetes is associated with both microvascular and macrovascular complications, duration of diabetes and severity of glycemia are strongly associated only with the former. Since prediabetic individuals are hyperinsulinemia, and since hyperinsulinemia may be a cardiovascular risk factor, we hypothesized that prediabetic individuals might have an atherogenic pattern of risk factors even before the onset of clinical diabetes, thereby explaining the relative lack of an association of macrovascular complications with either glycemic severity or disease duration. We documented the cardiovascular risk factor status of 614 initially nondiabetic Mexican Americans who later participated in an 8-year follow-up of the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease. Individuals who were nondiabetic at the time of baseline examination, but who subsequently developed type II diabetes (ie, confirmed prediabetic subjects, n = 43), had higher levels of total and low-density lipoprotein cholesterol, triglyceride, fasting glucose and insulin, 2-hour glucose, body mass index, and blood pressure, and lower levels of high-density lipoprotein cholesterol than subjects who remained nondiabetic (n = 571). Most of these differences persisted after adjustment for obesity and/or level of glycemia, but were abolished after adjustment for fasting insulin concentration. When subjects with impaired glucose tolerance at baseline (n = 106) were eliminated, the more atherogenic pattern of cardiovascular risk factors was still evident (and statistically significant) among initially normoglycemic prediabetic subjects. These results indicate that prediabetic subjects have an atherogenic pattern of risk factors (possibly caused by obesity, hyperglycemia, and especially hyperinsulinemia), which may be present for many years and may contribute to the risk of macrovascular disease as much as the duration of clinical diabetes itself. 1-hop neighbor's text information:Title: Diabetes and the risk of multi-system aging phenotypes: a systematic review and meta-analysis. Abstract: BACKGROUND: Observational studies suggested an association between diabetes and the risk of various geriatric conditions (i.e., cognitive impairment, dementia, depression, mobility impairment, disability, falls, and urinary incontinence). However, the magnitude and impact of diabetes on older adults have not been reviewed. METHODOLOGY/PRINCIPAL FINDINGS: MEDLINE and PSYCINFO databases were searched through November 2007 for published studies, supplemented by manual searches of bibliographies of key articles. Population-based, prospective cohort studies that reported risk of geriatric outcomes in relation to diabetes status at baseline were selected. Two authors independently extracted the data, including study population and follow-up duration, ascertainment of diabetes status at baseline, outcomes of interest and their ascertainment, adjusted covariates, measures of association, and brief results. Fifteen studies examined the association of DM with cognitive dysfunction. DM was associated with a faster decline in cognitive function among older adults. The pooled adjusted risk ratio (RR) for all dementia when persons with DM were compared to those without was 1.47 (95% CI, 1.25 to 1.73). Summary RRs for Alzheimer's disease and vascular dementia comparing persons with DM to those without were 1.39 (CI, 1.16 to 1.66) and 2.38 (CI, 1.79 to 3.18), respectively. Four of 5 studies found significant association of DM with faster mobility decline and incident disability. Two studies examined the association of diabetes with falls in older women. Both found statistically significant associations. Insulin users had higher RR for recurrent falls. One study for urinary incontinence in older women found statistically significant associations. Two studies for depression did not suggest that DM was an independent predictor of incident depression. CONCLUSIONS/SIGNIFICANCE: Current evidence supports that DM is associated with increased risk for selected geriatric conditions. Clinicians should increase their awareness and provide appropriate care. Future research is required to elucidate the underlying pathological pathway. 2-hop neighbor's text information:Title: Impact of diabetes on cognitive function among older Latinos: a population-based cohort study. Abstract: BACKGROUND AND OBJECTIVES: Type 2 diabetes, which is highly prevalent in older Mexican Americans, may influence cognitive functioning. We examined the association of diabetes with decline in global cognitive function and memory function over a 2-year period. METHODS: Study subjects were derived from an existing cohort of Latinos aged 60 and over in the SALSA project (n=1,789). Statistical analysis was conducted using logistic regression and a generalized estimating equation (GEE). RESULTS: Logistic regression analysis indicated that baseline diabetes was a significant predictor of major cognitive impairment in Modified Mini Mental State Exam (3MSE) (OR=1.68, 95% CI=1.21, 2.34) and word-list test (OR=1.31, 95% CI=0.99, 1.75). GEE analysis showed that there was no significant difference between diabetic and nondiabetic subjects in change of cognitive scores over 2 years (3MSE, mean=-0.58, 95% CI=-1.48, 0.32; word-list test, mean=-0.10, 95% CI=-0.32, 0.11). CONCLUSIONS: More diabetic complications were associated with major cognitive decline among diabetic subjects. Research on long-term impact of treatment for type 2 diabetes is warranted. 2-hop neighbor's text information:Title: The relationship between type 2 diabetes and cognitive dysfunction: longitudinal studies and their methodological limitations. Abstract: Type 2 diabetes and dementia in the elderly are major public health problems. Cross-sectional studies have suggested that these two conditions may be inter-related, but the nature of this association is uncertain. Causation can only be established through studies with a longitudinal design, taking into account the many potential confounding factors in any study of cognition. A literature search has identified 10 studies (nine population-based and one of case-controlled design) that included a definable diabetic population and assessments of cognitive function at baseline and at follow-up. These 10 studies utilised a combination of domain-specific cognitive assessments and a clinical diagnosis of dementia in the assessment of cognitive function. Diabetes was associated with either an accelerated cognitive decline or an increased incidence of dementia in eight of nine of the population-based studies. One study demonstrated a relationship between diabetes and vascular cognitive impairment, but not with other types of dementia. No association between type 2 diabetes and cognitive decline was demonstrated in the case-controlled study. These studies provide compelling evidence to support the view that people with type 2 diabetes are at increased risk of developing cognitive impairment in comparison with the general population. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2 2 2 2 2,2	2	pubmed	train	133
Title: Accelerated diabetes in non-obese diabetic (NOD) mice differing in incidence of spontaneous disease. Abstract: The NOD mouse is an established model of autoimmune diabetes mellitus. Various lines of NOD mice differ in their incidence of spontaneous diabetes, e.g. 93% of female NOD/Lt mice compared with 46% of female NOD/Wehi mice develop diabetes by 250 days. These two lines were studied under conditions which greatly accelerate the onset of hyperglycaemia. It was hoped that their responses to these manipulations would reveal characteristic differences which would increase our understanding of diabetes resistance in the low incidence NOD/Wehi line. One dose of 300 mg/kg of cyclophosphamide (CP) produced hyperglycaemia in 50% of NOD mice within 2 weeks in both lines. They were also equally susceptible to diabetes induced by splenocyte transfer at 21 days of age from prediabetic 150-day-old NOD/Lt or NOD/Wehi females. Five daily 40 mg/kg doses of streptozotocin (STZ) resulted in a severity of diabetes in the NOD mice greater than in C57BL or SJL/mice. While the incidence and severity of diabetes induced in the two NOD lines were similar, this appeared to be principally due to sensitivity to the toxic effects of STZ rather than its ability to exacerbate autoimmune beta cell destruction. It has previously been shown that it is possible to prevent diabetes in susceptible NOD mice with simple, relatively benign therapies and here we show that it is possible to induce diabetes in resistant animals at a rate indistinguishable from fully predisposed individuals. It therefore appears that the prediabetic NOD mouse is poised in an immunologically precarious state with the onset of disease being highly dependent on factors which exacerbate or moderate autoimmune destruction. 1-hop neighbor's text information:Title: Transfer of autoimmune diabetes mellitus with splenocytes from nonobese diabetic (NOD) mice. Abstract: The nonobese diabetic (NOD) mouse, a model of human type I diabetes, develops insulitis beginning at 4-6 wk of age. By 30 wk of age, 72% of females and 39% of males develop spontaneous diabetes, apparently because of an overwhelming autoimmune response to the insulin-producing beta-cells within the islets. To identify the immune mechanism responsible for destruction of beta-cells in the NOD mouse, we developed an adoptive transfer protocol that induces diabetes in NOD mice at an age when spontaneous diabetes is rarely observed. Splenocytes from overtly diabetic NOD mice were unable to transfer diabetes to very young (less than or equal to 6 wk) irradiated NOD mice but effectively transferred diabetes to irradiated NOD mice greater than 6 wk of age. In such transfers, overt diabetes was induced within 12-22 days in greater than 95% (79/82) of the recipients. Thus, transfer of splenocytes to young mice induces them to become diabetic at a higher frequency and at a younger age than their untreated littermates. Equally successful transfers with as few as 5 X 10(6) spleen cells have been performed in male and female NOD mice, even though males display a lower spontaneous incidence of diabetes than females. Splenocytes obtained from diabetic mice maintained on insulin for up to 2 mo also transferred diabetes. Because NOD mice display increasing levels of insulitis with age, spleen cells obtained from nondiabetic NOD mice of different ages were tested for their ability to transfer diabetes.(ABSTRACT TRUNCATED AT 250 WORDS) 1-hop neighbor's text information:Title: Raised temperature reduces the incidence of diabetes in the NOD mouse. Abstract: An association between the incidence of childhood Type 1 (insulin-dependent) diabetes mellitus and the average yearly temperature in different countries has been reported, the incidence being higher in countries with a lower mean temperature. We have studied the effect of environmental temperature on the incidence of diabetes in an animal model of Type 1 diabetes, the non-obese diabetic (NOD) mouse. Female NOD mice were divided at weaning, with one group placed at a higher temperature (mean 23.7 +/- 1.7 degrees C) and the other at a lower temperature (21.0 +/- 1.8 degrees C). At 20 weeks of age 6 of 16 mice at lower temperature and 1 of 17 mice at higher temperature had developed diabetes (p less than 0.02); at 30 weeks 10 of 16 and 5 of 17 mice had developed diabetes (p less than 0.05). Non-diabetic animals in the low temperature group had a higher food intake than those in the high temperature group between 13-15 weeks of age (28.0 +/- 1.2 g/week vs 24.8 +/- 0.7 g/week, p less than 0.05). In a parallel experiment, histological examination showed that there were similar degrees of insulitis in the high and low temperature groups at seven weeks of age. We conclude that environmental temperature can affect the incidence of diabetes in the NOD mouse and that this may be related to alterations in food intake. 1-hop neighbor's text information:Title: Syngeneic transfer of autoimmune diabetes from diabetic NOD mice to healthy neonates. Requirement for both L3T4+ and Lyt-2+ T cells. Abstract: We have developed a model of syngeneic adoptive transfer for type I diabetes mellitus of NOD mice. This model consists in injecting spleen cells from diabetic adult mice into newborn NOD recipients. 50% of recipients inoculated with 20 X 10(6) cells develop diabetes within the first 10 wk of life, at a time when none of the control littermates have yet become diabetic. The earliest successful transfers are observed at 3 wk of age, at a time when controls do not even exhibit histological changes in their pancreas. In addition we have shown that: (a) both males and females can be adoptively transferred, despite the fact that males rarely develop spontaneous diabetes in our colony; (b) diabetes transfer is a dose-dependent phenomenon that provides an in vivo assay for comparing the autoimmune potential of spleen cells from mice at various stages of their natural history; (c) the susceptibility of the recipients to the transfer is limited in time and declines after 3 wk; and (d) both L3T4+ and Lyt-2+ T cell subsets are necessary for the successful transfer. The neonatal syngeneic transfer provides an effective model for studies of the cellular events involved at regulatory and effector stages of autoimmune type I diabetes. 2-hop neighbor's text information:Title: Neonatal injections of cyclosporin enhance autoimmune diabetes in non-obese diabetic mice. Abstract: Since the modulation of the immune system at birth may influence the course of insulin-dependent (type 1) diabetes, we investigated whether neonatal injections of cyclosporin (CsA) to newborn non-obese diabetic (NOD) mice influence diabetes during later life. Two groups of 90 mice (45 female, 45 male) were injected intraperitoneally for the first 6 days of life with CsA (10 mg/kg per day) or with vehicle. In female NOD mice, the onset of diabetes was earlier and cumulative incidence was higher after neonatal treatment with CsA (P < 0.01). The incidence of diabetes was also dramatically enhanced in male NOD mice (P < 0.01), which normally display a very low disease incidence. Concomitantly, the severity of lymphocytic infiltration of the pancreatic islets was higher in female NOD mice neonatally treated by CsA (P < 0.02), and to a lesser extent in males, than in control mice. After administration of CsA to newborn NOD mice, there was a reduction (P < 0.01) of both CD4+CD8- and CD4-CD8+ thymocytes, whereas the number of double positive CD4+CD8+ thymocytes was increased. Concomitantly, Thy1-2+ cells in spleen were decreased (P < 0.01), and spleen cells expressing either CD3 molecule or alpha beta TCR complex were diminished (P < 0.01). Both CD4+ and CD8+ spleen T cells were depleted. By contrast, the low percentage of gamma delta TCR-expressing splenocytes was not modified. Numbers of MHC class 1+ or MHC class 2+ spleen cells were also depressed (P < 0.01). After neonatal injections of CsA, spleen cells showed a reduced response to concanavalin A (Con A) (P < 0.01). On the contrary, stimulation indices of splenocytes incubated with xenogeneic insulin-producing cell extracts were enhanced (P < 0.03). Proliferation indices of splenocytes to self class 2 antigens, generating suppressor cell activity, during syngeneic mixed lymphocyte reaction (SMLR) were significantly reduced (P < 0.01). Irradiated NOD mice were used as recipients for spleen cells from CsA-neonatally treated NOD mice. They displayed enhanced insulitis 2 weeks after transfer, and diabetes was successfully produced by 1 month after transfer in 50% of the recipients. By contrast, NOD mice which received control syngeneic spleen cells remained normoglycaemic, with only moderate islet infiltration which would be expected of NOD mice of this age. Thus, neonatal injections of CsA markedly enhance diabetes in both female and male NOD mice.(ABSTRACT TRUNCATED AT 400 WORDS) 2-hop neighbor's text information:Title: Abnormal T cell selection on nod thymic epithelium is sufficient to induce autoimmune manifestations in C57BL/6 athymic nude mice. Abstract: To investigate the role of primary T cell repertoire selection in the immunopathogenesis of autoimmune diseases, pure thymic epithelium (TE) from nonobese diabetic (NOD) embryos was grafted into non autoimmune prone newborn C57BL/6 athymic mice. The results show that NOD TE selects host T cell repertoires that establish autoimmunity in otherwise nondiabetic animals. Thus, such chimeras regularly show CD4 and CD8 T cell-mediated insulitis and sialitis, in contrast with syngeneic or allogeneic chimeras produced with TE from nonautoimmune strains. This is the first demonstration that autoimmunity to pancreatic beta cells and salivary glands can be established by the sole alteration of the thymic environment involved in T cell selection, regardless of the nature and presentation of both major histocompatibility complex and tissue-specific antigens on the target organ. These data indicate that T cell repertoire selection by the NOD thymic epithelium is sufficient to induce specific autoimmune characteristics in the context of an otherwise normal host. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	0 0 0 1 1,0	2	pubmed	train	134
Title: Reversed circadian blood pressure rhythm is associated with occurrences of both fatal and nonfatal vascular events in NIDDM subjects. Abstract: To assess the significance of reversed circadian blood pressure (BP) rhythms as a predictive factor of vascular events in NIDDM, vital status after an average 4-year follow-up was determined in 325 NIDDM subjects in whom the circadian BP profile had been monitored between 1988 and 1996. Circadian BP rhythm was analyzed by the COSINOR (a compound word for cosine and vector) method, as previously described. After exclusion of 37 dropped-out subjects, 288 were recruited to the further analysis, of which 201 had a normal circadian BP rhythm (group N) and the remaining 87 had a reversed one (group R). There was no difference in sex, HbA1c, the prevalence of smokers, serum lipids, or serum electrolytes between groups N and R at baseline, whereas age, the prevalence of hypertension, serum creatinine, and diabetic complications were more pronounced in group R than in group N. During the follow-up period (which averaged 52 months in group N and 36 months in group R), fatal and nonfatal vascular (cerebrovascular, cardiovascular, peripheral vascular arteries, and retinal artery) events occurred in 20 subjects in group N and 56 in group R. Unadjusted survival times and event-free times were estimated by the Kaplan-Meier product-limit method, and there was a significant difference in both unadjusted survival and event-free survival rates between groups N and R (P < 0.001 each; log-rank test). The Cox proportional-hazards model adjusted for age, sex, circadian BP pattern, duration of diabetes, therapy for diabetes, various diabetic complications, and hypertension demonstrated that circadian BP pattern and age exhibited significant, high adjusted relative risks for fatal events, and that diabetic nephropathy, postural hypotension, and hypertension as well as circadian BP pattern exhibited significant, high adjusted relative risks with respect to the occurrence of various nonfatal vascular events. These results suggest that reversed circadian BP rhythm is associated with occurrences of both fatal and nonfatal vascular events in NIDDM subjects. 1-hop neighbor's text information:Title: Diabetes and cardiovascular autonomic dysfunction: application of animal models. Abstract: When diabetes is associated with cardiovascular autonomic dysfunction, there is a poor prognosis and increased morbidity and mortality. Information on the mechanisms of diabetes-associated autonomic dysfunction has been provided by advanced studies using physiological, pharmacological, anatomical and molecular methods in experimental animal models of insulin deficiency and resistance. This has been augmented by new approaches which combine diabetes induction with genetically modified animal models. The aim of this review is to outline and discuss the animal models used for the study of insulin deficiency and insulin resistance with a focus on autonomic neural interactions. The goal is to better understand the clinical relevance of cardiovascular autonomic dysfunction associated with diabetes. 2-hop neighbor's text information:Title: Baroreflex and chemoreflex dysfunction in streptozotocin-diabetic rats. Abstract: Several investigators have demonstrated that streptozotocin (STZ) diabetes induces changes in the autonomic control of the cardiovascular system. Changes in cardiovascular function may be related to peripheral neuropathy. The aim of the present study was to analyze changes in heart rate (HR) and arterial pressure (AP) as well as baroreflex and chemoreflex sensitivity in STZ-induced diabetic male Wistar rats (STZ, 50 mg/kg, i.v., 15 days). Intra-arterial blood pressure signals were obtained for control and diabetic rats (N = 9, each group). Data were processed in a data acquisition system (CODAS, 1 kHz). Baroreflex sensitivity was evaluated by measuring heart rate changes induced by arterial pressure variation produced by phenylephrine and sodium nitroprusside injection. Increasing doses of potassium cyanide (KCN) were used to evaluate bradycardic and pressor responses evoked by chemoreflex activation. STZ induced hyperglycemia (447 +/- 49 vs 126 +/- 3 mg/dl), and a reduction in AP (99 +/- 3 vs 118 +/- 2 mmHg), resting HR (296 +/- 11 vs 355 +/- 16 bpm) and plasma insulin levels (16 +/- 1 vs 57 +/- 11 microU/ml). We also observed that the reflex bradycardia (-16.8 +/- 0.1 vs -12.5 +/- 0.1 bpm/mmHg, in the diabetic group) and tachycardia (-3.68 +/- 0.5 vs -1.75 +/- 0.3 bpm/mmHg, in the diabetic group) produced by vasopressor and depressor agents were impaired in the diabetic group. Bradycardia evoked by chemoreflex activation was attenuated in diabetic rats (control: -17 +/- 1, -86 +/- 19, -185 +/- 18, -208 +/- 17 vs diabetic: -7 +/- 1, -23 +/- 5, -95 +/- 13, -140 +/- 13 bpm), as also was the pressor response (control: 6 +/- 1, 30 +/- 7, 54 +/- 4, 59 +/- 5 vs diabetic: 6 +/- 1, 8 +/- 2, 33 +/- 4, 42 +/- 5 mmHg). In conclusion, the cardiovascular response evoked by baroreflex and chemoreflex activation are impaired in diabetic rats. The alterations of cardiovascular responses may be secondary to the autonomic dysfunction of cardiovascular control. 2-hop neighbor's text information:Title: Autonomic neuropathy is associated with increased cardiovascular risk factors: the EURODIAB IDDM Complications Study. Abstract: AIMS: To assess the prevalence of and risk factors for autonomic neuropathy in the EURODIAB IDDM Complications Study. METHODS: The study involved the examination of randomly selected Type I (insulin-dependent) diabetic patients from 31 centres in 16 European countries. Neuropathic symptoms and two tests of autonomic function (changes in heart rate and blood pressure from lying to standing) were assessed and data from 3007 patients were available for the present analysis. Autonomic neuropathy was defined as an abnormality of at least one of the tests. RESULTS: The prevalence of autonomic neuropathy was 36% with no sex differences. The frequency of one and two abnormal reflex tests was 30% and 6%, respectively. The R-R ratio was abnormal in 24% of patients while 18% had orthostatic hypotension defined as a fall in systolic blood pressure > 20 mmHg on standing. Significant correlations were observed between autonomic neuropathy and age (P < 0.01), duration of diabetes (P < 0.0001), HbA1c (P < 0.0001), diastolic blood pressure (P < 0.05), lower HDL-cholesterol (P < 0.01), the presence of retinopathy (P < 0.0001) and albuminuria (P < 0.0001). New associations have been identified from the study: the strong relationship of autonomic neuropathy to cigarette smoking (P < 0.01), total cholesterol/HDL-cholesterol ratio (P < 0.05) and fasting triglyceride (P < 0.0001). As a key finding, autonomic neuropathy was related to the presence of cardiovascular disease (P < 0.0001). All analyses were adjusted for age, duration of diabetes and HbA1c. However, data have been only partly confirmed by logistic regression analyses. Frequency of dizziness on standing up was 18%, while only 4% of patients had nocturnal diarrhoea and 5% had problems with bladder control. CONCLUSION: Cardiovascular reflex tests, even in the form of the two tests applied, rather than a questionnaire, seem to be appropriate for the diagnosis of autonomic neuropathy. The study has identified previously known and new potential risk factors for the development of autonomic neuropathy, which may be important for the development of risk reduction strategies. Our results may support the role of vascular factors in the pathogenesis of autonomic neuropathy. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	0 0 1,2	2	pubmed	train	135
Title: Direct involvement of macrophages in destruction of beta-cells leading to development of diabetes in virus-infected mice. Abstract: A single administration of complete Freund's adjuvant (CFA), type 1 carrageenan (Car), or silica 7, 2, and 2 days, respectively, before infection with a low dose (1 x 10(2) plaque-forming units/mouse) of encephalomyocarditis D (EMC-D) virus resulted in a significant increase in the incidence of diabetes in SJL/J mice (100%) compared with untreated EMC-D virus-infected mice (40%). Peritoneal macrophages were isolated from uninfected SJL/J mice, which had been treated once with silica, and transferred into SJL/J mice 2 days before low-dose EMC-D infection. Approximately 90% of the mice became diabetic, whereas 30% of mice that received virus alone became diabetic. The depletion of macrophages by treatment with the combined anti-Mac-1 and anti-Mac-2 monoclonal antibodies after a single administration of CFA, Car, or silica resulted in almost complete prevention of beta-cell destruction in EMC-D virus-infected mice. Furthermore, none of the mice in which macrophages were depleted by long-term treatment with silica and 10% of the mice treated with Car before virus infection became diabetic. On the basis of these observations, we conclude that macrophages are directly involved in the destruction of beta-cells, leading to the development of clinical diabetes in EMC-D virus-infected mice. 1-hop neighbor's text information:Title: Prevention of encephalomyocarditis virus-induced diabetes in mice by inhibition of the tyrosine kinase signalling pathway and subsequent suppression of nitric oxide production in macrophages. Abstract: Macrophages comprise the major population of cells infiltrating pancreatic islets during the early stages of infection in DBA/2 mice by the D variant of encephalomyocarditis virus (EMC-D virus). Inactivation of macrophages prior to viral infection almost completely prevents EMC-D virus-induced diabetes. This investigation was initiated to determine whether a tyrosine kinase signalling pathway might be involved in the activation of macrophages by EMC-D virus infection and whether tyrosine kinase inhibitors might, therefore, abrogate EMC-D virus-induced diabetes in vivo. When isolated macrophages were infected with EMC-D virus, inducible nitric oxide synthase mRNA was expressed and nitric oxide was subsequently produced. Treatment of macrophages with the tyrosine kinase inhibitor tyrphostin AG126, but not tyrphostin AG556, prior to EMC-D virus infection blocked the production of nitric oxide. The infection of macrophages with EMC-D virus also resulted in the activation of the mitogen-activated protein kinases (MAPKs) p42(MAPK/ERK2)/p44(MAPK/ERK1), p38(MAPK), and p46/p54(JNK). In accord with the greater potency of AG126 than of AG556 in blocking EMC-D virus-mediated macrophage activation, the incidence of diabetes in EMC-D virus-infected mice treated with AG126 (25%) was much lower than that in AG556-treated (75%) or vehicle-treated (88%) control mice. We conclude that EMC-D virus-induced activation of macrophages resulting in macrophage-mediated beta-cell destruction can be prevented by the inhibition of a tyrosine kinase signalling pathway involved in macrophage activation. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1,0	1	pubmed	train	136
Title: Inflammation is more persistent in type 1 diabetic mice. Abstract: Whether diabetes enhances or diminishes the host response to bacteria has been controversial. To determine how diabetes alters the inflammatory response, we inoculated P. gingivalis into the scalps of mice rendered diabetic with multiple low-dose streptozotocin treatment. On day 1, a moderate to severe inflammatory infiltrate was noted in both the diabetic and normoglycemic mice. After 3 days, the inflammatory infiltrate was significantly higher in the diabetic compared with the control group (P < 0.05). The mRNA expression of chemokines macrophage inflammatory protein-2 and monocyte chemoattractant protein-1 was strongly and similarly induced 3 hrs and 1 day post-inoculation. By day 3, the levels were reduced in normoglycemic mice but remained significantly higher in the diabetic group (P < 0.05). To determine whether persistent inflammation was specific for the streptozotocin-induced diabetic model, we directly compared the expression of TNF-alpha in streptozotocin-induced and db/db diabetic mice, which developed type 2 diabetes. Both exhibited prolonged TNF-alpha expression compared with controls. These results suggest that diabetes alters bacteria-host interactions by prolonging the inflammatory response. 1-hop neighbor's text information:Title: Alloxan-induced diabetes triggers the development of periodontal disease in rats. Abstract: BACKGROUND: Periodontal disease in diabetic patients presents higher severity and prevalence; and increased severity of ligature-induced periodontal disease has been verified in diabetic rats. However, in absence of aggressive stimuli such as ligatures, the influence of diabetes on rat periodontal tissues is incompletely explored. The aim of this study was to evaluate the establishment and progression of periodontal diseases in rats only with diabetes induction. METHODOLOGY/PRINCIPAL FINDINGS: Diabetes was induced in Wistar rats (n = 25) by intravenous administration of alloxan (42 mg/kg) and were analyzed at 1, 3, 6, 9 and 12 months after diabetes induction. The hemimandibles were removed and submitted to radiographical and histopathological procedures. A significant reduction was observed in height of bone crest in diabetic animals at 3, 6, 9 and 12 months, which was associated with increased numbers of osteoclasts and inflammatory cells. The histopathological analyses of diabetic rats also showed a reduction in density of collagen fibers, fibroblasts and blood vessels. Severe caries were also detected in the diabetic group. CONCLUSIONS/SIGNIFICANCE: The results demonstrate that diabetes induction triggers, or even co-induces the onset of alterations which are typical of periodontal diseases even in the absence of aggressive factors such as ligatures. Therefore, diabetes induction renders a previously resistant host into a susceptible phenotype, and hence diabetes can be considered a very important risk factor to the development of periodontal disease. 1-hop neighbor's text information:Title: Diabetes causes the accelerated loss of cartilage during fracture repair which is reversed by insulin treatment. Abstract: Fracture healing in diabetic individuals and in animal models of diabetes is impaired. To investigate mechanisms by which diabetes may affect fracture healing we focused on the transition from cartilage to bone, a midpoint in the fracture healing process. Femoral fractures were induced in mice rendered diabetic by multiple low dose streptozotocin treatment and compared to matching normoglycemic mice. One group of diabetic animals was treated with slow release insulin to maintain normal serum glucose levels. The results indicate that there was relatively little difference in the initial formation of the fracture callus on day 10. However, on day 16 the diabetic group had significantly smaller callus, greater loss of cartilage and enhanced osteoclastogenesis that was normalized by treatment with insulin when assessed by histomorphometric analysis. Chondrocyte apoptosis was significantly higher in diabetic mice and this increase was blocked by insulin. These changes were accompanied by diabetes-increased mRNA levels of RANKL, TNF-alpha, and ADAMTS-4 and -5 measured by real-time PCR, which was reversed by insulin treatment. On days 16 and 22 bone formation within the callus of diabetic mice was significantly less than the normoglycemic and brought to normal levels by insulin treatment. These results suggest that a significant effect of diabetes on fracture healing is increased chondrocyte apoptosis and osteoclastogenesis that accelerates the loss of cartilage and reduces the anlage for endochondral bone formation during fracture repair. That insulin reverses these effects demonstrates that they are directly related to the diabetic condition. 1-hop neighbor's text information:Title: Diabetes enhances periodontal bone loss through enhanced resorption and diminished bone formation. Abstract: Using a ligature-induced model in type-2 Zucker diabetic fatty (ZDF) rat and normoglycemic littermates, we investigated whether diabetes primarily affects periodontitis by enhancing bone loss or by limiting osseous repair. Diabetes increased the intensity and duration of the inflammatory infiltrate (P < 0.05). The formation of osteoclasts and percent eroded bone after 7 days of ligature placement was similar, while four days after removal of ligatures, the type 2 diabetic group had significantly higher osteoclast numbers and activity (P < 0.05). The amount of new bone formation following resorption was 2.4- to 2.9-fold higher in normoglycemic vs. diabetic rats (P < 0.05). Diabetes also increased apoptosis and decreased the number of bone-lining cells, osteoblasts, and periodontal ligament fibroblasts (P < 0.05). Thus, diabetes caused a more persistent inflammatory response, greater loss of attachment and more alveolar bone resorption, and impaired new bone formation. The latter may be affected by increased apoptosis of bone-lining and PDL cells. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	0 0 2,0	1	pubmed	train	137
Title: Prevalence and risk factors for urinary incontinence in women with type 2 diabetes and impaired fasting glucose: findings from the National Health and Nutrition Examination Survey (NHANES) 2001-2002. Abstract: OBJECTIVE: Diabetes is associated with increased risk of urinary incontinence. It is unknown whether women with pre-diabetes, or impaired fasting glucose (IFG), have increased prevalence of incontinence. We determined the prevalence of, and risk factors for, incontinence among U.S. women with diabetes and IFG. RESEARCH DESIGN AND METHODS: The 2001-2002 National Health and Nutrition Examination Survey measured fasting plasma glucose and obtained information about diabetes and urinary incontinence among 1,461 nonpregnant adult women. Self-reported weekly or more frequent incontinence, both overall and by type (urge and stress), was our outcome. RESULTS: Of the 1,461 women, 17% had diabetes and 11% met criteria for IFG. Prevalence of weekly incontinence was similar among women in these two groups (35.4 and 33.4%, respectively) and significantly higher than among women with normal fasting glucose (16.8%); both urge and stress incontinence were increased. In addition to well-recognized risk factors including age, weight, and oral estrogen use, two microvascular complications caused by diabetes, specifically macroalbuminuria and peripheral neuropathic pain, were associated with incontinence. CONCLUSIONS: Physicians should be alert for incontinence, an often unrecognized and therefore undertreated disorder, among women with diabetes and IFG, in particular those with microvascular complications. The additional prospect of improvements in their incontinence may help motivate some high-risk women to undertake difficult lifestyle changes to reduce their more serious risk of diabetes and its sequelae. 1-hop neighbor's text information:Title: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Abstract: BACKGROUND: Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial. METHODS: 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48-60 years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6.1-15.0 mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. In the conventional group, the aim was the best achievable FPG with diet alone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy. FINDINGS: Over 10 years, haemoglobin A1c (HbA1c) was 7.0% (6.2-8.2) in the intensive group compared with 7.9% (6.9-8.8) in the conventional group--an 11% reduction. There was no difference in HbA1c among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-related endpoint; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40, p=0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints between the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p<0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg). INTERPRETATION: Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes.(ABSTRACT TRUNCATED) 1-hop neighbor's text information:Title: Type 2 diabetes mellitus and risk of developing urinary incontinence. Abstract: OBJECTIVES: To evaluate the association between type 2 diabetes mellitus (DM) and development of urinary incontinence in women. DESIGN: Prospective, observational study. SETTING: The Nurses' Health Study cohort. PARTICIPANTS: Eighty-one thousand eight hundred forty-five women who reported information on urinary function in 1996. MEASUREMENTS: Self-reported, physician-diagnosed DM was ascertained using questionnaire from 1976 to 1996 and confirmed using standard criteria. Self-reported urinary incontinence, defined as leakage at least weekly, was ascertained in 1996 and 2000. Logistic regression models were used to calculate multivariate-adjusted relative risks (RRs) and 95% confidence intervals (CIs) for the relationship between DM (as of 1996) and prevalent and incident incontinence. RESULTS: The risk of prevalent incontinence (multivariate RR=1.28, 95% CI=1.18-1.39) and incident incontinence (multivariate RR=1.21, 95% CI=1.02-1.43) was significantly greater in women with DM than women without. Using a validated severity index, risk of developing severe incontinence was even more substantial in women with DM than in those without (multivariate RR=1.40, 95% CI=1.15-1.71 for leakage enough to wet the underwear; RR=1.97, 95% CI=1.24-3.12 for leakage enough to wet the outer clothing). In addition, risk of incontinence increased with duration of DM (P-trend=.03 for prevalent incontinence; P=.001 for incident incontinence). CONCLUSION: DM independently increases risk of urinary incontinence in women. Because risk of incontinence appeared associated with longer duration of DM, even delaying the onset of DM could have important public health implications. 1-hop neighbor's text information:Title: Urinary incontinence among women with type 1 diabetes--how common is it? Abstract: PURPOSE: We compared the prevalence, level of bother and effect on daily activities of urinary incontinence among women with type 1 diabetes enrolled in the Epidemiology of Diabetes Interventions and Complications study to a population based sample of women with normal glucose. MATERIALS AND METHODS: We performed a cross-sectional analysis of women with type 1 diabetes and normal glucose tolerance using 2 study populations. The Diabetes Control and Complications Trial cohort followup, Epidemiology of Diabetes Interventions and Complications, began in 1994. In 2004 women participants (550) completed a self-administered questionnaire on urinary incontinence. Our primary outcome was weekly or greater incontinence, overall and by type. Prevalence of urinary incontinence was compared to a subgroup of women with normal glucose in the 2001 to 2002 National Health and Nutrition Examination Survey (NHANES). RESULTS: Overall 65% of women with type 1 diabetes reported any urinary incontinence (17% reported weekly incontinence). Nearly 40% of these women were greatly bothered by their incontinence and 9% believed it affected their day-to-day activities. Women with type 1 diabetes had a nearly 2-fold greater prevalence of weekly urge incontinence compared to those without diabetes in the NHANES cohort (8.8% vs 4.5%, p = 0.01). CONCLUSIONS: Urinary incontinence is common in women with type 1 diabetes and the prevalence of weekly urge incontinence is far greater compared to that in women with normal glucose levels. Moreover, the prevalence of urinary incontinence in women with type 1 diabetes was greater than that of neuropathy, retinopathy and nephropathy. These findings highlight the importance of screening for urinary incontinence among women with type 1 diabetes. Studies examining factors associated with urinary incontinence in women with type 1 diabetes are warranted. 2-hop neighbor's text information:Title: Improved glycaemic control by switching from insulin NPH to insulin glargine: a retrospective observational study. Abstract: BACKGROUND: Insulin glargine (glargine) and insulin NPH (NPH) are two basal insulin treatments. This study investigated the effect on glycaemic control of switching from a NPH-based regimen to a glargine-based regimen in 701 patients with type 1 (n= 304) or type 2 (n= 397) diabetes, using unselected primary care data. METHODS: Data for this retrospective observational study were extracted from a UK primary care database (The Health Improvement Network). Patients were required to have at least 12 months of data before and after switching from NPH to glargine. The principal analysis was the change in HbA(1c) after 12 months treatment with glargine; secondary analyses included change in weight and total daily insulin dose. Inconsistent reporting of hypoglycemic episodes precludes reliable reporting of this outcome. Multivariate analyses were used to adjust for baseline characteristics and confounding variables. RESULTS: After adjustment, both diabetic cohorts showed statistically significant reductions in mean HbA(1c) 12 months after the switch, by 0.38% (p < 0.001) in type 1 patients and 0.31% (p < 0.001) in type 2 patients. Improvement in HbA1c was positively correlated with baseline HbA(1c); patients with baseline HbA(1c) > or = 8% had reductions of 0.57% (p < 0.001) and 0.47% (p < 0.001), respectively. There was no significant change in weight or total daily insulin dose while on glargine. The majority of patients received a basal-bolus regimen prior to and after the switch (mean 79.3% before and 77.2% after switch in type 1 patients, and 80.4% and 76.8%, respectively in type 2 patients, p > 0.05). CONCLUSION: In routine clinical practice, switching from NPH to glargine provides the opportunity for improving glycaemic control in diabetes patients inadequately controlled by NPH. 2-hop neighbor's text information:Title: Can a chronic care model collaborative reduce heart disease risk in patients with diabetes? Abstract: BACKGROUND: There is a need to identify effective practical interventions to decrease cardiovascular disease risk in patients with diabetes. OBJECTIVE: We examine the impact of participation in a collaborative implementing the chronic care model (CCM) on the reduction of cardiovascular disease risk in patients with diabetes. DESIGN: Controlled pre- and postintervention study. PATIENTS/PARTICIPANTS: Persons with diabetes receiving care at 13 health care organizations exposed to the CCM collaborative and controls receiving care in nonexposed sites. MEASUREMENTS AND MAIN RESULTS: Ten-year risk of cardiovascular disease; determined using a modified United Kingdom Prospective Diabetes Study risk engine score. A total number of 613 patients from CCM intervention sites and 557 patients from usual care control sites met the inclusion criteria. The baseline mean 10-year risk of cardiovascular disease was 31% for both the intervention group and the control group. Participants in both groups had improved blood pressure, lipid levels, and HbA1c levels during the observation period. Random intercept hierarchical regression models showed that the intervention group had a 2.1% (95% CI -3.7%, -0.5%) greater reduction in predicted risk for future cardiovascular events when compared to the control group. This would result in a reduced risk of one cardiovascular disease event for every 48 patients exposed to the intervention. CONCLUSIONS: Over a 1-year interval, this collaborative intervention using the CCM lowered the cardiovascular disease risk factors of patients with diabetes who were cared for in the participating organization's settings. Further work could enhance the impact of this promising multifactorial intervention on cardiovascular disease risk reduction. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2 2 1 1 2,2	2	pubmed	train	140
Title: Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects. Abstract: Mutations in several genes encoding transcription factors of the hepatocyte nuclear factor (HNF) cascade are associated with maturity-onset diabetes of the young (MODY), a monogenic form of early-onset diabetes mellitus. The ability of the orphan nuclear receptor small heterodimer partner (SHP, NR0B2) to modulate the transcriptional activity of MODY1 protein, the nuclear receptor HNF-4alpha, suggested SHP as a candidate MODY gene. We screened 173 unrelated Japanese subjects with early-onset diabetes for mutations in this gene and found five different mutations (H53fsdel10, L98fsdel9insAC, R34X, A195S, and R213C) in 6 subjects as well as one apparent polymorphism (R216H), all present in the heterozygous state. Interestingly, all of the subjects with the mutations were mildly or moderately obese at onset of diabetes, and analysis of the lineages of these individuals indicated that the SHP mutations were associated with obesity rather than with diabetes. Therefore, an additional group of 101 unrelated nondiabetic subjects with early-onset obesity was screened for mutations in the SHP gene. Two of the previously observed mutations (R34X and A195S) and two additional mutations (R57W and G189E) were identified in 6 subjects, whereas no mutations were identified in 116 young nondiabetic lean controls (P = 0.0094). Functional studies of the mutant proteins show that the mutations result in the loss of SHP activity. These results suggest that genetic variation in the SHP gene contributes to increased body weight and reveal a pathway leading to this common metabolic disorder in Japanese. 1-hop neighbor's text information:Title: Phenotypic characteristics of early-onset autosomal-dominant type 2 diabetes unlinked to known maturity-onset diabetes of the young (MODY) genes. Abstract: OBJECTIVE: To investigate whether there are forms of early-onset autosomal-dominant type 2 diabetes that are distinct from typical maturity-onset diabetes of the young (MODY) and to characterize their phenotypic characteristics. RESEARCH DESIGN AND METHODS: The study included 220 affected subjects from 29 families in which early-onset type 2 diabetes occurred in multiple generations and was not linked to known MODY genes (MODY gene-negative families). All individuals underwent an oral glucose tolerance test and other clinical measurements aimed at investigating the underlying metabolic defect and the presence of diabetic complications. For comparison, 79 affected carriers of MODY3 (hepatocyte nuclear factor [HNF]-1 alpha) mutations were similarly examined. RESULTS: Subjects from MODY gene-negative pedigrees were diagnosed with diabetes at an older age (36 +/- 17 vs. 21 +/- 10 years, P = 0.0001) and were more frequently obese (52 vs. 18%, P = 0.0001) than MODY3 individuals. MODY gene-negative patients who were insulin treated required more exogenous insulin than did MODY3 subjects (0.7 +/- 0.4 vs. 0.45 +/- 0.2 U.kg-1.day-1, P = 0.04), despite similar C-peptide levels. Among subjects not treated with insulin, MODY gene-negative subjects had significantly higher serum insulin levels, both fasting (16.5 +/- 15 vs. 6.5 +/- 5 microU/ml, P = 0.027) and 2 h after a glucose load (53 +/- 44 vs. 11 +/- 10, P = 0.002). They also had higher serum triglycerides (P = 0.02), higher cholesterol levels (P = 0.02), more hypertension (P = 0.0001), and more nephropathy (P = 0.001). Differences persisted when families were matched for age at diagnosis. CONCLUSIONS: Our findings indicate the existence of forms of early-onset autosomal-dominant type 2 diabetes that are distinct from MODY and are frequently characterized by insulin resistance, similar to later-onset type 2 diabetes. Because of the Mendelian pattern of inheritance, the goal of identifying the genes involved in these forms of diabetes appears to be particularly feasible. 1-hop neighbor's text information:Title: Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3) Abstract: The disease non-insulin-dependent (type 2) diabetes mellitus (NIDDM) is characterized by abnormally high blood glucose resulting from a relative deficiency of insulin. It affects about 2% of the world's population and treatment of diabetes and its complications are an increasing health-care burden. Genetic factors are important in the aetiology of NIDDM, and linkage studies are starting to localize some of the genes that influence the development of this disorder. Maturity-onset diabetes of the young (MODY), a single-gene disorder responsible for 2-5% of NIDDM, is characterized by autosomal dominant inheritance and an age of onset of 25 years or younger. MODY genes have been localized to chromosomes 7, 12 and 20 (refs 5, 7, 8) and clinical studies indicate that mutations in these genes are associated with abnormal patterns of glucose-stimulated insulin secretion. The gene on chromosome 7 (MODY2) encodes the glycolytic enzyme glucokinases which plays a key role in generating the metabolic signal for insulin secretion and in integrating hepatic glucose uptake. Here we show that subjects with the MODY3-form of NIDDM have mutations in the gene encoding hepatocyte nuclear factor-1alpha (HNF-1alpha, which is encoded by the gene TCF1). HNF-1alpha is a transcription factor that helps in the tissue-specific regulation of the expression of several liver genes and also functions as a weak transactivator of the rat insulin-I gene. 1-hop neighbor's text information:Title: Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Abstract: The steady-state basal plasma glucose and insulin concentrations are determined by their interaction in a feedback loop. A computer-solved model has been used to predict the homeostatic concentrations which arise from varying degrees beta-cell deficiency and insulin resistance. Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment of the contributions of insulin resistance and deficient beta-cell function to the fasting hyperglycaemia (homeostasis model assessment, HOMA). The accuracy and precision of the estimate have been determined by comparison with independent measures of insulin resistance and beta-cell function using hyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate of insulin resistance obtained by homeostasis model assessment correlated with estimates obtained by use of the euglycaemic clamp (Rs = 0.88, p less than 0.0001), the fasting insulin concentration (Rs = 0.81, p less than 0.0001), and the hyperglycaemic clamp, (Rs = 0.69, p less than 0.01). There was no correlation with any aspect of insulin-receptor binding. The estimate of deficient beta-cell function obtained by homeostasis model assessment correlated with that derived using the hyperglycaemic clamp (Rs = 0.61, p less than 0.01) and with the estimate from the intravenous glucose tolerance test (Rs = 0.64, p less than 0.05). The low precision of the estimates from the model (coefficients of variation: 31% for insulin resistance and 32% for beta-cell deficit) limits its use, but the correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2 2 2,2	1	pubmed	train	141
Title: Reversal of diabetes in BB rats by transplantation of encapsulated pancreatic islets. Abstract: Prolonged survival of pancreatic islet allografts implanted in diabetic BB rats was achieved by encapsulation of individual islets in a protective biocompatible alginate-polylysine-alginate membrane without immunosuppression. Intraperitoneal transplantation of the encapsulated islets reversed the diabetic state of the recipients within 3 days and maintained normoglycemia for 190 days. Normal body weight and urine volume were maintained during this period, and no cataracts were detected in the transplant recipients. In contrast, control rats receiving transplants of unencapsulated islets experienced normoglycemia for less than 2 wk. These results demonstrated that microencapsulation can protect allografted islets from both graft rejection and autoimmune destruction without immunosuppression in an animal model that mimics human insulin-dependent diabetes. 1-hop neighbor's text information:Title: Normalization of diabetes in spontaneously diabetic cynomologus monkeys by xenografts of microencapsulated porcine islets without immunosuppression. Abstract: Porcine pancreatic islets were microencapsulated in alginate-polylysine-alginate capsules and transplanted intraperitoneally into nine spontaneously diabetic monkeys. After one, two, or three transplants of 3-7 x 10(4) islets per recipient, seven of the monkeys became insulin independent for periods ranging from 120 to 804 d with fasting blood glucose levels in the normoglycemic range. Glucose clearance rates in the transplant recipients were significantly higher than before the graft administration and the insulin secretion during glucose tolerance tests was significantly higher compared with pretransplant tests. Porcine C-peptide was detected in all transplant recipients throughout their period of normoglycemia while none was found before the graft administration. Hemoglobin A1C levels dropped significantly within 2 mo after transplantation. While ketones were detected in the urine of all recipients before the graft administration, all experimental animals became ketone free 2 wk after transplantation. Capsules recovered from two recipients 3 mo after the restoration of normoglycemia were found physically intact with enclosed islets clearly visible. The capsules were free of cellular overgrowth. Examination of internal organs of two of the animals involved in our transplantation studies for the duration of 2 yr revealed no untoward effect of the extended presence of the microcapsules. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	0,0	1	pubmed	train	143
Title: Islet transplantation in treating diabetes. Abstract: Remarkable progress made in the past few years has brought pancreatic islet transplantation to the threshold of human clinical trials. Islet transplants have reversed diabetes in experimental animals and prevented or reversed early diabetic complications in the recipients. Methods have been developed that prevent rejection of islets transplanted across major histocompatibility barriers in rodents without requiring the continuous use of immunosuppressive drugs to maintain the transplants. A new method has been developed for isolating 40% of the islets from a single human pancreas. Based upon these accomplishments, the first phase of human clinical trials on islet transplantation was initiated during the past few months. 1-hop neighbor's text information:Title: Allogeneic beta-islet cells correct diabetes and resist immune rejection. Abstract: Allogeneic MHC-incompatible organ or cell grafts are usually promptly rejected by immunocompetent hosts. Here we tested allogeneic beta-islet cell graft acceptance by immune or naive C57BL/6 mice rendered diabetic with streptozotocin (STZ). Fully MHC-mismatched insulin-producing growth-regulated beta-islet cells were transplanted under the kidney capsule or s.c. Although previously or simultaneously primed mice rejected grafts, STZ-treated diabetic mice accepted islet cell grafts, and hyperglycemia was corrected within 2-4 weeks in absence of conventional immunosuppression. Allogeneic grafts that controlled hyperglycemia expressed MHC antigens, were not rejected for >100 days, and resisted a challenge by allogeneic skin grafts or multiple injections of allogeneic cells. Importantly, the skin grafts were rejected in a primary fashion by the grafted and corrected host, indicating neither tolerization nor priming. Such strictly extralymphatic cell grafts that are immunologically largely ignored should be applicable clinically. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	0,0	1	pubmed	train	144
Title: Serum ferritin levels in poorly- and well-controlled diabetes mellitus. Abstract: Serum ferritin level is related to body iron stores and is influenced by several diseases. We aimed to evaluate the association between serum ferritin concentration and the complications and nature of diabetes mellitus (DM). We examined association of ferritin concentration, fasting and post-prandial glucose levels and glycated hemoglobin in 329 patients with type 2 diabetes mellitus and 269 healthy controls. In the present study, 41 of 150 poorly controlled diabetic patients and 31 of 119 cases had hyperferritinemia. We confirmed that serum ferritin was increased in diabetic patients as long as glycemic control is not achieved. There was also a correlation between ferritin level and diabetic retinopathy. In conclusion, this study showed an independent positive association between serum ferritin concentration and markers of glucose homeostasis. 1-hop neighbor's text information:Title: The metal chelators, trientine and citrate, inhibit the development of cardiac pathology in the Zucker diabetic rat. Abstract: PURPOSE: The objective of this study was to determine the efficacy of dietary supplementation with the metal chelators, trientine or citric acid, in preventing the development of cardiomyopathy in the Zucker diabetic rat. HYPOTHESIS: We hypothesized that dietary chelators would attenuate metal-catalyzed oxidative stress and damage in tissues and protect against pathological changes in ventricular structure and function in type II diabetes. METHODS: Animals (10 weeks old) included lean control (LC, fa/+), untreated Zucker diabetic fatty (ZDF, fa/fa), and ZDF rats treated with either trientine (triethylenetetramine) or citrate at 20 mg/d in drinking water, starting when rats were frankly diabetic. Cardiac functional assessment was determined using a Millar pressure/volume catheter placed in the left ventricle at 32 weeks of age. RESULTS: End diastolic volume for the ZDF animals increased by 36% indicating LV dilatation (P < .05) and was accompanied by a 30% increase in the end diastolic pressure (P <or= .05). Both trientine and citric acid prevented the increases in EDV and EDP (P < .05). Ejection fraction and myocardial relaxation were also significantly improved with chelator treatment. CONCLUSION: Dietary supplementation with trientine and citric acid significantly prevented structural and functional changes in the diabetic heart, supporting the merits of mild chelators for prevention of cardiovascular disease in diabetes. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2,2	1	pubmed	train	146
Title: Accelerated diabetes in non-obese diabetic (NOD) mice differing in incidence of spontaneous disease. Abstract: The NOD mouse is an established model of autoimmune diabetes mellitus. Various lines of NOD mice differ in their incidence of spontaneous diabetes, e.g. 93% of female NOD/Lt mice compared with 46% of female NOD/Wehi mice develop diabetes by 250 days. These two lines were studied under conditions which greatly accelerate the onset of hyperglycaemia. It was hoped that their responses to these manipulations would reveal characteristic differences which would increase our understanding of diabetes resistance in the low incidence NOD/Wehi line. One dose of 300 mg/kg of cyclophosphamide (CP) produced hyperglycaemia in 50% of NOD mice within 2 weeks in both lines. They were also equally susceptible to diabetes induced by splenocyte transfer at 21 days of age from prediabetic 150-day-old NOD/Lt or NOD/Wehi females. Five daily 40 mg/kg doses of streptozotocin (STZ) resulted in a severity of diabetes in the NOD mice greater than in C57BL or SJL/mice. While the incidence and severity of diabetes induced in the two NOD lines were similar, this appeared to be principally due to sensitivity to the toxic effects of STZ rather than its ability to exacerbate autoimmune beta cell destruction. It has previously been shown that it is possible to prevent diabetes in susceptible NOD mice with simple, relatively benign therapies and here we show that it is possible to induce diabetes in resistant animals at a rate indistinguishable from fully predisposed individuals. It therefore appears that the prediabetic NOD mouse is poised in an immunologically precarious state with the onset of disease being highly dependent on factors which exacerbate or moderate autoimmune destruction. 1-hop neighbor's text information:Title: An explanation for the protective effect of the MHC class II I-E molecule in murine diabetes. Abstract: Insulin-dependent diabetes mellitus is widely believed to be an autoimmune disease. Recent onset diabetics show destruction of insulin-secreting pancreatic beta-cells associated with a lymphocytic infiltrate (insulitis), with autoantibodies to beta-cells being found even before the onset of symptoms. Susceptibility to the disease is strongly influenced by major histocompatibility complex (MHC) class II polymorphism in both man and experimental animal models such as the non-obese diabetic (NOD) mouse. As MHC class II molecules are usually associated with dominant immune responsiveness, it was surprising that introduction of a transgenic class II molecule, I-E, protected NOD mice from insulitis and diabetes. This could be explained by a change either in the target tissue or in the T cells presumed to be involved in beta-cell destruction. Recently, several studies have shown that I-E molecules are associated with ontogenetic deletion of T cells bearing antigen/MHC receptors encoded in part by certain T-cell receptor V beta gene segments. To determine the mechanism of the protective effect of I-E, we have produced cloned CD4+ and CD8+ T-cell lines from islets of recently diabetic NOD mice. These cloned lines are islet-specific and pathogenic in both I-E- and I-E+ mice. Both CD4+ and CD8+ cloned T cells bear receptors encoded by a V beta 5 gene segment, known to be deleted during development in I-E expressing mice. Our data provide, therefore, an explanation for the puzzling effect of I-E on susceptibility to diabetes in NOD mice. 1-hop neighbor's text information:Title: Prevention of type I diabetes in nonobese diabetic mice by virus infection. Abstract: The nonobese diabetic (NOD) mouse is an animal model of type I diabetes and develops a characteristic autoimmune lesion in the islets of Langerhans with lymphocytic infiltration and destruction of pancreatic beta cells. The result is hypoinsulinemia, hyperglycemia, ketoacidosis, and death. Diabetes usually begins by the sixth month of age but can occur earlier when young NOD mice are infused with lymphocytes from older NOD donors. When newborn or adult NOD mice were infected with a lymphotropic virus they did not become diabetic. The interaction between viruses and lymphocytes is pivotal in aborting diabetes, as established by experiments in which lymphocytes from virus-infected donors failed to transfer diabetes. In contrast, lymphocytes from age- and sex-matched uninfected donors caused disease. Therefore, viruses and, presumably, their products can be developed to be beneficial and may have potential as a component for treatment of human diseases. Further, these results point to the utility of viruses as probes for dissecting the pathogenesis of a nonviral disease. 1-hop neighbor's text information:Title: Cyclophosphamide-induced diabetes in NOD/WEHI mice. Evidence for suppression in spontaneous autoimmune diabetes mellitus. Abstract: Nonobese diabetic (NOD) mice spontaneously develop a lymphocytic infiltration of pancreatic islets (insulitis) that may progress to overt diabetes. Virtually all NOD/WEHI mice develop insulitis, but very few progress to diabetes. However, cyclophosphamide (CY) can promote the onset of diabetes in NOD mice, including the NOD/WEHI strain. The means by which CY produces diabetes was investigated in NOD/WEHI mice, in which it was hypothesized that active suppression mechanisms prevented the progression from insulitis to diabetes. A study of the time course of insulitis in the islets after CY was given showed that insulitis was initially reduced but rapidly increased over 16 days, and T-lymphocytes were predominant in the lesion. This suggested a compression of the normal time course of the disease seen in NOD mice. CY did not produce diabetes in any of 11 non-NOD strains studied. Fetal isografts in NOD mice given CY several days before were subjected to lymphocytic infiltration and beta-cell destruction. These findings suggested that CY was not directly beta-cell toxic and that altered beta-cells were not essential for beta-cell destruction. This was further demonstrated with subdiabetogenic doses of streptozocin, which significantly damaged beta-cells but did not increase the severity of insulitis or induce diabetes as did CY. Most important, the transfer of mononuclear cells from nondiabetic NOD mice to mice given CY prevented diabetes, which indicated that the likely effect of CY was via immunomodulation, possibly by allowing poised effector cells to act on beta-cells.(ABSTRACT TRUNCATED AT 250 WORDS) 2-hop neighbor's text information:Title: Induction of diabetes with islet-specific T-cell clones is age dependent. Abstract: To investigate the effects of recipient age on the induction of diabetes by CD4+ islet-specific T-cell clones, we tested four different clones in non-obese diabetic (NOD) mice of different ages. Transfer of each of the T-cell clones resulted in insulitis and full development of diabetes in unirradiated 8-18-day-old NOD mice within 2-3 weeks. A small gender bias in disease susceptibility was seen in 8-14-day-old female NOD mice, which showed a twofold increase in disease incidence over both age-matched males and slightly older (15-18-day-old) females. In contrast, both male and female NOD mice, 19 days or older, were highly resistant to T-cell clone-induced insulitis and completely resistant to the development of diabetes. In mice of an intermediate age range (15-18 days old), two of the clones showed a three- to fourfold reduction in transfer of overt diabetes regardless of gender. These results suggest that an important developmental event occurs in both male and female NOD mice between the age of 15 and 19 days, leading to the inhibition of disease induced by T-cell clones. 2-hop neighbor's text information:Title: The A3 allele of the HLA-DQA1 locus is associated with susceptibility to type 1 diabetes in Japanese. Abstract: Analysis of the frequencies of class II HLA-DR and HLA-DQ alleles by serological and DNA typing in 49 Japanese patients with type 1 (insulin-dependent) diabetes and 31 Japanese controls indicates the following. (i) Susceptibility is more strongly associated with the HLA-DQ subregion than with the HLA-DR subregion. (ii) Of the class II alleles detected, the A3 allele of the DQA1 locus was the most strongly associated with disease. Ninety-six percent of the patients were positive for the A3 allele compared to 53% of the controls (P = 0.001; relative risk = 19.7; confidence limits = 3.72-188.64). (iii) The DQw8 allele of the DQB1 locus, which is associated with susceptibility to type 1 diabetes in Caucasians and Blacks, was not increased in frequency in Japanese patients (22%) versus controls (19%). (iv) Asp-57-encoding DQB1 alleles are associated with reduced susceptibility to type 1 diabetes in Caucasians. The major predisposing haplotypes in Japanese are DR4 and DR9. By DNA sequence analysis, both of these Japanese haplotypes have Asp-57-encoding DQB1 alleles. Oligonucleotide dot blot analysis showed that all, except 1, of the 49 Japanese patients and all of the 31 controls have at least one Asp-57-encoding DQB1 allele. In addition, 40% of the patients were homozygous for Asp-57-encoding DQB1 alleles versus 35% of the controls. The high frequencies of Asp-57-encoding DQB1 alleles in this ethnic group may account for the rarity of type 1 diabetes in Japan. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	0 0 0 1 1,0	2	pubmed	train	147
Title: Platelet expression of tumour necrosis factor-alpha (TNF-alpha), TNF receptors and intercellular adhesion molecule-1 (ICAM-1) in patients with proliferative diabetic retinopathy. Abstract: Microvascular complications of insulin-dependent diabetes mellitus (IDDM) have been strongly associated with platelet abnormalities, whilst TNF-alpha has been implicated in the pathogenesis of this condition. However, at present it is not clear whether human circulating platelets express TNF-alpha or TNF receptors (TNF-R) or whether impaired expression of these molecules and of the TNF-reactive adhesion molecule ICAM-1 may be associated with platelet abnormalities in patients with IDDM. On this basis we investigated the platelet expression of these molecules in patients with IDDM complicated or uncomplicated by proliferative diabetic retinopathy (PDR) and in healthy subjects. We observed that the proportion of platelets staining for TNF-alpha was significantly higher in IDDM patients with active PDR than in patients without microvascular complications (P = 0.0078), quiescent PDR (P = 0.003) or healthy subjects (P = 0.0013). Patients with active PDR also showed a higher proportion of platelets expressing TNF-RI (P = 0. 0052) and TNF-RII (P = 0.015) than healthy controls or patients with quiescent PDR (P = 0.009 and 0.0006, respectively). In addition, the percentage of ICAM-1+ platelets was significantly higher in patients with active PDR than in patients with quiescent PDR (P = 0.0065) or normal subjects (P = 0.013). There was a direct correlation between platelet expression of TNF-alpha and that of TNF-R in PDR patients, indicating that platelet staining for TNF-alpha may be due to binding of this cytokine to its receptors. The results suggest that increased platelet expression of TNF-alpha, TNF-R and ICAM-1 in IDDM patients may constitute important markers of thrombocyte abnormalities during the development of microvascular complications of diabetes mellitus. 1-hop neighbor's text information:Title: Accelerated beta-cell destruction in adoptively transferred autoimmune diabetes correlates with an increased expression of the genes coding for TNF-alpha and granzyme A in the intra-islet infiltrates. Abstract: Autoimmune destruction of beta-cells in nonobese diabetic (NOD) mice is greatly accelerated by adoptive cotransfer of syngeneic CD4+ and CD8+ T-cells from diabetic animals into newborn NOD mice. We followed, by in situ hybridization, the appearance of mRNA of the tumor necrosis factor (TNF)-alpha gene and, as a marker for activated cytotoxic T-cells, of the serine protease granzyme A gene in the cellular infiltrates generated by cell transfer at birth. Cells expressing the genes for granzyme A or TNF-alpha were seen in considerable numbers already on day 14, after adoptive transfer. These numbers gradually increased in the intra-islet infiltrates from day 14 through day 30 after adoptive transfer. Compared with our previous findings in NOD mice developing spontaneous insulin-dependent diabetes mellitus (IDDM) (Held W, MacDonald HR, Weissman IL, Hess MW, Mueller C: Genes encoding tumor necrosis factor alpha and granzyme A are expressed during development of autoimmune diabetes. Proc Natl Acad Sci USA 87:2239-2243, 1990), frequencies of cells with TNF-alpha and granzyme A mRNA were 2- and 12-fold higher, respectively, in transferred IDDM (trIDDM). TNF-alpha mRNA positive cells were predominantly found in the CD4+ T-cell subset of the pancreas-infiltrating cells, whereas granzyme A mRNA positive cells were mainly observed in the CD4- T-cell subset. The effects of the observed enhanced TNF expression upon the pathogenesis of trIDDM are as yet unknown.(ABSTRACT TRUNCATED AT 250 WORDS) 1-hop neighbor's text information:Title: Effect of tumor necrosis factor alpha on insulin-dependent diabetes mellitus in NOD mice. I. The early development of autoimmunity and the diabetogenic process. Abstract: Tumor necrosis factor (TNF) alpha is a cytokine that has potent immune regulatory functions. To assess the potential role of this cytokine in the early development of autoimmunity, we investigated the effect of TNF on the development of insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice, a spontaneous murine model for autoimmune, insulin-dependent type I diabetes. Treatment of newborn female NOD mice with TNF every other day for 3 wk, led to an earlier onset of disease (10 versus 15 wk of age in control mice) and 100% incidence before 20 wk of age (compared to 45% at 20 wk of age in control phosphate-buffered saline treated female mice). In contrast, administration of an anti-TNF monoclonal antibody, TN3.19.12, resulted in complete prevention of IDDM. In vitro proliferation assays demonstrated that mice treated with TNF developed an increased T cell response to a panel of beta cell autoantigens, whereas anti-TNF treatment resulted in unresponsiveness to the autoantigens. In addition, autoantibody responses to the panel of beta cell antigens paralleled the T cell responses. The effects mediated by TNF appear to be highly age dependent. Treatment of animals either from birth or from 2 wk of age had a similar effect. However, if treatment was initiated at 4 wk of age, TNF delayed disease onset. These data suggest that TNF has a critical role in the early development of autoimmunity towards beta-islet cells. 1-hop neighbor's text information:Title: An association in non-insulin-dependent diabetes mellitus subjects between susceptibility to retinopathy and tumor necrosis factor polymorphism. Abstract: In IDDM an association between diabetic retinopathy and polymorphic markers of MHC has been described. However, these associations are complicated by a primary association between the MHC and IDDM. Because the pathogenesis of retinopathy is likely to be the same in IDDM and NIDDM, NIDDM subjects with retinopathy would be the ideal population to study for an association with MHC markers. The following South Indian subjects were therefore studied: unselected NIDDM (n = 76), unselected IDDM (n = 99), non-diabetic controls (n = 96), NIDDM subjects with maculopathy (MAC), n = 55, NIDDM subjects with proliferative retinopathy (PR), n = 53, and without retinopathy (LTD), n = 46. DNA was amplified and studied using a microsatellite polymorphism located 3.5 kb upstream of TNF-beta within the MHC class III region on the short arm of chromosome 6. No differences in allelic distribution were observed between the random NIDDM subjects and controls (p = 0.17). Differences in allelic distribution were found between unselected IDDM and controls (P = 0.016) and between the NIDDM subjects with maculopathy and/or proliferative retinopathy and no retinopathy (P = 0.006). This association could be accounted for by those patients with proliferative retinopathy (MAC vs LTD, p = 0.23; MAC vs PR, p = 0.07; and PR vs LTD, p = 0.002). 2-hop neighbor's text information:Title: Tumor necrosis factor production is deficient in diabetes-prone BB rats and can be corrected by complete Freund's adjuvant: a possible immunoregulatory role of tumor necrosis factor in the prevention of diabetes. Abstract: The Bio-Breeding (BB) rat develops spontaneous insulin-dependent diabetes mellitus (IDDM) and provides a useful animal model to study this human autoimmune disease. Treatment of BB rats with tumor necrosis factor (TNF) has been reported to prevent the development of IDDM. This suggests that deficient TNF production may be involved in the immunopathogenesis of autoimmune diabetes. In this study, we evaluated TNF production in diabetes-resistant (DR) BB rats, diabetes-prone (DP) BB rats, and DP BB rats protected from diabetes by the immunoadjuvant, complete Freund's adjuvant (CFA). TNF production in short-term cultures of peritoneal macrophages from DP rats was significantly less than that from control DR rats, both in the basal state and after stimulation with either interferon-gamma (IFN-gamma) or lipopolysaccharide (LPS) in vivo and in vitro. In contrast, TNF production by macrophages from CFA-injected DP rats (basal and IFN-gamma or LPS-stimulated) was equal to or greater than that by macrophages from DP rats and similar to TNF production by macrophages from CFA-injected DR rats. These results suggest that development of autoimmune diabetes in BB rats may be causally related to deficient macrophage production of TNF, and that upregulation of TNF production may protect against diabetes development. 2-hop neighbor's text information:Title: Suppression of insulitis in non-obese diabetic (NOD) mice by oral insulin administration is associated with selective expression of interleukin-4 and -10, transforming growth factor-beta, and prostaglandin-E. Abstract: Oral administration of autoantigens suppresses development of autoimmunity in several animal models, and is being tested in clinical trials in patients with autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. Non-obese diabetic (NOD) mice spontaneously develop insulin-dependent diabetes mellitus at 15 to 20 weeks of age, after mononuclear cell (MNC) infiltration of the pancreatic islets of Langerhans and destruction of insulin-producing beta cells. We have previously shown that oral administration of insulin suppresses insulitis and development of diabetes in the NOD mouse. Oral insulin has no metabolic effect on blood glucose. Oral insulin mediates its effect through a T cell-dependent mechanism as shown by adoptive transfer and T cell depletion experiments, but the mechanisms responsible have not been fully explored. We now report a serial analysis of the cells and cytokines associated with development of diabetes in NOD mice, and contrast this with the findings in animals fed equine insulin or a control protein (ovalbumin). Animals were fed 1 mg twice a week for 5 weeks, beginning at 5 weeks of age. Marked insulitis in naive or ovalbumin-fed NOD mice occurred at 10 weeks, at which time a dense peri-islet and intra-islet MNC infiltration was observed. Immunohistological studies using monoclonal antibodies showed that infiltrating MNC consisted mainly of CD4+ T cells ( > 75% of leukocytes) plus smaller numbers of macrophages and CD8+ T cells. These cells displayed evidence of immune activation with expression of receptors for interleukin-2 (IL-2R) plus Th1 cytokines; dense labeling for IFN-gamma and tumor necrosis factor-alpha, plus lesser amounts of IL-2, was observed. MNC lacked labeling for IL-4, IL-10, prostaglandin-E, or transforming growth factor-beta. By contrast, at 10 weeks, pancreatic tissues from NOD mice fed insulin showed considerably less insulitis, and the residual MNC, although still largely CD4+ T cells plus macrophages, showed dense labeling for IL-4, IL-10, prostaglandin-E, and transforming growth factor-beta and an absence of IL-2, IFN-gamma or tumor necrosis factor-alpha Taken together with our previous findings, these data indicate that oral administration of insulin affects the development of diabetes in NOD mice through the generation of cells that elaborate immunoregulatory cytokines within the target organ and shift the balance from a Th1 to a Th2 pattern of cytokine expression. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1 2 1 1,1	2	pubmed	train	149
Title: IL-1alpha, IL-1beta, and IFN-gamma mark beta cells for Fas-dependent destruction by diabetogenic CD4(+) T lymphocytes. Abstract: Cytokines such as IL-1alpha, IL-1beta, and IFN-gamma have long been implicated in the pathogenesis of autoimmune diabetes, but the mechanisms through which they promote diabetogenesis remain unclear. Here we show that CD4(+) T lymphocytes propagated from transgenic nonobese diabetic (NOD) mice expressing the highly diabetogenic, beta cell-specific 4.1-T-cell receptor (4.1-TCR) can kill IL-1alpha-, IL-1beta-, and IFN-gamma-treated beta cells from NOD mice. Untreated NOD beta cells and cytokine-treated beta cells from Fas-deficient NOD.lpr mice are not targeted by these T cells. Killing of islet cells in vitro was associated with cytokine-induced upregulation of Fas on islet cells and was independent of MHC class II expression. Abrogation of Fas expression in 4.1-TCR-transgenic NOD mice afforded nearly complete protection from diabetes and did not interfere with the development of the transgenic CD4(+) T cells or with their ability to cause insulitis. In contrast, abrogation of perforin expression did not affect beta cell-specific cytotoxicity or the diabetogenic potential of these T cells. These data demonstrate a novel mechanism of action of IL-1alpha, IL-1beta, and IFN-gamma in autoimmune diabetes, whereby these cytokines mark beta cells for Fas-dependent lysis by autoreactive CD4(+) T cells. 1-hop neighbor's text information:Title: Autoantigen-independent deletion of diabetogenic CD4+ thymocytes by protective MHC class II molecules. Abstract: Some MHC class II genes provide dominant resistance to certain autoimmune diseases via mechanisms that remain unclear. We have shown that thymocytes bearing a highly diabetogenic, I-Ag7-restricted beta-cell-reactive TCR (4.1-TCR) undergo negative selection in diabetes-resistant H-2g7/x mice by engaging several different antidiabetogenic MHC class II molecules on thymic (but not peripheral) hemopoietic cells, independently of endogenous superantigens. Here we have investigated 1) whether this TCR can also engage protective MHC class II molecules (I-Ab) on cortical thymic epithelial cells in the absence of diabetogenic (I-Ag7) molecules, and 2) whether deletion of 4.1-CD4+ thymocytes in I-Ab-expressing mice might result from the ability of I-Ab molecules to present the target beta-cell autoantigen of the 4.1-TCR. We show that, unlike I-Ag7 molecules, I-Ab molecules can restrict neither the positive selection of 4.1-CD4+ thymocytes in the thymic cortex nor the presentation of their target autoantigen in the periphery. Deletion of 4.1-CD4+ thymocytes by I-Ab molecules in the thymic medulla, however, is a peptide-specific process, since it can be triggered by hemopoietic cells expressing heterogeneous peptide/I-Ab complexes, but not by hemopoietic cells expressing single peptide/I-Ab complexes. Thus, unlike MHC-autoreactive or alloreactive TCRs, which can engage deleting MHC molecules in the thymic cortex, thymic medulla, and peripheral APCs, the 4.1-TCR can only engage deleting MHC molecules (I-Ab) in the thymic medulla. We therefore conclude that this form of MHC-induced protection from diabetes is based on the presentation of an anatomically restricted, nonautoantigenic peptide to highly diabetogenic thymocytes. 1-hop neighbor's text information:Title: Major histocompatibility complex class I molecules are required for the development of insulitis in non-obese diabetic mice. Abstract: An early step in the development of autoimmune diabetes is lymphocyte infiltration into the islets of Langerhans of the pancreas, or insulitis. The infiltrate contains both CD4+ and CD8+ T cells and both are required for progression to diabetes in non-obese diabetic (NOD) mice. It has been thought that the CD4+ lymphocytes are the initiators of the disease, the islet invaders, while CD8+ cells are the effectors, the islet destroyers. We question this interpretation because NOD mice lacking MHC class I molecules, hence CD8+ T cells, do not display even insulitis when expected. 1-hop neighbor's text information:Title: Evidence that beta cell death in the nonobese diabetic mouse is Fas independent. Abstract: Recent studies suggest that Fas expression on pancreatic beta cells may be important in the development of autoimmune diabetes in the nonobese diabetic (NOD) mouse. To address this, pancreatic islets from NOD mice were analyzed by flow cytometry to directly identify which cells express Fas and Fas ligand (FasL) ex vivo and after in vitro culture with cytokines. Fas expression was not detected on beta cells isolated from young (35 days) NOD mice. In vitro, incubation of NOD mouse islets with both IL-1 and IFN-gamma was required to achieve sufficient Fas expression and sensitivity for islets to be susceptible to lysis by soluble FasL. In islets isolated from older (>/=125 days) NOD mice, Fas expression was detected on a limited number of beta cells (1-5%). FasL was not detected on beta cells from either NOD or Fas-deficient MRLlpr/lpr islets. Also, both NOD and MRLlpr/lpr islets were equally susceptible to cytokine-induced cell death. This eliminates the possibility that cytokine-treated murine islet cells commit "suicide" due to simultaneous expression of Fas and FasL. Last, we show that NO is not required for cytokine-induced Fas expression and Fas-mediated apoptosis of islet cells. These findings indicate that beta cells can be killed by Fas-dependent cytotoxicity; however, our results raise further doubts about the clinical significance of Fas-mediated beta cell destruction because few Fas-positive cells were isolated immediately before the development of diabetes. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1 1,1	1	pubmed	train	150
Title: Involvement of endothelial cells in relaxation and contraction responses of the aorta to isoproterenol in naive and streptozotocin-induced diabetic rats. Abstract: Experiments were designed to investigate the importance of the endothelium in the relaxation of isolated rat aorta caused by a beta adrenoceptor agonist. Mechanical removal of the endothelium attenuated the relaxation induced by isoproterenol (ISO) and did not affect the relaxation produced by forskolin and by sodium nitroprusside. High concentrations of ISO produced an increase in the resting tension of aortic strips with and without endothelium in a concentration-dependent manner. Mechanical removal of the endothelium or treatment with methylene blue enhanced the maximal contraction induced by ISO. Phentolamine antagonized the contractile responses induced by ISO. In the case of streptozotocin-induced diabetic rats, both aortic strips with and without endothelium generated concentration-response curves for ISO-induced relaxation that were shifted to the right. The relaxant responses to forskolin and sodium nitroprusside were not significantly different between vessels from diabetic and age-matched control rats. In both aortic strips with and without endothelium, the maximal contraction in response to high concentrations of ISO was significantly enhanced in strips from diabetic rats. These results suggest that ISO-induced relaxation of aortic strips with endothelium is mediated by beta adrenoceptors on both the endothelium and the smooth muscle, and high concentrations of ISO produce an increase in the resting tension through alpha adrenoceptors. It is further suggested that the decreased relaxant response of the aorta to ISO in diabetes may be due to decreased density or affinity of beta adrenoceptors on the smooth muscle. 1-hop neighbor's text information:Title: P2y purinoceptor responses of beta cells and vascular bed are preserved in diabetic rat pancreas. Abstract: 1. To investigate the effect of experimental diabetes on the P2y purinoceptor responses of pancreatic beta-cells and vascular bed, we used adenosine-5'-O-(2-thiodiphosphate) (ADP beta S), a potent and stable P2y agonist. This work was performed in the isolated perfused pancreas of the rat. 2. Diabetes was induced by streptozotocin (66 mg kg-1, i.p.). Five weeks after the induction of diabetes, on the day of pancreas isolation, the animals displayed marked hyperglycaemia (37.6 +/- 2.7 mM). Age-matched rats were used as controls. 3. Insulin response to a glucose stimulation from 5 to 10 mM was completely lost and stimulation of insulin release by the sulphonylurea, tolbutamide (185 microM), was drastically impaired in the diabetic pancreas (maximum responses were 1.5 +/- 0.4 and 7.0 +/- 1.4 ng min-1 for diabetic and age-matched rats respectively). 4. In contrast, in the diabetic pancreas ADP beta S (15 microM), infused in the presence of glucose 5 mM, elicited an immediate and significant insulin release similar to that observed in the age-matched pancreas (maximum responses were 7.6 +/- 1.5 and 6.7 +/- 1.3 ng min-1 respectively). This ADP beta S stimulating effect occurred independently of the glucose concentration (5, 8.3 and 28 mM) in the diabetic pancreas. On pancreatic vascular resistance, ADP beta S induced a similar vasodilatation in diabetic and age-matched rats. 5. In conclusion, ADP beta S retains its insulin stimulatory and vasodilator effects in experimental diabetes; P2y purinoceptors could therefore be considered as a new target for the development of antidiabetic drugs. 1-hop neighbor's text information:Title: Mechanisms underlying the attenuation of endothelium-dependent vasodilatation in the mesenteric arterial bed of the streptozotocin-induced diabetic rat. Abstract: Experiments were designed to investigate the mechanisms underlying the diabetes-related impairment of the vasodilatations of the perfused mesenteric arterial bed induced by acetylcholine (ACh) and K(+). In streptozotocin (STZ)-diabetic rats, the ACh-induced endothelium-dependent vasodilatation was attenuated. The dose-response curves for ACh in control and diabetic rats were each shifted to the right by N(G)-nitro-L-arginine (L-NOARG) and by isotonic high K(+) (60 mM). The ACh dose-response curves under isotonic high K(+) were not different between control and diabetic rats. We also examined the vasodilatation induced by K(+), which is a putative endothelium-derived hyperpolarizing factor (EDHF). The mesenteric vasodilatation induced by a single administration of K(+) was greatly impaired in STZ-induced diabetic rats. Treatment with charybdotoxin plus apamin abolished the ACh-induced vasodilatation but enhanced the K(+)-induced response in controls and diabetic rats. After pretreatment with ouabain plus BaCl(2), the ACh-induced vasodilatation was significantly impaired and the K(+)-induced relaxation was abolished in both control and diabetic rats. The impairment of the endothelium-dependent vasodilatation of the mesenteric arterial bed seen in STZ-induced diabetic rats may be largely due to a defective vascular response to EDHF. It is further suggested that K(+) is one of the endothelium-derived hyperpolarizing factors and that the vasodilatation response to K(+) is impaired in the mesenteric arterial bed from diabetic rats. 1-hop neighbor's text information:Title: Preservation of endothelium-dependent relaxation in cholesterol-fed and streptozotocin-induced diabetic mice by the chronic administration of cholestyramine. Abstract: 1. Experiments were designed to investigate the effects of the low density lipoprotein (LDL)-lowering drugs cholestyramine on serum LDL levels and endothelium-dependent relaxation to acetylcholine (ACh) in cholesterol-fed or streptozotocin (STZ)-induced diabetic mice. 2. In aortic rings from control mice, ACh or A23187 caused concentration-dependent relaxation. The relaxations caused by ACh or A23187 were significantly attenuated in aortic rings from cholesterol-fed and STZ-diabetic mice. The attenuated vasodilatation in both cholesterol-fed and diabetic mice was returned to normal by chronic administration of cholestyramine. The endothelium-independent relaxations of aortic rings induced by sodium nitroprusside (SNP) were not significantly different between control, cholesterol-fed and STZ-induced diabetic mice. 3. The increased LDL levels in cholesterol-fed and diabetic mice were returned to normal by the chronic administration of cholestyramine. Chronic administration of cholestyramine had no effects on serum glucose levels. 4. These results suggest that attenuated endothelium-dependent vasodilatations in both cholesterol-fed and STZ-diabetic mice are improved by the chronic administration of cholestyramine, and these effects are, at least in part, due to lowering serum LDL levels. 2-hop neighbor's text information:Title: Impairment of endothelium-dependent relaxation in aortae from spontaneously diabetic rats. Abstract: 1. Diabetes mellitus is known to produce alterations in vascular reactivity. The present study examined the effects of endothelium-dependent and endothelium-independent relaxing substances on thoracic aorta from control and spontaneously diabetic rats. 2. Endothelium-dependent relaxation produced by acetylcholine or the calcium ionophore, A23187, in aortic rings precontracted with phenylephrine was significantly attenuated in diabetic vessels. 3. Relaxations produced by sodium nitroprusside or adenosine in diabetic preparations were comparable to those in control vessels. 4. The results show that diabetes leads to a specific impairment of endothelial-dependent relaxation. 2-hop neighbor's text information:Title: Effect of insulin treatment on smooth muscle contractility and endothelium-dependent relaxation in rat aortae from established STZ-induced diabetes. Abstract: 1. This study involved the chronic administration of low or high insulin to rats with established streptozotocin (STZ)-induced diabetes. We studied the effect of such treatment on smooth muscle contractility and endothelium-dependent relaxation using aortic strips. 2. Aortae from diabetic rats, but not those from high-insulin-treated diabetic rats, showed an impaired endothelium-dependent in response to acetylcholine (ACh) by comparison with untreated controls. 3. Isotonic high K+-induced contractility was impaired in diabetic aortae. This impairment was prevented by high-insulin treatment. 4. Noradrenaline (NA)-induced contractility was enhanced in aortae from high-insulin-treated diabetic rats, but not in those from untreated diabetic or low-insulin treated diabetic rats. 5. In the combined presence of the nitric oxide inhibitor N(G)-nitro-L-arginine and the cyclo-oxygenase inhibitor indomethacin, NA-induced contractility was significantly greater in aortae from high-insulin-treated diabetic rats than in those from controls or untreated diabetic rats. 6. An increased expression of the mRNA for the alpha1D and alpha1B adrenergic receptors was found in aortae from high-insulin-treated diabetic rats. 7. These results demonstrate that in rats with established STZ-induced diabetes, high-insulin treatment prevents the development of an impaired endothelium-dependent relaxation in the aorta, and that such treatment enhances NA-induced contractility. This enhancement may be related to an upregulation in the expression of the mRNA for the alpha1B or alpha1D adrenergic receptor that is secondary to the hyperinsulinaemia. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	0 0 0 0 0,0	2	pubmed	train	152
Title: IL-1alpha, IL-1beta, and IFN-gamma mark beta cells for Fas-dependent destruction by diabetogenic CD4(+) T lymphocytes. Abstract: Cytokines such as IL-1alpha, IL-1beta, and IFN-gamma have long been implicated in the pathogenesis of autoimmune diabetes, but the mechanisms through which they promote diabetogenesis remain unclear. Here we show that CD4(+) T lymphocytes propagated from transgenic nonobese diabetic (NOD) mice expressing the highly diabetogenic, beta cell-specific 4.1-T-cell receptor (4.1-TCR) can kill IL-1alpha-, IL-1beta-, and IFN-gamma-treated beta cells from NOD mice. Untreated NOD beta cells and cytokine-treated beta cells from Fas-deficient NOD.lpr mice are not targeted by these T cells. Killing of islet cells in vitro was associated with cytokine-induced upregulation of Fas on islet cells and was independent of MHC class II expression. Abrogation of Fas expression in 4.1-TCR-transgenic NOD mice afforded nearly complete protection from diabetes and did not interfere with the development of the transgenic CD4(+) T cells or with their ability to cause insulitis. In contrast, abrogation of perforin expression did not affect beta cell-specific cytotoxicity or the diabetogenic potential of these T cells. These data demonstrate a novel mechanism of action of IL-1alpha, IL-1beta, and IFN-gamma in autoimmune diabetes, whereby these cytokines mark beta cells for Fas-dependent lysis by autoreactive CD4(+) T cells. 1-hop neighbor's text information:Title: IFN-gamma action on pancreatic beta cells causes class I MHC upregulation but not diabetes. Abstract: We have generated transgenic nonobese diabetic (NOD) mice expressing dominant negative mutant IFN-gamma receptors on pancreatic beta cells to investigate whether the direct effects of IFN-gamma on beta cells contribute to autoimmune diabetes. We have also quantitated by flow cytometry the rise in class I MHC on beta cells of NOD mice with increasing age and degree of islet inflammatory infiltrate. Class I MHC expression increases gradually with age in wild-type NOD mice; however, no such increase is observed in the transgenic beta cells. The transgenic mice develop diabetes at a similar rate to that of wild-type animals. This study dissociates class I MHC upregulation from progression to diabetes, shows that the rise in class I MHC is due to local IFN-gamma action, and eliminates beta cells as the targets of IFN-gamma in autoimmune diabetes. 1-hop neighbor's text information:Title: Prevalent CD8(+) T cell response against one peptide/MHC complex in autoimmune diabetes. Abstract: Spontaneous autoimmune diabetes in nonobese diabetic (NOD) mice is the result of a CD4(+) and CD8(+) T cell-dependent autoimmune process directed against the pancreatic beta cells. CD8(+) T cells play a critical role in the initiation and progression of diabetes, but the specificity and diversity of their antigenic repertoire remain unknown. Here, we define the structure of a peptide mimotope that elicits the proliferation, cytokine secretion, differentiation, and cytotoxicity of a diabetogenic H-2K(d)-restricted CD8(+) T cell specificity (NY8.3) that uses a T cell receptor alpha (TCRalpha) rearrangement frequently expressed by CD8(+) T cells propagated from the earliest insulitic lesions of NOD mice (Valpha17-Jalpha42 elements, often joined by the N-region sequence M-R-D/E). Stimulation of splenic CD8(+) T cells from single-chain 8. 3-TCRbeta-transgenic NOD mice with this mimotope leads to preferential expansion of T cells bearing an endogenously derived TCRalpha chain identical to the one used by their islet-associated CD8(+) T cells, which is also identical to the 8.3-TCRalpha sequence. Cytotoxicity assays using islet-derived CD8(+) T cell clones from nontransgenic NOD mice as effectors and peptide-pulsed H-2K(d)-transfected RMA-S cells as targets indicate that nearly half of the CD8(+) T cells recruited to islets in NOD mice specifically recognize the same peptide/H-2K(d) complex. This work demonstrates that beta cell-reactive CD8(+) T cells mount a prevalent response against a single peptide/MHC complex and provides one peptide ligand for CD8(+) T cells in autoimmune diabetes. 1-hop neighbor's text information:Title: Adoptive transfer of diabetes into immunodeficient NOD-scid/scid mice. Relative contributions of CD4+ and CD8+ T-cells from diabetic versus prediabetic NOD.NON-Thy-1a donors. Abstract: Precise definition of the role of both CD4 and CD8 T-cell subsets from NOD mice in the adoptive transfer of diabetes has been complicated by the possibility that endogenous T-cells may be recruited. Two newly created NOD congenic stocks, NOD.NON-Thy-1a and NOD/LtSz-scid, have been used as T-cell donors and recipients, respectively, to eliminate contributions from endogenous T-cells and thus to define the requirement for transferred T-cell subsets as a function of underlying diabetes development in the NOD donor. Total T-cells and T-cell subsets prepared from either prediabetic or diabetic NOD.NON-Thy-1a donors were adoptively transferred into 6-wk-old NOD-scid/scid recipients that were monitored for diabetes development. Both flow cytometric and histological analysis of recipient spleen and pancreas after adoptive transfer showed lymphocytes of donor (Thy1.1+) origin exclusively. Total T-cell and enriched CD4+ T-cell preparations from both diabetic and young prediabetic donors transferred diabetes to NOD-scid/scid recipients. However, the mean time to diabetes onset was doubled when CD4+ lymphocytes were isolated from prediabetic versus diabetic donors, and these transfers were complicated by the generation of small but significant numbers of CD8+ cells over time. Enriched CD8+ populations alone were unable to transfer disease. More rigorous exclusion of CD8+ cells by means of anti-CD8 MoAb treatment in vivo of the recipients of enriched CD4+ cells demonstrated a significant difference in the diabetogenic potency of CD4+ lymphocytes from diabetic versus nondiabetic donors. Diabetes was adoptively transferred to 58% of the recipients of enriched CD4+ lymphocytes from diabetic donors. In contrast, none of the recipients of enriched CD4+ lymphocytes from young prediabetic donors developed diabetes after MoAb treatment in vivo. The ability of a T-cell population to produce severe insulitis and sialitis in NOD-scid/scid recipients of T-cells closely paralleled its ability to induce diabetes. In an effort to suppress insulitis by suppression of macrophage migration to the islets, NOD-scid/scid mice were treated with silica in conjunction with adoptive transfer of T-cells from diabetic donors. Chronic silica treatment failed to deplete tissue macrophages and did not prevent diabetes development after transfer of unfractionated T-cells. Evidence is discussed indicating that the age-associated differences in ability of CD4+ T-cells to adoptively transfer diabetes in the absence of the CD8+ T-cells subset is a function of prior, chronic exposure of the CD4+ lymphocytes to beta-cell antigens in the donor.(ABSTRACT TRUNCATED AT 400 WORDS) 2-hop neighbor's text information:Title: IDDM in BB rats. Enhanced MHC class I heavy-chain gene expression in pancreatic islets. Abstract: Modulation in major histocompatibility complex (MHC) gene expression correlates with the inflammatory reactions that occur during graft rejection and autoimmune disease. We analyzed the expression of class I and II MHC genes in the pancreatic islets of prediabetic and newly diabetic BB rats by immunohistochemistry of tissue sections and Northern blotting of RNA extracted from isolated islets. We show that enhanced levels of MHC class I heavy-chain RNA are present in pancreatic islets before overt inflammation and the onset of insulin-dependent diabetes mellitus (IDDM) in the spontaneously diabetic BB rat. Immunohistochemical analysis revealed enhanced class I antigen expression throughout the pancreatic islets of newly diabetic animals but no induction of class II antigen on endocrine cells within the islet. Varying degrees of inflammatory infiltrate were observed in the sections exhibiting enhanced class I antigen expression or in nearby serial sections. Southern blot analysis revealed no restriction-fragment-length polymorphism or amplification of the endogenous class I heavy-chain genes compared with those of seroidentical disease-resistant Wistar-Furth rats. I-A alpha and I-E alpha hybridizing RNA appeared de novo before overt diabetes, although concomitantly with T-lymphocyte-receptor beta-chain and interferon-gamma gene hybridizing RNA and after MHC class I heavy-chain RNA enhancement was observed. These data indicate the possibility that enhanced class I heavy-chain gene expression plays a role in the progression of IDDM. 2-hop neighbor's text information:Title: Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune response. Abstract: We investigated the potential association between viruses and insulin-dependent (type 1) diabetes (IDDM) by developing a transgenic mouse model. By inserting into these mice a unique viral protein that was then expressed as a self-antigen in the pancreatic islets of Langerhans, we could study the effect on that expressed antigen alone, or in concert with an induced antiviral (i.e., autoimmune) response manifested later in life in causing IDDM. Our results indicate that a viral gene introduced as early as an animal's egg stage, incorporated into the germline, and expressed in islet cells does not produce tolerance when the host is exposed to the same virus later in life. We observed that the induced anti-self (viral) CTL response leads to selective and progressive damage of beta cells, resulting in IDDM. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1 1 0 0,1	2	pubmed	train	154
Title: Administering glutamic acid decarboxylase to NOD mice prevents diabetes. Abstract: Type 1 diabetes is the result of an ongoing autoimmune response to specific proteins expressed by the insulin producing beta cells. Recently, a number of beta cell autoantigens have been identified. However, their role in mediating the diabetogenic response is not known. Here we assess the relative importance of a panel of beta cell autoantigens in the disease process. The approach was to inhibit T cell proliferation to a given autoantigen by either i.t. or i.v. injections, and then determine the effect this had on the diabetogenic response. We show that administering murine glutamic acid decarboxylase (GAD) to 3-week-old NOD females can reduce the frequency of insulitis and prevent the onset of diabetes. In contrast, carboxypeptidase H or peripherin do not induce a similar protective effect, suggesting that GAD has a critical role in the diabetogenic response. These results also suggest that GAD may provide a useful target for antigen-specific immunotherapy. 1-hop neighbor's text information:Title: Modulation of diabetes in NOD mice by GAD65-specific monoclonal antibodies is epitope specific and accompanied by anti-idiotypic antibodies. Abstract: Type 1 diabetes is caused by the autoimmune destruction of pancreatic beta cells. Here we show that administration of a human monoclonal antibody (b96.11) specific to the 65-kDa isoform of glutamate decarboxylase (GAD65) to prediabetic non-obese diabetic (NOD) mice significantly delays the onset of autoimmune diabetes. We found this effect to be epitope-specific, as only b96.11 showed this therapeutic property, while a GAD65-specific human monoclonal control antibody (b78) derived from the same patient, but specific to a different determinant of GAD65, had no significant effect on the progression of disease. Administration of b96.11 or b78 to NOD mice was accompanied by the generation of anti-idiotypic antibodies. Importantly, the induced anti-idiotypic antibodies were specific for the immunizing antibody and blocked the binding of GAD65 by the respective antibody. These findings suggest a potential role for the internal image of the GAD65 determinant recognized by b96.11 in the anti-idiotypic antibody, supporting an immunomodulatory role for GAD65-specific autoantibodies, as originally postulated by Jerne. 1-hop neighbor's text information:Title: Autoreactive human T-cell receptor initiates insulitis and impaired glucose tolerance in HLA DR4 transgenic mice. Abstract: A human T-cell receptor (TcR) derived from an autoreactive T-cell specific for GAD65, from a subject at high risk for autoimmune diabetes, was introduced into HLA-DR4 transgenic mice. The source of TcR was a CD4(+) T(H)1(+) T-cell clone which responded to an immunodominant epitope of the human islet protein GAD65, an epitope shared with both GAD65 and GAD67 in the mouse. The resulting HLA-DR4/GAD-TcR transgenic mice on a Rag2(o/o)/I-Ab(o/o)/B6 background exhibited a CD4(+) infiltrate into pancreatic islets that correlated with a loss of insulin in infiltrated islets. These mice also exhibited a subclinical impaired tolerance to exogenously fed glucose as assayed by an intraperitoneal glucose tolerance test. T cells containing the GAD65/67 (555-567) responsive TcR undergo strong negative selection as evidenced by a 10-fold lower thymocyte cellularity compared to non-TcR transgenic mice, and clonotype peripheral T cells represented approximately 1% of CD4(+) T cells in Rag2 sufficient mice. Upon in vitro stimulation, GAD65/67 555-567 responsive T cells secrete interferon-gamma, minimal interleukin (IL)-2 and tumor necrosis factor-alpha, and no IL-4, IL-5, IL-10, or IL-17, consistent with a T(H)1 profile. These data demonstrate that CD4(+) T cells specific for a naturally processed epitope within GAD can specifically home to pancreatic islets and lead to impaired islet beta-cell function in diabetes-associated HLA-DR4 transgenic mice on the relatively non-autoimmune C57BL/6 background. The relatively slow progression and patchy insulitis are reminiscent of the chronic pre-clinical phase similar to a majority of human at-risk subjects, and models these indolent features of human T1D. 1-hop neighbor's text information:Title: Absence of significant Th2 response in diabetes-prone non-obese diabetic (NOD) mice. Abstract: Accumulating evidence suggests that Th1 T cells play a pivotal role in the development of autoimmune diabetes. Conversely, promoting a Th2 response inhibits disease progression. However, it has not been determined whether Th2 cells are regulatory T cells that fail at the time of diabetes development in naive non-diabetic NOD mice. Therefore, in order to evaluate cytokine secretion by spleen and islet infiltrating T cells in NOD mice at different stages of the autoimmune process, we developed an ELISPOT assay that detects IL-2, IL-4, and interferon-gamma (IFN-gamma) secretion in vitro at the single-cell level. We showed that, whatever the age considered, IFN-gamma is predominantly secreted, and that no IL-4-secreting cells are detected in the islets of male and female NOD mice. Spleen cells from 8-week-old female NOD mice, which include regulatory suppressor T cells, do not secrete IL-4, either upon presentation of islet cell antigens in vitro, or after transfer in vivo, but do secrete IFN-gamma. IFN-gamma secretion by T cells from diabetic mice results from CD4 but not CD8 T cells in transfer experiments into NOD/severe combined immunodeficient (SCID) recipients. These results suggest that (i) detection of regulatory CD4 T cells in NOD mice is not paralleled by a Th2 response; (ii) beta cell destruction does not depend on a switch from a Th2 to a Th1-type response; and (iii) CD8 T cells do not participate in induction of diabetes by secreting IFN-gamma. 2-hop neighbor's text information:Title: Identification of immunodominant T cell epitopes of human glutamic acid decarboxylase 65 by using HLA-DR(alpha10101,beta10401) transgenic mice. Abstract: Glutamic acid decarboxylase isoform 2 (GAD65; EC 4.1.1.15) has been identified as a key target autoantigen of insulin-dependent diabetes mellitus (IDDM). IDDM is genetically associated with the major histocompatibility complex (MHC), and particular alleles from the HLA-DQ and HLA-DR loci contribute to disease. Among DR4 subtypes, HLA-DRB10401, HLA-DRB10402, and HLA-DRB10405 alleles lend susceptibility, while HLA-DRB10403 confers protection. We have utilized HLA-DR(alpha10101,beta10401) (hereafter referred to as DR0401), human CD4, murine class II null triple transgenic mice and recombinant GAD65 to generate T cell hybridomas, and we have used overlapping sets of peptides to map the immunodominant epitopes of this autoantigen. We have identified 10 immunogenic regions for GAD65, of which 6 are recognized by multiple hybridomas. These epitopes are also generated by human antigen-presenting cells and their presentation is DR0401 restricted, as shown by the use of typed human lymphoblastoid cell lines and antibody blocking experiments. Immunodominant GAD65 epitopes defined in transgenic mice correspond to GAD65 regions previously shown to elicit T cell responses specifically in DR0401 IDDM patients, underscoring the validity of this approach. Interestingly, although the major epitopes contain DR0401 binding motifs, one of the epitopes contains a DR0405 motif. 2-hop neighbor's text information:Title: Active stage of autoimmune diabetes is associated with the expression of a novel cytokine, IGIF, which is located near Idd2. Abstract: Recently, interferon-gamma-inducing-factor (IGIF) has been described as a novel monokine that is a more potent interferon-gamma (IFN-gamma) inducer than IL-12. By cloning IGIF from affected tissue and studying IGIF gene expression, we describe for the first time a close association of this cytokine with an autoimmune disease. The non-obese diabetic (NOD) mouse spontaneously develops autoimmune insulitis and diabetes which can be accelerated and synchronized by a single injection of cyclophosphamide. IGIF mRNA was demonstrated by reverse transcriptase PCR in NOD mouse pancreas during early stages of insulitis. Levels of IGIF mRNA increased rapidly after cyclophosphamide treatment and preceded a rise in IFN-gamma mRNA, and subsequently diabetes. Interestingly, these kinetics mimick that of IL-12p40 mRNA, resulting in a close correlation of individual mRNA levels. Cloning of the IGIF cDNA from pancreas RNA followed by sequencing revealed identity with the IGIF sequence cloned from Kupffer cells and in vivo preactivated macrophages. When extending our study to macrophages of the spleen we observed that NOD mouse macrophages responded to cyclophosphamide with IGIF gene expression while macrophages from Balb/c mice treated in parallel did not. The IGIF gene position is located within the Idd2 interval on mouse chromosome 9 and therefore it is a candidate for the Idd2 susceptible gene. We conclude that IGIF expression is abnormally regulated in autoimmune NOD mice and closely associated with diabetes development. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1 1 1 1,1	2	pubmed	train	160
Title: How, when, and why to predict IDDM. Abstract: Insulin-dependent diabetes remains a serious disease replete with life-threatening complications. The onset of the disease is becoming increasingly predictable through the detection of its associated autoantibodies. The natural history of pathogenic events is attenuated in those with adult onset over that seen in infants and children. Immunosuppression therapies in newly diagnosed patients have been shown to induce remissions, whereas various intervention strategies in rodent models (BB rats and nonobese diabetic mice) can delay and even prevent the onset of diabetes. The stage is set for serious consideration of intervention trials to delay the clinical disease in humans. 1-hop neighbor's text information:Title: Rapamycin prevents the onset of insulin-dependent diabetes mellitus (IDDM) in NOD mice. Abstract: The effect of the immunosuppressive agent rapamycin (RAPA) was assessed in the non-obese diabetic (NOD) mouse which is an autoimmune model of IDDM. RAPA was prepared in a vehicle of 8% cremophor EL/2% ethanol and investigated in two studies. NOD/MrK female mice (six per group, study no. 1; 10 per group, study no. 2) were dosed three times per week p.o. by gavage from 56 to 170 days of age (study no. 1) or from 64 to 176 days of age (study no. 2). Mice treated with RAPA at 0.6 mg/kg, 6 mg/kg, or 12 mg/kg maintained normal plasma glucose through 170 or 176 days of age with 10%, 0%, and 0% incidence of diabetes respectively. In contrast, naive, vehicle-treated, or RAPA 0.06 mg/kg-treated mice exhibited elevated plasma glucose and disease incidence typical for female NOD mice. Mice which became diabetic had elevated levels of beta-hydroxybutyrate, triglycerides and cholesterol. These plasma lipid concentrations were positively correlated with the duration of hyperglycaemia (r = 0.85, 0.87 and 0.84 respectively). Outside of its ability to prevent diabetes, RAPA itself did not affect the lipid profile of the mice. Intervention therapy with RAPA was ineffective at reversing the course of disease after IDDM onset under these experimental conditions. Finally, we report here that prophylactic treatment with RAPA was able to protect against IDDM development in some RAPA-treated mice 41 weeks after cessation of treatment. These data show that orally administered RAPA is effective in preventing onset of disease in the NOD mouse, a relevant model of autoimmune type I diabetes in man. 1-hop neighbor's text information:Title: Autoimmunity to two forms of glutamate decarboxylase in insulin-dependent diabetes mellitus. Abstract: Insulin-dependent diabetes mellitus (IDDM) is thought to result from the autoimmune destruction of the insulin-producing beta cells of the pancreas. Years before IDDM symptoms appear, we can detect autoantibodies to one or both forms of glutamate decarboxylase (GAD65 and GAD67), synthesized from their respective cDNAs in a bacterial expression system. Individual IDDM sera show distinctive profiles of epitope recognition, suggesting different humoral immune responses. Although the level of GAD autoantibodies generally decline after IDDM onset, patients with IDDM-associated neuropathies have high levels of antibodies to GAD, years after the appearance of clinical IDDM. We note a striking sequence similarity between the two GADs and Coxsackievirus, a virus that has been associated with IDDM both in humans and in experimental animals. This similarity suggests that molecular mimicry may play a role in the pathogenesis of IDDM. 1-hop neighbor's text information:Title: Islet cell cytoplasmic autoantibody reactivity to glutamate decarboxylase in insulin-dependent diabetes. Abstract: Individuals with or at risk for insulin-dependent diabetes (IDD) frequently have autoantibodies against an islet cell cytoplasmic (ICA) antigen thought to be a sialoglycolipid. However, we now report that preabsorption of ICA-positive sera with recombinant glutamate decarboxylase (human GAD 65 and/or GAD 67) reduced or blocked the ICA reactivity of 5/18 (27%) new-onset IDD patients and 7/18 (39%) prediabetics. Interestingly, nondiabetic subjects with ICA of > or = 5 yr in duration had GAD-reactive ICA significantly more often (16/24, 67%, P < 0.04) than the diabetic groups. ICA reactivity to GAD was not related to serum ICA titer nor the age of the individual, and in all cases tested was blocked by GAD 65 or GAD 67 with equivalent efficiency. The ICA observed in 21/25 (84%) IDD patients with ICA long after clinical onset of disease (9-42 yr) was reactive to GAD. A natural history analysis of three individuals showed conversions from ICA which was reactive to GAD to a non-GAD-reactive ICA nearer to their clinical onsets of IDD. This study further defines the autoantigens reactive to ICA, and suggests that, whereas ICA that are not reactive to GAD may identify an advanced and more prognostic lesion, GAD-reactive ICA may typify the early or inductive lesion that may or may not progress to clinically significant beta cell injury. 2-hop neighbor's text information:Title: Heterogeneity in the occurrence of a subset of autoantibodies to glutamic acid decarboxylase in autoimmune polyendocrine patients with islet cell antibodies. Abstract: Glutamic acid decarboxylase-65 (GAD-65) is a major target for autoantibodies and autoreactive T cells in patients with insulin-dependent diabetes mellitus (IDDM). Autoantibodies to GAD are also found in patients with stiff man syndrome (SMS) or polyendocrine autoimmunity (PE). The epitope specificities of autoantibodies to GAD in IDDM and SMS have been well documented, but the locations of autoantibody epitopes of GAD in PE patients have not been mapped. Thus, the properties of anti-GAD antibodies in PE patients (with or without diabetes) were investigated. The ability of PE serum antibodies to inhibit the binding of the mouse monoclonal antibody, GAD-6, to native GAD in ELISA was determined. For PE patients without diabetes, levels of inhibition of GAD-6 binding ranged from 0% to almost 70% and were unrelated to the level of binding of serum antibodies to GAD (P = 0.351) or to the functional affinities of these antibodies. This suggests differences in the epitope specificities of anti-GAD antibodies in different patients. Levels of inhibition were also unrelated to clinical condition. SMS antibodies showed similar levels of inhibition of GAD-6 binding. Similar analysis was applied to PE patients with diabetes and levels of inhibition of GAD-6 binding to GAD were determined. These ranged from 0% to 80%, and levels of inhibition were similar in samples taken before or after diabetes onset. There was no significant difference between anti-GAD antibodies from PE patients with or without diabetes in the range of abilities to inhibit GAD-6 binding to GAD, although the highest levels of inhibition were given by sera from non-diabetic patients. This raises the possibility of differential expression of subsets of anti-GAD antibodies in progressive versus slow or non-progressive anti-islet autoimmune responses. Serum antibodies of PE and SMS patients did not inhibit the binding of antibodies specific for the extreme C-terminus of GAD, indicating that this is not the site of the epitopes for the patients' antibodies or for GAD-6. 2-hop neighbor's text information:Title: HLA Class II molecules on haplotypes associated with type 1 diabetes exhibit similar patterns of binding affinities for coxsackievirus P2C peptides. Abstract: Enteroviruses such as coxsackievirus B4 (CVB4) are proposed as possible environmental triggers or accelerants of the autoimmune process that leads to type 1 diabetes mellitus. One putative mechanism to account for this association is mimicry between virus components and islet autoantigens. Particular interest has focused on the CVB4 non-structural protein P2C, which we previously showed to be a major target of the effector memory anti-CVB4 CD4 T-cell response, and which harbours a region of sequence similarity with the islet autoantigen, glutamic acid decarboxylase (GAD65). Since several distinct human leucocyte antigen (HLA) Class II molecules are associated with development of type 1 diabetes, we hypothesized that for functional mimicry to be important, any potential region(s) of mimicry in P2C should bind to each of these susceptibility molecules. In the present study therefore we examined the affinity of 20-mer overlapping P2C peptides for soluble HLA-DR4, -DR3, -DQ2 and -DQ8. We identified one discrete region of P2C with high binding affinities for all of these HLA Class II molecules. Moreover, the binding affinity of P2C peptides was significantly correlated between HLA molecules present on the same susceptibility haplotype (e.g. DR4 and DQ8, P =0.0076; DR3 and DQ2 P = 0.002). We conclude that possession of these haplotypes favours restricted presentation of viral epitopes, and speculate that this could promote the potential for mimicry between microbial proteins and islet autoantigens. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 2 1 1 1,1	2	pubmed	train	163
Title: Relationships between angiotensin I converting enzyme gene polymorphism, plasma levels, and diabetic retinal and renal complications. Abstract: Insulin-dependent diabetes mellitus (IDDM), cardiovascular morbidity, and vital prognosis are linked to diabetic nephropathy, which is probably determined by renal hemodynamic abnormalities and by a genetic predisposition. Angiotensin I converting enzyme (ACE) regulates systemic and renal circulations through angiotensin II formation and kinins metabolism. Plasma and cellular ACE levels are genetically determined; an insertion/deletion polymorphism of the ACE gene is strongly associated with ACE levels, subjects homozygote for insertion (genotype II) having the lowest plasma values. We studied the relationship between the ACE gene polymorphism or plasma levels and microcirculatory disorders of IDDM through two independent studies: one involved 57 subjects with or without diabetic retinopathy, and the other compared 62 IDDM subjects with diabetic nephropathy to 62 diabetic control subjects with the same characteristics (including retinopathy severity) but with normal kidney function. The ACE genotype distribution was not different in diabetic subjects with or without retinopathy and in a healthy population. Conversely, an imbalance of ACE genotype distribution, with a low proportion of II subjects, was observed in IDDM subjects with diabetic nephropathy compared with their control subjects (P = 0.006). Plasma ACE levels were mildly elevated in all diabetic groups, independently of retinopathy, but they were higher in subjects with nephropathy than in those without nephropathy (P = 0.0022). The II genotype of ACE gene is a marker for reduced risk for diabetic nephropathy. 1-hop neighbor's text information:Title: Contribution of genetic polymorphism in the renin-angiotensin system to the development of renal complications in insulin-dependent diabetes: Genetique de la Nephropathie Diabetique (GENEDIAB) study group. Abstract: Diabetic nephropathy is a glomerular disease due to uncontrolled diabetes and genetic factors. It can be caused by glomerular hypertension produced by capillary vasodilation, due to diabetes, against constitutional glomerular resistance. As angiotensin II increases glomerular pressure, we studied the relationship between genetic polymorphisms in the renin-angiotensin system-angiotensin I converting enzyme (ACE), angiotensinogen (AGT), and angiotensin II, subtype 1, receptor-and the renal involvement of insulin-dependent diabetic subjects with proliferative retinopathy: those exposed to the risk of nephropathy due to diabetes. Of 494 subjects recruited in 17 centers in France and Belgium (GENEDIAB Study), 157 (32%) had no nephropathy, 104 (21%) incipient (microalbuminuria), 126 (25 %) established (proteinuria), and 107 (22%) advanced (plasma creatinine > or = 150 micromol/liter or renal replacement therapy) nephropathy. The severity of renal involvement was associated with ACE insertion/deletion (I/D) polymorphism: chi2 for trend 5.135, P = 0.023; adjusted odds ratio attributable to the D allele 1.889 (95% CI 1.209-2.952, P = 0.0052). Renal involvement was not directly linked to other polymorphisms. However, ACE I-D and AGT M235T polymorphisms interacted significantly (P = 0.0166): in subjects with ACE ID and DD genotypes, renal involvement increased from the AGT MM to TT genotypes. Thus, genetic determinants that affect renal angiotensin II and kinin productions are risk factors for the progression of glomerular disease in uncontrolled insulin-dependent diabetic patients. 1-hop neighbor's text information:Title: Role of glycaemic control in development of microalbuminuria in patients with insulin dependent diabetes. Abstract: OBJECTIVE: To ascertain which factors determine the progression from very low rates of albumin excretion to persistent microalbuminuria in patients with insulin dependent diabetes mellitus. DESIGN: A 10 year prospective study of a cohort of diabetic patients. SETTING: Outpatient department of the Portsmouth District Hospitals. SUBJECTS: 97 patients with insulin dependent diabetes mellitus who were initially free of microalbuminuria and hypertension. MAIN OUTCOME MEASURE: Urinary albumin: creatinine ratio. RESULTS: Eight of the 97 patients had developed microalbuminuria (urinary albumin:creatinine ratio > 3 mg/mmol in three consecutive early morning samples) by the 10 year follow up. The group who developed microalbuminuria had higher baseline log10 plasma glucose concentrations (mean (SD), 1.210 (0.122) v 0.984 (0.196) mmol/l, P < 0.001) and glycated haemoglobin concentrations (1.112% (0.069%) v 0.997% (0.076%), P < 0.001) and a younger age at onset of diabetes (10.0 (5.5) v 15.6 (7.8) years, P < 0.05). There was no difference in baseline duration of diabetes, smoking, sex, insulin dose, body mass index, serum creatinine concentration, or systolic, diastolic, or mean arterial blood pressure between the two groups. Multiple linear regression analysis showed that urinary albumin:creatinine ratio at 10 years was influenced by initial albumin:creatinine ratio (P = 0.006), initial glycated haemoglobin concentration (P = 0.002), and duration of diabetes (P = 0.045). Genotype for angiotensin converting enzyme was not related to the development of microalbuminuria nor, in a larger group of patients, the presence of any degree of diabetic nephropathy. CONCLUSION: In patients with insulin dependent diabetes mellitus the progression of minimal albuminuria and the development of microalbuminuria is determined primarily by poor long term glycaemic control. There is a weaker relation with longer duration of disease and younger age at onset of diabetes, but blood pressure does not seem to be implicated. Gene polymorphism for angiotensin converting enzyme is not linked to the development of microalbuminuria or established diabetic nephropathy. 1-hop neighbor's text information:Title: Prognostic value of the insertion/deletion polymorphism of the ACE gene in type 2 diabetic subjects: results from the Non-insulin-dependent Diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR), Diabete de type 2, Nephropathie et Genetique (DIAB2NEPHROGENE), and Survie, Diabete de type 2 et Genetique (SURDIAGENE) studies. Abstract: OBJECTIVE: We tested whether determination of the ACE insertion/deletion polymorphism is useful for renal and cardiovascular prognoses of type 2 diabetic subjects. RESEARCH DESIGN AND METHODS: The French participants (3,126 of 4,912) in the Non-Insulin-Dependent Diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR) trial were studied for their prognosis over 4 years according to their ACE insertion/deletion polymorphism. We used two cohorts of French type 2 diabetic patients for replication: a 3-year follow-up study (n = 917; Survie, Diabete de type 2 et Genetique [SURDIAGENE] study) and a case-control study on diabetic nephropathy (n = 1,277; Diabete de type 2, Nephropathie et Genetique [DIAB2NEPHROGENE] study). We investigated the effect of the insertion/deletion polymorphism on the primary outcome in the DIABHYCAR trial (defined as the first of the following events to occur: cardiovascular death, nonfatal myocardial infarction, stroke, heart failure leading to hospital admission, or end-stage renal failure) and its components. RESULTS: In DIABHYCAR, the primary outcome and most of its components were not affected by the ACE insertion/deletion genotype. Only renal outcome was favored by the I allele (P = 0.03). The risk of myocardial infarction was not affected by ACE genotype, but the probability of fatal outcome increased with the number of D alleles (P < 0.03). In SURDIAGENE, the association between the ACE I allele and renal outcome was not replicated. In DIAB2NEPHROGENE, no association was found with nephropathy. CONCLUSIONS: We were not able to demonstrate the manifest usefulness of the ACE insertion/deletion polymorphism for the prognosis of type 2 diabetic subjects. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1 2,1	1	pubmed	train	164
Title: Accelerated diabetes in non-obese diabetic (NOD) mice differing in incidence of spontaneous disease. Abstract: The NOD mouse is an established model of autoimmune diabetes mellitus. Various lines of NOD mice differ in their incidence of spontaneous diabetes, e.g. 93% of female NOD/Lt mice compared with 46% of female NOD/Wehi mice develop diabetes by 250 days. These two lines were studied under conditions which greatly accelerate the onset of hyperglycaemia. It was hoped that their responses to these manipulations would reveal characteristic differences which would increase our understanding of diabetes resistance in the low incidence NOD/Wehi line. One dose of 300 mg/kg of cyclophosphamide (CP) produced hyperglycaemia in 50% of NOD mice within 2 weeks in both lines. They were also equally susceptible to diabetes induced by splenocyte transfer at 21 days of age from prediabetic 150-day-old NOD/Lt or NOD/Wehi females. Five daily 40 mg/kg doses of streptozotocin (STZ) resulted in a severity of diabetes in the NOD mice greater than in C57BL or SJL/mice. While the incidence and severity of diabetes induced in the two NOD lines were similar, this appeared to be principally due to sensitivity to the toxic effects of STZ rather than its ability to exacerbate autoimmune beta cell destruction. It has previously been shown that it is possible to prevent diabetes in susceptible NOD mice with simple, relatively benign therapies and here we show that it is possible to induce diabetes in resistant animals at a rate indistinguishable from fully predisposed individuals. It therefore appears that the prediabetic NOD mouse is poised in an immunologically precarious state with the onset of disease being highly dependent on factors which exacerbate or moderate autoimmune destruction. 1-hop neighbor's text information:Title: Prevention of diabetes in NOD mice by injection of autoreactive T-lymphocytes. Abstract: The nonobese diabetic (NOD) mouse develops a high incidence of autoimmune diabetes and is believed to be a good model for insulin-dependent diabetes mellitus (IDDM) in humans. We isolated T-lymphocyte lines from islets of newly diabetic NOD mice, some of which are autoreactive to NOD spleen cells. Because autoreactive T-lymphocytes have been implicated in immune suppression, we injected NOD mice with an autoreactive T-lymphocyte line. The injected mice had a marked decrease in incidence of IDDM compared with control mice. Moreover, their islets showed no insulitis at 1 yr of age. We conclude that autoreactive T-lymphocytes can prevent the development of IDDM in NOD mice. This result suggests that 1) islets contain both effector cells capable of damaging pancreatic beta-cells and cells able to regulate this autoimmune response, and 2) development of IDDM depends on the balance between these opposing forces. 1-hop neighbor's text information:Title: Promotion of spontaneous diabetes in non-obese diabetes-prone mice by cyclophosphamide. Abstract: Cyclophosphamide promoted the onset of overt diabetes in non-obese diabetes-prone mice of both sexes. Two injections of this agent at 2 weeks apart were necessary to obtain a constant high incidence, although even a single injection was effective in some animals. Clinical symptoms of the cyclophosphamide-induced diabetes were similar to those of the naturally occurring type. The same schedule of cyclophosphamide treatment failed to induce diabetes in non-diabetic mouse strains, such as DS/Shi,Jcl:ICR or in non-obese non-diabetes-prone mice, which suggests that the promotion of diabetes by cyclophosphamide in non-obese diabetes-prone mice is not due to the simple pharmacological action of this agent but to some immunopharmacological action. 2-hop neighbor's text information:Title: Beta cell MHC class I is a late requirement for diabetes. Abstract: Type 1 diabetes occurs as a result of an autoimmune attack on the insulin-producing beta cells. Although CD8 T cells have been implicated both early and late in this process, the requirement for direct interaction between these cells and MHC class I on the beta cells has not been demonstrated. By using nonobese diabetic mice lacking beta cell class I expression, we show that both initiation and progression of insulitis proceeds unperturbed. However, without beta cell class I expression, the vast majority of these mice do not develop hyperglycemia. These findings demonstrate that a direct interaction between CD8 T cells and beta cells is not required for initiation or early disease progression. The requirement for class I on beta cells is a relatively late checkpoint in the development of diabetes. 2-hop neighbor's text information:Title: Apoptosis resistance of nonobese diabetic peripheral lymphocytes linked to the Idd5 diabetes susceptibility region. Abstract: Defects in lymphocyte apoptosis may lead to autoimmune disorders and contribute to the pathogenesis of type 1 diabetes. Lymphocytes of nonobese diabetic (NOD) mice, an animal model of autoimmune diabetes, have been found resistant to various apoptosis signals, including the alkylating drug cyclophosphamide. Using an F2 intercross between the apoptosis-resistant NOD mouse and the apoptosis-susceptible C57BL/6 mouse, we define a major locus controlling the apoptosis-resistance phenotype and demonstrate its linkage (logarithm of odds score = 3.9) to a group of medial markers on chromosome 1. The newly defined gene cannot be dissociated from Ctla4 and Cd28 and in fact marks a 20-centimorgan region encompassing Idd5, a previously postulated diabetes susceptibility locus. Interestingly, we find that the CTLA-4 (cytotoxic T lymphocyte-associated antigen 4) and the CD28 costimulatory molecules are defectively expressed in NOD mice, suggesting that one or both of these molecules may be involved in the control of apoptosis resistance and, in turn, in diabetes susceptibility. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	0 0 1 1,0	2	pubmed	train	165
Title: Acidic drinking water and risk of childhood-onset type 1 diabetes. Abstract: OBJECTIVE: To estimate the associations of acidity and concentration of selected minerals in household tap water with the risk of type 1 diabetes. RESEARCH DESIGN AND METHODS: We designed a population-based case-control study with 64 cases of type 1 diabetes and 250 randomly selected control subjects. Acidity, color, and mineral content were measured in tap water from each participant's household. RESULTS: Tap water pH 6.2-6.9 was associated with a fourfold higher risk of type 1 diabetes compared with pH > or =7.7 (OR 3.73, 95% CI 1.52-9.15). This result was similar after exclusion of individuals with the highly protective HLA-DQB1*0602 allele, but adjustment for maternal education, urban/rural residence, sex, and age tended to strengthen the estimated association. Higher tap water concentration of zinc was associated with lower risk of type 1 diabetes after adjustment for pH and other possible confounders, but the overall association was strictly not significant. CONCLUSIONS: These results suggest the possibility that quality of drinking water influences the risk of type 1 diabetes. The possible mechanisms by which water acidity or mineral content may be involved in the etiology of type 1 diabetes remain unknown, but the mechanisms are most likely indirect and may involve an influence on survival of microorganisms in the water. 1-hop neighbor's text information:Title: Geographical mapping of type 1 diabetes in children and adolescents in south east Sweden. Abstract: STUDY OBJECTIVE: As earlier studies have shown space-time clusters at onset of type 1 diabetes in the south east region of Sweden we investigated if there also has been any geographical clusters of diabetes in this region. DESIGN: The place of residence (coordinates) at the time of diagnosis were geocoded in a geographical information system (GIS). All children diagnosed with type 1 diabetes up to 16 years of age at diagnosis between 1977-1995 were included. The population at risk was obtained directly from the population registry for the respective years and geographical area levels. SETTING: South east region of Sweden containing 5 counties, 49 municipalities, and 525 parishes. MAIN RESULTS: A significant geographical variation in incidence rate were found between the municipalities (p<0.001) but not between the counties. The variation became somewhat weaker when excluding the six largest municipalities (p<0.02). In municipalities with increased risk (>35.1/100 000) the major contribution comes from children in age group 6-10 years of age at diagnosis. There were no obvious differences between the age groups in municipalities with decreased risk (<20.1/100 000). Boys and girls had about the same degree of geographical variation. CONCLUSIONS: Apart from chance, the most probable explanation for the geographical variation in the risk for children and adolescents to develop type 1 diabetes between the municipalities in the region is that local environmental factors play a part in the process leading to the disease. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1,1	1	pubmed	train	166
Title: Effects of varying carbohydrate content of diet in patients with non-insulin-dependent diabetes mellitus. Abstract: OBJECTIVE: To study effects of variation in carbohydrate content of diet on glycemia and plasma lipoproteins in patients with non-insulin-dependent diabetes mellitus (NIDDM). DESIGN: A four-center randomized crossover trial. SETTING: Outpatient and inpatient evaluation in metabolic units. PATIENTS: Forty-two NIDDM patients receiving glipizide therapy. INTERVENTIONS: A high-carbohydrate diet containing 55% of the total energy as carbohydrates and 30% as fats was compared with a high-monounsaturated-fat diet containing 40% carbohydrates and 45% fats. The amounts of saturated fats, polyunsaturated fats, cholesterol, sucrose, and protein were similar. The study diets, prepared in metabolic kitchens, were provided as the sole nutrients to subjects for 6 weeks each. To assess longer-term effects, a subgroup of 21 patients continued the diet they received second for an additional 8 weeks. MAIN OUTCOME MEASURES: Fasting plasma glucose, insulin, lipoproteins, and glycosylated hemoglobin concentrations. Twenty-four-hour profiles of glucose, insulin, and triglyceride levels. RESULTS: The site of study as well as the diet order did not affect the results. Compared with the high-monounsaturated-fat diet, the high-carbohydrate diet increased fasting plasma triglyceride levels and very low-density lipoprotein cholesterol levels by 24% (P < .0001) and 23% (P = .0001), respectively, and increased daylong plasma triglyceride, glucose, and insulin values by 10% (P = .03), 12% (P < .0001), and 9% (P = .02), respectively. Plasma total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels remained unchanged. The effects of both diets on plasma glucose, insulin, and triglyceride levels persisted for 14 weeks. CONCLUSIONS: In NIDDM patients, high-carbohydrate diets compared with high-monounsaturated-fat diets caused persistent deterioration of glycemic control and accentuation of hyperinsulinemia, as well as increased plasma triglyceride and very-low-density lipoprotein cholesterol levels, which may not be desirable. 1-hop neighbor's text information:Title: Association of diet with glycated hemoglobin during intensive treatment of type 1 diabetes in the Diabetes Control and Complications Trial. Abstract: BACKGROUND: Persons with type 1 diabetes have received widely varying dietary advice based on putative effects on glycemic control. OBJECTIVE: The objective was to determine whether diet composition was associated with subsequent glycated hemoglobin (Hb A1c) concentrations during intensive therapy for type 1 diabetes. DESIGN: We examined associations between quantiles of dietary intake and Hb A1c adjusted for age and sex in 532 intensively treated participants in the Diabetes Control and Complications Trial (DCCT) who had complete dietary data through 5 y of follow-up. Multivariate macronutrient density linear regression models tested the association of Hb A1c at year 5 with macronutrient composition and were adjusted for age, sex, exercise, triglyceride concentration, body mass index (BMI), baseline Hb A1c, and concurrent insulin dose. RESULTS: Higher insulin dose, lower carbohydrate intake, and higher saturated, monounsaturated, and total fat intakes were associated with higher Hb A1c concentrations at year 5. In age- and sex-adjusted multivariate macronutrient models, substitution of fat for carbohydrate was associated with higher Hb A1c concentrations (P = 0.01); this relation remained significant after adjustment for exercise level, serum triglycerides, and BMI (P = 0.02) but was no longer significant (P = 0.1) after adjustment for baseline Hb A1c and concurrent insulin dose. CONCLUSION: Among intensively treated patients with type 1 diabetes, diets higher in fat and saturated fat and lower in carbohydrate are associated with worse glycemic control, independent of exercise and BMI. 1-hop neighbor's text information:Title: Modifications of coronary risk factors. Abstract: In addition to the revascularization and glycemic management interventions assigned at random, the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) design includes the uniform control of major coronary artery disease risk factors, including dyslipidemia, hypertension, smoking, central obesity, and sedentary lifestyle. Target levels for risk factors were adjusted throughout the trial to comply with changes in recommended clinical practice guidelines. At present, the goals are low-density lipoprotein cholesterol <2.59 mmol/L (<100 mg/dL) with an optional goal of <1.81 mmol/L (<70 mg/dL); plasma triglyceride level <1.70 mmol/L (<150 mg/dL); blood pressure level <130 mm Hg systolic and <80 mm Hg diastolic; and smoking cessation treatment for all active smokers. Algorithms were developed for the pharmacologic management of dyslipidemia and hypertension. Dietary prescriptions for the management of glycemia, plasma lipid profiles, and blood pressure levels were adapted from existing clinical practice guidelines. Patients with a body mass index >25 were prescribed moderate caloric restriction; after the trial was under way, a lifestyle weight-management program was instituted. All patients were formally prescribed both endurance and resistance/flexibility exercises, individually adapted to their level of disability and fitness. Pedometers were distributed as a biofeedback strategy. Strategies to achieve the goals for risk factors were designed by BARI 2D working groups (lipid, cardiovascular and hypertension, and nonpharmacologic intervention) and the ongoing implementation of the strategies is monitored by lipid, hypertension, and lifestyle intervention management centers. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1,2	1	pubmed	train	167
Title: Longitudinal patterns of glycemic control and diabetes care from diagnosis in a population-based cohort with type 1 diabetes. The Wisconsin Diabetes Registry. Abstract: Glycosylated hemoglobin is an indicator of long-term glycemic control and a strong predictor of diabetic complications. This paper provides a comprehensive description of glycemic control (total glycosylated hemoglobin (GHb)) up to 4.5 years duration of diabetes by age, duration, and sex in a population-based cohort (n = 507) aged less than 20 years followed from diagnosis of Type 1 diabetes in Wisconsin during 1987-1994 Important aspects of demographics and diabetes care are described to allow comparison with other populations. Since large variations between laboratories are known to exist in the measurement of GHb, levels are also interpreted relative to the frequency of short-term complications. GHb increased after diagnosis, but leveled off after 2-3 years. Peak GHb values occurred in the age group 12-15 years. The within-individual standard deviation in GHb between tests, adjusted for age and duration was 1.6%. The mean GHb at last testing was 11.3%, with a standard deviation across individuals of 2.9%. The majority (74%) of individuals saw a diabetes specialist at least once. The mean number of insulin injections per day increased from 2.2 to 2.5 across the 4.5-year duration, and the insulin dose increased from 0.6 to 0.9 units per day per kg body weight. Despite the quite satisfactory level of care, 38% of subjects had GHb levels associated with significant short-term complications. 1-hop neighbor's text information:Title: The association of increased total glycosylated hemoglobin levels with delayed age at menarche in young women with type 1 diabetes. Abstract: CONTEXT: Delayed menarche is associated with subsequent reproductive and skeletal complications. Previous research has found delayed growth and pubertal maturation with type 1 diabetes and poor glycemic control. The effect of diabetes management on menarche is important to clarify, because tighter control might prevent these complications. OBJECTIVE: The objective of this study was to investigate age at menarche in young women with type 1 diabetes and examine the effect of diabetes management [e.g. total glycosylated hemoglobin (GHb) level, number of blood glucose checks, insulin therapy intensity, and insulin dose] on age at menarche in those diagnosed before menarche. DESIGN: The Wisconsin Diabetes Registry Project is a follow-up study of a type 1 diabetes population-based incident cohort initially enrolled between 1987 and 1992. SETTING: This study was performed in 28 counties in south-central Wisconsin. PATIENTS OR OTHER PARTICIPANTS: The study participants were recruited through referrals, self-report, and hospital/clinic ascertainment. Individuals with newly diagnosed type 1 diabetes, less than 30 yr old, were invited to participate. Of 288 young women enrolled, 188 reported menarche by 2002; 105 were diagnosed before menarche. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURE: The main outcome measure was age at menarche. RESULTS: Mean age at menarche was 12.78 yr, compared with 12.54 yr in the United States (P = 0.01). Ages at menarche and diagnosis were not associated. For those diagnosed before menarche, age at menarche was delayed 1.3 months with each 1% increase in mean total GHb level in the 3 yr before menarche. CONCLUSIONS: Age at menarche was moderately delayed in young women with type 1 diabetes. Delayed menarche could potentially be minimized with improved GHb levels. 1-hop neighbor's text information:Title: Hospital admission patterns subsequent to diagnosis of type 1 diabetes in children : a systematic review. Abstract: BACKGROUND: Patients with type 1 diabetes are known to have a higher hospital admission rate than the underlying population and may also be admitted for procedures that would normally be carried out on a day surgery basis for non-diabetics. Emergency admission rates have sometimes been used as indicators of quality of diabetes care. In preparation for a study of hospital admissions, a systematic review was carried out on hospital admissions for children diagnosed with type 1 diabetes, whilst under the age of 15. The main thrust of this review was to ascertain where there were gaps in the literature for studies investigating post-diagnosis hospitalisations, rather than to try to draw conclusions from the disparate data sets. METHODS: A systematic search of the electronic databases PubMed, Cochrane LibrarMEDLINE and EMBASE was conducted for the period 1986 to 2006, to identify publications relating to hospital admissions subsequent to the diagnosis of type 1 diabetes under the age of 15. RESULTS: Thirty-two publications met all inclusion criteria, 16 in Northern America, 11 in Europe and 5 in Australasia. Most of the studies selected were focussed on diabetic ketoacidosis (DKA) or diabetes-related hospital admissions and only four studies included data on all admissions. Admission rates with DKA as primary diagnosis varied widely between 0.01 to 0.18 per patient-year as did those for other diabetes-related co-morbidity ranging from 0.05 to 0.38 per patient year, making it difficult to interpret data from different study designs. However, people with Type 1 diabetes are three times more likely to be hospitalised than the non-diabetic populations and stay in hospital twice as long. CONCLUSION: Few studies report on all admissions to hospital in patients diagnosed with type 1 diabetes whilst under the age of 15 years. Health care costs for type 1 patients are higher than those for the general population and information on associated patterns of hospitalisation might help to target interventions to reduce the cost of hospital admissions. 2-hop neighbor's text information:Title: Routine hospital admission versus out-patient or home care in children at diagnosis of type 1 diabetes mellitus. Abstract: BACKGROUND: In many places, children newly diagnosed with type 1 diabetes mellitus are admitted to hospital for metabolic stabilisation and training, even if they are not acutely ill. Out-patient or home based management of these children could avoid the stress associated with a hospital stay, could provide a more natural learning environment for the child and its family, and might reduce costs for both the health care system and the families. OBJECTIVES: To assess the effects of routine hospital admission compared to out-patient or home-based management in children newly diagnosed with type 1 diabetes mellitus. SEARCH STRATEGY: We searched The Cochrane Library, MEDLINE, EMBASE, CINAHL, and the British Nursing Index. Additionally, we searched reference lists of relevant studies identified and contacted one of the trialists about further studies. SELECTION CRITERIA: Comparative studies of initial hospitalisation compared to home-based and/or out-patient management in children with newly diagnosed type 1 diabetes. DATA COLLECTION AND ANALYSIS: Studies were independently selected by two reviewers. Data extraction and quality assessment of trials were done independently by two reviewers. Authors of included studies were contacted for missing information. Results were summarised descriptively, using tables and text. MAIN RESULTS: Seven studies were included in the review, including a total of 298 children in the out-patient/home group. The one high quality trial identified suggested that home-based management of children with newly diagnosed type 1 diabetes may lead to slightly improved long term metabolic control (at two and three years follow-up). No differences between comparison groups were found in any of the psychosocial and behavioural variables assessed or in rates of acute diabetic complications within two years. Parental costs were found to be decreased, while health system costs were increased, leaving total social costs virtually unchanged. None of the other studies assessing metabolic control found a difference between the comparison groups. There seemed to be no differences in hospitalisations or acute diabetic complications between the out-patient/home groups and the hospital groups. AUTHORS' CONCLUSIONS: Due to the generally low quality or limited applicability of the studies identified, the results of this review are inconclusive. On the whole, the data seem to suggest that where adequate out-patient/home management of type 1 diabetes in children at diagnosis can be provided, this does not lead to any disadvantages in terms of metabolic control, acute diabetic complications and hospitalisations, psychosocial variables and behaviour, or total costs. 2-hop neighbor's text information:Title: Readmissions of children with diabetes mellitus to a children's hospital. Abstract: The characteristics of children with diabetes readmitted to Children's Hospital during a 5-year period, 1984 to 1989, were compared with those characteristics of new-onset patients admitted for stabilization and education and to outpatients in the Children's Hospital diabetes program to determine which characteristics were associated with patients who were readmitted. Changes in the frequency of readmissions were examined to determine whether the introduction of a diabetes team and a program that emphasizes the importance of ensuring that patients at risk of readmission consistently received insulin injections resulted in a reduction of readmissions. Readmissions occurred more frequently in patients who were black (71% compared with 38% of new-onset patients and 31% of outpatients) (P less than .001), from one-parent homes (56% compared with 27% of new-onset patients and 24% of outpatients) (P less than .001), and without third-party insurance (45% compared with 18% of new-onset patients and 15% of outpatients) (P less than .001). Readmissions were very common at 14 to 15 years of age (39% of readmissions vs 18% of outpatients) and very uncommon in children younger than age 9 (6% of readmissions vs 27% of outpatients) (P less than .001). Fewer readmissions for ketoacidosis occurred in the summer than in any other season (P less than .05). Readmissions fell by 47% over the 5-year period while new-onset patients increased by 85%. The reduction in frequency of readmissions was due to fewer readmissions for ketoacidosis and fewer readmissions in blacks, in patients from one-parent homes, and in patients without third-party insurance.(ABSTRACT TRUNCATED AT 250 WORDS) I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1 1 1,1	2	pubmed	train	171
Title: Direct involvement of macrophages in destruction of beta-cells leading to development of diabetes in virus-infected mice. Abstract: A single administration of complete Freund's adjuvant (CFA), type 1 carrageenan (Car), or silica 7, 2, and 2 days, respectively, before infection with a low dose (1 x 10(2) plaque-forming units/mouse) of encephalomyocarditis D (EMC-D) virus resulted in a significant increase in the incidence of diabetes in SJL/J mice (100%) compared with untreated EMC-D virus-infected mice (40%). Peritoneal macrophages were isolated from uninfected SJL/J mice, which had been treated once with silica, and transferred into SJL/J mice 2 days before low-dose EMC-D infection. Approximately 90% of the mice became diabetic, whereas 30% of mice that received virus alone became diabetic. The depletion of macrophages by treatment with the combined anti-Mac-1 and anti-Mac-2 monoclonal antibodies after a single administration of CFA, Car, or silica resulted in almost complete prevention of beta-cell destruction in EMC-D virus-infected mice. Furthermore, none of the mice in which macrophages were depleted by long-term treatment with silica and 10% of the mice treated with Car before virus infection became diabetic. On the basis of these observations, we conclude that macrophages are directly involved in the destruction of beta-cells, leading to the development of clinical diabetes in EMC-D virus-infected mice. 1-hop neighbor's text information:Title: Circulating monocytes are activated in newly diagnosed type 1 diabetes mellitus patients. Abstract: Investigations in the BB rat and the non-obese diabetic (NOD) mouse have provided substantial evidence for the involvement of the monocyte/macrophage system in the development of type 1 diabetes mellitus. However, it is not known whether monocytes play the same role in the pathogenesis of human type 1 diabetes. We investigated this problem in a longitudinal study of 29 recent-onset type 1 diabetes mellitus patients. Monocyte chemotaxis, phagocytosis and superoxide production as well as metabolic and haematological parameters were studied immediately after diagnosis and 6 months later. At diagnosis the patients had activated casein and C5a chemotaxis (casein 70 +/- 9 versus 150 +/- 5 (mean +/- s.e.m.), P < 0.001; C5a 137 +/- 10 versus 158 +/- 5, P < 0.05 (activation immobilizes monocytes, reducing the measured values)), and activated superoxide production (3.6 +/- 0.3 versus 3.0 +/- 0.3, P < 0.05). After 6 months casein chemotaxis (115 +/- 16 versus 150 +/- 5, P < 0.05) and Candida phagocytosis (3.3 +/- 0.1 versus 2.8 +/- 0.2, P < 0.001) were still activated. There was no correlation with other clinical or paraclinical parameters. We conclude that the circulating monocytes in newly diagnosed type 1 diabetes patients are activated. It is reasonable to expect that monocytes at the local site of inflammation in pancreas are even further activated. This could play a pathogenic role in beta cell destruction. 1-hop neighbor's text information:Title: Possible role of macrophage-derived soluble mediators in the pathogenesis of encephalomyocarditis virus-induced diabetes in mice. Abstract: Pancreatic islets from DBA/2 mice infected with the D variant of encephalomyocarditis (EMC-D) virus revealed lymphocytic infiltration with moderate to severe destruction of pancreatic beta cells. Our previous studies showed that the major population of infiltrating cells at the early stages of infection is macrophages. The inactivation of macrophages prior to viral infection resulted in the prevention of diabetes, whereas activation of macrophages prior to viral infection resulted in the enhancement of beta-cell destruction. This investigation was initiated to determine whether macrophage-produced soluble mediators play a role in the destruction of pancreatic beta cells in mice infected with a low dose of EMC-D virus. When we examined the expression of the soluble mediators interleukin-1 beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), and inducible nitric oxide synthase (iNOS) in the pancreatic islets, we found that these mediators were clearly expressed at an early stage of insulitis and that this expression was evident until the development of diabetes. We confirmed the expression of these mediators by in situ hybridization with digoxigenin-labelled RNA probes or immunohistochemistry in the pancreatic islets. Mice treated with antibody against IL-1beta or TNF-alpha or with the iNOS inhibitor aminoguanidine exhibited a significant decrease in the incidence of diabetes. Mice treated with a combination of anti-IL-1beta antibody, anti-TNF-alpha antibody, and aminoguanidine exhibited a greater decrease in the incidence of disease than did mice treated with one of the antibodies or aminoguanidine. On the basis of these observations, we conclude that macrophage-produced soluble mediators play an important role in the destruction of pancreatic beta cells, resulting in the development of diabetes in mice infected with a low dose of EMC-D virus. 1-hop neighbor's text information:Title: Role of Hck in the pathogenesis of encephalomyocarditis virus-induced diabetes in mice. Abstract: Soluble mediators such as interleukin-1beta, tumor necrosis factor alpha (TNF-alpha), and inducible nitric oxide synthase (iNOS) produced from activated macrophages play an important role in the destruction of pancreatic beta cells in mice infected with a low dose of the D variant of encephalomyocarditis (EMC-D) virus. The tyrosine kinase signaling pathway was shown to be involved in EMC-D virus-induced activation of macrophages. This investigation was initiated to determine whether the Src family of kinases plays a role in the activation of macrophages, subsequently resulting in the destruction of beta cells, in mice infected with a low dose of EMC-D virus. We examined the activation of p59/p56(Hck), p55(Fgr), and p56/p53(Lyn) in macrophages from DBA/2 mice infected with the virus. We found that p59/p56(Hck) showed a marked increase in both autophosphorylation and kinase activity at 48 h after infection, whereas p55(Fgr) and p56/p53(Lyn) did not. The p59/p56(Hck) activity was closely correlated with the tyrosine phosphorylation level of Vav. Treatment of EMC-D virus-infected mice with the Src kinase inhibitor, PP2, resulted in the inhibition of p59/p56(Hck) activity and almost complete inhibition of the production of TNF-alpha and iNOS in macrophages and the subsequent prevention of diabetes in mice. On the basis of these observations, we conclude that the Src kinase, p59/p56(Hck), plays an important role in the activation of macrophages and the subsequent production of TNF-alpha and nitric oxide, leading to the destruction of pancreatic beta cells, which results in the development of diabetes in mice infected with a low dose of EMC-D virus. 2-hop neighbor's text information:Title: Tumour necrosis factor alpha production is upregulated in diabetes prone BB rats. Abstract: Following activation peritoneal macrophages from diabetes prone BB rats secreted strikingly higher amounts of tumour necrosis factor alpha than found for macrophages from diabetes resistant or normal Wistar rats. Enhanced tumour necrosis factor alpha production was detected prior to the occurrence of insulitis. Cultures of macrophages derived from precursor cells in diabetes prone BB rat bone marrow also showed upregulated tumour necrosis factor alpha secretion upon challenge with endotoxin and interferon gamma. Tumour necrosis factor alpha hypersecretion may contribute to autoimmune diabetes by affecting thymic and post-thymic T-cell maturation and by promoting pancreatic islet inflammation. 2-hop neighbor's text information:Title: Macrophage-mediated islet cell cytotoxicity in BB rats. Abstract: Islet cell killing mediated by natural killer cells and T-lymphocytes in diabetes-prone (DP) and diabetic BB rats has been described, but other killing mechanisms may also be involved. Histopathologic studies suggest that macrophages are the first immune cells to infiltrate islets. To determine if macrophages are the first cells mediating islet damage, macrophage-mediated cytotoxicity was evaluated in BB rats of different ages. Splenic macrophages isolated from DP rats at 33, 100, 120, and 140 days of age showed no enhanced islet killing compared with diabetes-resistant rats. Killing at diabetes onset (121 +/- 14 days) was markedly increased (43 +/- 9.3%) compared with age-matched diabetes-resistant controls (19 +/- 8.3%, P less than .001). Islet inflammation was monitored at all time points. At 120 and 140 days of age, 9 of 11 (82%) DP rats had insulitis, and cytotoxicity was increased in 6 of 11 (55%) rats, which is similar to the number of DP rats that progress to diabetes. At 100 days, 3 of 6 (50%) DP rats again showed diabetic levels of killing, even in the absence of insulitis. These data indicate that 1) islet inflammation is dissociated from clinical diabetes onset, 2) splenic macrophages may have islet-killing potential before islet inflammation, 3) macrophage-mediated islet killing is elevated in all animals immediately after diabetes onset, and 4) macrophages, in addition to natural killer cells and T-lymphocytes, are responsible for cell-mediated islet destruction and thus are candidates for the first cellular effector to result in islet killing. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1 1 0 0,0	2	pubmed	train	172
Title: Osmotically-induced nerve taurine depletion and the compatible osmolyte hypothesis in experimental diabetic neuropathy in the rat. Abstract: Diabetic neuropathy results from progressive nerve fibre damage with blunted nerve regeneration and repair and may be complicated by nerve hyperexcitability resulting in pain. The naturally occurring amino acid taurine functions as an osmolyte, inhibitory neurotransmitter, and modulator of pain perception. It is also known to have neurotrophic actions. The compatible osmolyte hypothesis proposes that levels of intracellular organic osmolytes including taurine and myo-inositol, respond co-ordinately in response to changes in intracellular sorbitol or external osmolality to maintain the intracellular milieu. We hypothesize that glucose-induced sorbitol accumulation in diabetes mellitus will result in taurine depletion in peripheral nerve which may potentially impair nerve regeneration and precipitate neuronal hyperexcitability and pain. This study explored the relationships of taurine, myo-inositol and sorbitol in the rat nerve and their effects on nerve conduction velocity. Osmolyte levels and nerve conduction velocity were determined in sciatic nerve from non-diabetic and streptozotocin-induced diabetic rats, with or without dietary taurine or myo-inositol supplementation. Taurine levels decreased by 31% (p < 0.01) and myo-inositol decreased by 37% (p < 0.05) in diabetic nerve as sorbitol accumulated. Taurine supplementation of diabetic animals did not affect nerve conduction velocity but further reduced nerve myo-inositol levels. Prevention of sorbitol accumulation with the aldose reductase inhibitor sorbinil increased nerve taurine levels by 22% (p < 0.05) when compared with untreated diabetic animals. Thus, we have demonstrated an interdependence of organic osmolytes within the nerve. Abnormal accumulation of one osmolyte results in reciprocal depletion of others. Diabetic neuropathy may be an example of maladaptive osmoregulation, nerve damage and instability being aggravated by taurine depletion. 1-hop neighbor's text information:Title: Myenteric neurons and intestinal mucosa of diabetic rats after ascorbic acid supplementation. Abstract: AIM: To investigate the effect of ascorbic acid (AA) dietary supplementation on myenteric neurons and epithelial cell proliferation of the jejunum of adult rats with chronic diabetes mellitus. METHODS: Thirty rats at 90 d of age were divided into three groups: Non-diabetic, diabetic and diabetic treated with AA (DA) (1 g/L). After 120 d of treatment with AA the animals were killed. The myenteric neurons were stained for myosin-V and analyzed quantitatively in an area of 11.2 mm(2)/animal. We further measured the cellular area of 500 neurons per group. We also determined the metaphasic index (MI) of the jejunum mucosa layer of about 2500 cells in the intestinal crypts, as well as the dimensions of 30 villi and 30 crypts/animal. The data area was analyzed using the Olympus BX40 microscope. RESULTS: There was an increase of 14% in the neuronal density (792.6 +/- 46.52 vs 680.6 +/- 30.27) and 4.4% in the cellular area (303.4 +/- 5.19 vs 291.1 +/- 6.0) respectively of the diabetic group treated with AA when compared to control diabetic animals. There were no significant differences in MI parameters, villi height or crypt depths among the groups. CONCLUSION: Supplementation with AA in the diabetic animal promoted moderate neuroprotection. There was no observation of alteration of the cellular proliferation of the jejunum mucosa layer of rats with chronic diabetes mellitus with or without supplementation with AA. 1-hop neighbor's text information:Title: Aldose reductase inhibition counteracts nitrosative stress and poly(ADP-ribose) polymerase activation in diabetic rat kidney and high-glucose-exposed human mesangial cells. Abstract: Both increased aldose reductase (AR) activity and oxidative/nitrosative stress have been implicated in the pathogenesis of diabetic nephropathy, but the relation between the two factors remains a subject of debate. This study evaluated the effects of AR inhibition on nitrosative stress and poly(ADP-ribose) polymerase (PARP) activation in diabetic rat kidney and high-glucose-exposed human mesangial cells. In animal experiments, control (C) and streptozotocin-diabetic (D) rats were treated with/without the AR inhibitor fidarestat (F, 16 mg kg(-1) day(-1)) for 6 weeks starting from induction of diabetes. Glucose, sorbitol, and fructose concentrations were significantly increased in the renal cortex of D vs C (p < 0.01 for all three comparisons), and sorbitol pathway intermediate, but not glucose, accumulation, was completely prevented in D + F. F at least partially prevented diabetes-induced increase in kidney weight as well as nitrotyrosine (NT, a marker of peroxynitrite-induced injury and nitrosative stress), and poly(ADP-ribose) (a marker of PARP activation) accumulation, assessed by both immunohistochemistry and Western blot analysis, in glomerular and tubular compartments of the renal cortex. In vitro studies revealed the presence of both AR and PARP-1 in human mesangial cells, and none of these two variables were affected by high glucose or F treatment. Nitrosylated and poly(ADP-ribosyl)ated proteins (Western blot analysis) accumulated in cells cultured in 30 mM D-glucose (vs 5.55 mM glucose, p < 0.01), but not in cells cultured in 30 mM L-glucose or 30 mM D-glucose plus 10 microM F. AR inhibition counteracts nitrosative stress and PARP activation in the diabetic renal cortex and high-glucose-exposed human mesangial cells. These findings reveal new beneficial properties of the AR inhibitor F and provide the rationale for detailed studies of F on diabetic nephropathy. 1-hop neighbor's text information:Title: The linked roles of nitric oxide, aldose reductase and, (Na+,K+)-ATPase in the slowing of nerve conduction in the streptozotocin diabetic rat. Abstract: Metabolic and vascular factors have been invoked in the pathogenesis of diabetic neuropathy but their interrelationships are poorly understood. Both aldose reductase inhibitors and vasodilators improve nerve conduction velocity, blood flow, and (Na+,K+)-ATPase activity in the streptozotocin diabetic rat, implying a metabolic-vascular interaction. NADPH is an obligate cofactor for both aldose reductase and nitric oxide synthase such that activation of aldose reductase by hyperglycemia could limit nitric oxide synthesis by cofactor competition, producing vasoconstriction, ischemia, and slowing of nerve conduction. In accordance with this construct, N-nitro-L-arginine methyl ester, a competitive inhibitor of nitric oxide synthase reversed the increased nerve conduction velocity afforded by aldose reductase inhibitor treatment in the acutely diabetic rat without affecting the attendant correction of nerve sorbitol and myo-inositol. With prolonged administration, N-nitro-L-arginine methyl ester fully reproduced the nerve conduction slowing and (Na+,K+)-ATPase impairment characteristic of diabetes. Thus the aldose reductase-inhibitor-sensitive component of conduction slowing and the reduced (Na+,K+)-ATPase activity in the diabetic rat may reflect in part impaired nitric oxide activity, thus comprising a dual metabolic-ischemic pathogenesis. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	0 0 0,0	1	pubmed	train	173
Title: Enhanced hepatic insulin sensitivity, but peripheral insulin resistance in patients with type 1 (insulin-dependent) diabetes. Abstract: Sensitivity to insulin in vivo was studied in 8 normal weight C-peptide negative Type 1 (insulin-dependent) diabetic patients (age 23 +/- 1 years, diabetes duration 6 +/- 2 years), and in 8 age, weight and sex matched healthy subjects, using the euglycaemic clamp and 3-3H-glucose tracer technique. Prior to the study diabetic patients were maintained normoglycaemic overnight by a glucose controlled insulin infusion. Sequential infusions of insulin in 3 periods of 2 h resulted in mean steady state insulin levels of 12 +/- 2 versus 11 +/- 1, 18 +/- 2 versus 18 +/- 2 and 28 +/- 3 versus 24 +/- 2 microU/ml in diabetic patients and control subjects. Corresponding glucose utilization rates were 2.4 +/- 0.2 versus 2.4 +/- 0.1, 2.4 +/- 0.2 versus 3.0 +/- 0.3 and 2.9 +/- 0.3 versus 4.6 +/- 0.6 mg.kg-1.min-1, p less than 0.02. Portal insulin values in the three periods were calculated to 12 +/- 2 versus 25 +/- 3, 18 +/- 2 versus 32 +/- 3 and 28 +/- 3 versus 37 +/- 3 microU/ml in the diabetic patients and control subjects using peripheral insulin and C-peptide concentrations and assuming a portal to peripheral insulin concentration gradient of 1 in diabetic patients and of 2.4 in control subjects. Corresponding glucose production rates were 2.5 +/- 0.2 versus 2.4 +/- 0.1, 1.6 +/- 0.1 versus 0.9 +/- 0.2 and 0.7 +/- 0.1 versus 0.4 +/- 0.2 mg.kg-1.min-1.(ABSTRACT TRUNCATED AT 250 WORDS) 1-hop neighbor's text information:Title: The effects of non-insulin-dependent diabetes mellitus on the kinetics of onset of insulin action in hepatic and extrahepatic tissues. Abstract: The mechanism(s) of insulin resistance in non-insulin-dependent diabetes mellitus remains ill defined. The current studies sought to determine whether non-insulin-dependent diabetes mellitus is associated with (a) a delay in the rate of onset of insulin action, (b) impaired hepatic and extrahepatic kinetic responses to insulin, and (c) an alteration in the contribution of gluconeogenesis to hepatic glucose release. To answer these questions, glucose disappearance, glucose release, and the rate of incorporation of 14CO2 into glucose were measured during 0.5 and 1.0 mU/kg-1 per min-1 insulin infusions while glucose was clamped at approximately 95 mg/dl in diabetic and nondiabetic subjects. The absolute rate of disappearance was lower (P < 0.05) and the rate of increase slower (P < 0.05) in diabetic than nondiabetic subjects during both insulin infusions. In contrast, the rate of suppression of glucose release in response to a change in insulin did not differ in the diabetic and nondiabetic subjects during either the low (slope 30-240 min:0.02 +/- 0.01 vs 0.02 +/- 0.01) or high (0.02 +/- 0.00 vs 0.02 +/- 0.00) insulin infusions. However, the hepatic response to insulin was not entirely normal in the diabetic subjects. Both glucose release and the proportion of systemic glucose being derived from 14CO2 (an index of gluconeogenesis) was inappropriately high for the prevailing insulin concentration in the diabetic subjects. Thus non-insulin-dependent diabetes mellitus slows the rate-limiting step in insulin action in muscle but not liver and alters the relative contribution of gluconeogenesis and glycogenolysis to hepatic glucose release. 1-hop neighbor's text information:Title: Glycogen synthase and phosphofructokinase protein and mRNA levels in skeletal muscle from insulin-resistant patients with non-insulin-dependent diabetes mellitus. Abstract: In patients with non-insulin-dependent diabetes mellitus (NIDDM) and matched control subjects we examined the interrelationships between in vivo nonoxidative glucose metabolism and glucose oxidation and the muscle activities, as well as the immunoreactive protein and mRNA levels of the rate-limiting enzymes in glycogen synthesis and glycolysis, glycogen synthase (GS) and phosphofructokinase (PFK), respectively. Analysis of biopsies of quadriceps muscle from 19 NIDDM patients and 19 control subjects showed in the basal state a 30% decrease (P < 0.005) in total GS activity and a 38% decrease (P < 0.001) in GS mRNA/microgram DNA in NIDDM patients, whereas the GS protein level was normal. The enzymatic activity and protein and mRNA levels of PFK were all normal in diabetic patients. In subgroups of NIDDM patients and control subjects an insulin-glucose clamp in combination with indirect calorimetry was performed. The rate of insulin-stimulated nonoxidative glucose metabolism was decreased by 47% (P < 0.005) in NIDDM patients, whereas the glucose oxidation rate was normal. The PFK activity, protein level, and mRNA/microgram DNA remained unchanged. The relative activation of GS by glucose-6-phosphate was 33% lower (P < 0.02), whereas GS mRNA/micrograms DNA was 37% lower (P < 0.05) in the diabetic patients after 4 h of hyperinsulinemia. Total GS immunoreactive mass remained normal. In conclusion, qualitative but not quantitative posttranslational abnormalities of the GS protein in muscle determine the reduced insulin-stimulated nonoxidative glucose metabolism in NIDDM. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 2,1	1	pubmed	train	174
Title: HLA and insulin gene associations with IDDM. Abstract: The HLA DR genotype frequencies in insulin-dependent diabetes mellitus (IDDM) patients and the frequencies of DR alleles transmitted from affected parent to affected child both indicate that the DR3-associated predisposition is more "recessive" and the DR4-associated predisposition more "dominant" in inheritance after allowing for the DR3/DR4 synergistic effect. B locus distributions on patient haplotypes indicate that only subsets of both DR3 and DR4 are predisposing. Heterogeneity is detected for both the DR3 and DR4 predisposing haplotypes based on DR genotypic class. With appropriate use of the family structure of the data a control population of "unaffected" alleles can be defined. Application of this method confirms the predisposing effect associated with the class 1 allele of the polymorphic region 5' to the insulin gene. 1-hop neighbor's text information:Title: Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Abstract: A population association has consistently been observed between insulin-dependent diabetes mellitus (IDDM) and the "class 1" alleles of the region of tandem-repeat DNA (5' flanking polymorphism [5'FP]) adjacent to the insulin gene on chromosome 11p. This finding suggests that the insulin gene region contains a gene or genes contributing to IDDM susceptibility. However, several studies that have sought to show linkage with IDDM by testing for cosegregation in affected sib pairs have failed to find evidence for linkage. As means for identifying genes for complex diseases, both the association and the affected-sib-pairs approaches have limitations. It is well known that population association between a disease and a genetic marker can arise as an artifact of population structure, even in the absence of linkage. On the other hand, linkage studies with modest numbers of affected sib pairs may fail to detect linkage, especially if there is linkage heterogeneity. We consider an alternative method to test for linkage with a genetic marker when population association has been found. Using data from families with at least one affected child, we evaluate the transmission of the associated marker allele from a heterozygous parent to an affected offspring. This approach has been used by several investigators, but the statistical properties of the method as a test for linkage have not been investigated. In the present paper we describe the statistical basis for this "transmission test for linkage disequilibrium" (transmission/disequilibrium test [TDT]). We then show the relationship of this test to tests of cosegregation that are based on the proportion of haplotypes or genes identical by descent in affected sibs. The TDT provides strong evidence for linkage between the 5'FP and susceptibility to IDDM. The conclusions from this analysis apply in general to the study of disease associations, where genetic markers are usually closely linked to candidate genes. When a disease is found to be associated with such a marker, the TDT may detect linkage even when haplotype-sharing tests do not. 1-hop neighbor's text information:Title: T cell receptor haplotypes in families of patients with insulin-dependent diabetes mellitus. Abstract: The frequencies of Bgl 11 and BamH1 restriction fragment length polymorphisms (RFLP) of C beta, V beta 8, V beta 11 and V beta 7.2 have been defined in a healthy Australian population. Linkage disequilibrium between alleles of the T cell receptor (TCR) V beta 8 and V beta 11 gene segments has been confirmed. We have also confirmed the lack of linkage disequilibrium between either of these loci and alleles at C beta or V beta 7.2. Using RFLPs at V beta 11 and V beta 8 loci TCR beta haplotypes have been identified in five families in which the probands have insulin-dependent diabetes mellitus (IDDM). An extremely rare haplotype, marked by the higher molecular weight BamH1 allele (H, H) at each of V beta 11 and V beta 8, was found in the DR4+ DR3- probands of two families (P = 0.004). In three families in which the probands had DR3, the more common TCR haplotype LH (V beta 11, V beta 8) was found. Taken together, these data confirm that linkage disequilibrium does exist in the TCR beta locus, at least in some regions, and suggest that detailed analysis of the relationship between TCR V beta haplotypes and HLA is warranted since these RFLPs may be markers for important allelic V gene sequence variations. 2-hop neighbor's text information:Title: Type 1 (insulin-dependent) diabetes and a highly variable locus close to the insulin gene on chromosome 11. Abstract: A polymorphic DNA sequence in the 5'-flanking region of the human insulin gene was studied in relation to Type 1 (insulin-dependent) diabetes. In 141 Caucasoid subjects analysed by Southern blot hybridisation techniques, two major DNA insertions were observed: a Class 1 allele or a Class 3 allele. The Class 2 allele was not observed in this group of subjects. Genotype frequencies in a control population (n = 88) were: homozygous 1/1, 42%; heterozygous 1/3, 50%; and homozygous 3/3, 8%. Corresponding genotype frequencies in 53 Type 1 diabetic patients were 79%, 21% and 0%, respectively (p less than 0.0005 from chi 2 test). This confirms prevalence data reported by Bell et al. [16]. There appeared to be no coinheritance with HLA-DR3/DR4 related antigens, nor with autoimmune features. Analysis of 17 Type 1 diabetic pedigrees including 34 diabetic and 69 non-diabetic subjects did not demonstrate genetic linkage of these DNA inserts with diabetes, using an autosomal recessive, single locus model of inheritance. 2-hop neighbor's text information:Title: Haplotype relative risks: an easy reliable way to construct a proper control sample for risk calculations. Abstract: An alternative to Woolf's (1955) relative risk (RR) statistic is proposed for use in calculating the risk of disease in the presence of particular antigens or phenotypes. This alternative uses, as the control sample, the parental antigens or haplotypes not present in the affected child. The formulation of a haplotype relative risk (HRR) thus eliminates the problems of sampling from the same homogeneous population to form both the disease sample and an appropriate control. We show that, in families selected through a single affected individual, where transmission of the four parental haplotypes can be followed unambiguously, the mathematical expectation of the HRR is identical to that of the RR. Since the sample formed from the 'non-affected' parental haplotypes is clearly from the same population as the disease sample, the HRR thus provides a reliable alternative to the RR. A further advantage obtains when family data are being collected as part of a study since the control sample is then automatically contained in the family material. Data from studies of patients with insulin dependent diabetes mellitus (IDDM) are used to obtain an estimate of the risk to those with HLA antigens or phenotypes associated with IDDM using the HRR statistic. A comparison of the HRR's and RR's for these data is also presented. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1 1 1,1	2	pubmed	train	175
Title: How, when, and why to predict IDDM. Abstract: Insulin-dependent diabetes remains a serious disease replete with life-threatening complications. The onset of the disease is becoming increasingly predictable through the detection of its associated autoantibodies. The natural history of pathogenic events is attenuated in those with adult onset over that seen in infants and children. Immunosuppression therapies in newly diagnosed patients have been shown to induce remissions, whereas various intervention strategies in rodent models (BB rats and nonobese diabetic mice) can delay and even prevent the onset of diabetes. The stage is set for serious consideration of intervention trials to delay the clinical disease in humans. 1-hop neighbor's text information:Title: Rapamycin prevents the onset of insulin-dependent diabetes mellitus (IDDM) in NOD mice. Abstract: The effect of the immunosuppressive agent rapamycin (RAPA) was assessed in the non-obese diabetic (NOD) mouse which is an autoimmune model of IDDM. RAPA was prepared in a vehicle of 8% cremophor EL/2% ethanol and investigated in two studies. NOD/MrK female mice (six per group, study no. 1; 10 per group, study no. 2) were dosed three times per week p.o. by gavage from 56 to 170 days of age (study no. 1) or from 64 to 176 days of age (study no. 2). Mice treated with RAPA at 0.6 mg/kg, 6 mg/kg, or 12 mg/kg maintained normal plasma glucose through 170 or 176 days of age with 10%, 0%, and 0% incidence of diabetes respectively. In contrast, naive, vehicle-treated, or RAPA 0.06 mg/kg-treated mice exhibited elevated plasma glucose and disease incidence typical for female NOD mice. Mice which became diabetic had elevated levels of beta-hydroxybutyrate, triglycerides and cholesterol. These plasma lipid concentrations were positively correlated with the duration of hyperglycaemia (r = 0.85, 0.87 and 0.84 respectively). Outside of its ability to prevent diabetes, RAPA itself did not affect the lipid profile of the mice. Intervention therapy with RAPA was ineffective at reversing the course of disease after IDDM onset under these experimental conditions. Finally, we report here that prophylactic treatment with RAPA was able to protect against IDDM development in some RAPA-treated mice 41 weeks after cessation of treatment. These data show that orally administered RAPA is effective in preventing onset of disease in the NOD mouse, a relevant model of autoimmune type I diabetes in man. 1-hop neighbor's text information:Title: Autoimmunity to two forms of glutamate decarboxylase in insulin-dependent diabetes mellitus. Abstract: Insulin-dependent diabetes mellitus (IDDM) is thought to result from the autoimmune destruction of the insulin-producing beta cells of the pancreas. Years before IDDM symptoms appear, we can detect autoantibodies to one or both forms of glutamate decarboxylase (GAD65 and GAD67), synthesized from their respective cDNAs in a bacterial expression system. Individual IDDM sera show distinctive profiles of epitope recognition, suggesting different humoral immune responses. Although the level of GAD autoantibodies generally decline after IDDM onset, patients with IDDM-associated neuropathies have high levels of antibodies to GAD, years after the appearance of clinical IDDM. We note a striking sequence similarity between the two GADs and Coxsackievirus, a virus that has been associated with IDDM both in humans and in experimental animals. This similarity suggests that molecular mimicry may play a role in the pathogenesis of IDDM. 1-hop neighbor's text information:Title: Islet cell cytoplasmic autoantibody reactivity to glutamate decarboxylase in insulin-dependent diabetes. Abstract: Individuals with or at risk for insulin-dependent diabetes (IDD) frequently have autoantibodies against an islet cell cytoplasmic (ICA) antigen thought to be a sialoglycolipid. However, we now report that preabsorption of ICA-positive sera with recombinant glutamate decarboxylase (human GAD 65 and/or GAD 67) reduced or blocked the ICA reactivity of 5/18 (27%) new-onset IDD patients and 7/18 (39%) prediabetics. Interestingly, nondiabetic subjects with ICA of > or = 5 yr in duration had GAD-reactive ICA significantly more often (16/24, 67%, P < 0.04) than the diabetic groups. ICA reactivity to GAD was not related to serum ICA titer nor the age of the individual, and in all cases tested was blocked by GAD 65 or GAD 67 with equivalent efficiency. The ICA observed in 21/25 (84%) IDD patients with ICA long after clinical onset of disease (9-42 yr) was reactive to GAD. A natural history analysis of three individuals showed conversions from ICA which was reactive to GAD to a non-GAD-reactive ICA nearer to their clinical onsets of IDD. This study further defines the autoantigens reactive to ICA, and suggests that, whereas ICA that are not reactive to GAD may identify an advanced and more prognostic lesion, GAD-reactive ICA may typify the early or inductive lesion that may or may not progress to clinically significant beta cell injury. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 2 1,1	1	pubmed	train	177
Title: Is there a role for alpha-glucosidase inhibitors in the prevention of type 2 diabetes mellitus? Abstract: Type 2 diabetes mellitus is a major health problem associated with excess morbidity and mortality. As the prevalence of this metabolic disorder is rapidly increasing and current treatment fails to stabilise the disease in most patients, prevention should be considered as a key objective in the near future. People who develop type 2 diabetes pass through a phase of impaired glucose tolerance (IGT). Defects in the action and/or secretion of insulin are the two major abnormalities leading to development of glucose intolerance. Any intervention in the impaired glucose tolerance phase that reduces resistance to insulin or protects the beta-cells, or both, should prevent or delay progression to diabetes.Acarbose, miglitol and voglibose act by competitively inhibiting the alpha-glucosidases, a group of key intestinal enzymes involved in the digestion of carbohydrates. They decrease both postprandial hyperglycaemia and hyperinsulinaemia, and thereby may improve sensitivity to insulin and release the stress on beta-cells. These compounds do not induce hypoglycaemia and have a good safety profile, although gastrointestinal adverse effects may limit long-term compliance to therapy. The recent placebo-controlled prospective STOP-noninsulin-dependent diabetes mellitus (STOP-NIDDM) trial demonstrated that acarbose 100mg three times daily reduces the risk of developing type 2 diabetes in patients with IGT (relative risk reduction of 25% after a mean follow-up of 3.3 years). The 6-year Early Diabetes Intervention Trial (EDIT), comparing the effect of acarbose 50mg three times daily to that of metformin, showed a trend to a positive effect of acarbose compared with placebo, in a mid-term 3-year analysis, which should be confirmed in the final analysis. To our knowledge, no such prevention intervention trials have been or are currently being performed with miglitol or voglibose. In conclusion, because of its absence of toxicity and its particular mechanism of action on gastrointestinal tract and indirect consequences on both insulin action and beta-cell function, acarbose may be used to prevent type 2 diabetes. If the ongoing EDIT trial confirms the positive results of the recent STOP-NIDDM trial, acarbose could be used, either as an alternative or in addition to changes in lifestyle, to delay development of diabetes in patients with IGT. However, the best dosage of acarbose for this specific indication remains to be specified, especially when all three important parameters, efficacy, tolerance and cost, are taken into consideration. 1-hop neighbor's text information:Title: Orlistat in the prevention of diabetes in the obese patient. Abstract: There has been an increase in the concern about preventing type 2 diabetes mellitus (T2DM), a disease with great and increasing prevalence. The prevalence of obesity, physical inactivity, Western processed diet, important risk factors for the development of T2DM, are also rising. Free fatty acids are increased in obesity and reduce insulin clearance and increase hepatic glucose production. Implementation of a healthy lifestyle has been show to slow the progression of impaired glucose tolerance to T2DM. Orlistat is an inhibitor of lipase activity, with proved efficacy in body weight reduction and long-term management of obesity and more favorable effects on carbohydrate metabolism and it was prospectively shown in XENDOS study that orlistat promoted long-term weight loss and prevented T2DM onset in obese individuals with normal and impaired glucose tolerance at baseline over four years. This benefit could be associated to the weight loss itself, to the limited absorption of lipids and reduction of plasma free fatty acids, to increased production of incretins or to modulation of secretion of cytokines by adipocytes, all effects secondary to orlistat treatment. A proposed strategy is to identify subjects at highest risk to receive a drug intervention, using lifestyle interventions alone at the community level. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	2,2	1	pubmed	train	180
Title: HLA and insulin gene associations with IDDM. Abstract: The HLA DR genotype frequencies in insulin-dependent diabetes mellitus (IDDM) patients and the frequencies of DR alleles transmitted from affected parent to affected child both indicate that the DR3-associated predisposition is more "recessive" and the DR4-associated predisposition more "dominant" in inheritance after allowing for the DR3/DR4 synergistic effect. B locus distributions on patient haplotypes indicate that only subsets of both DR3 and DR4 are predisposing. Heterogeneity is detected for both the DR3 and DR4 predisposing haplotypes based on DR genotypic class. With appropriate use of the family structure of the data a control population of "unaffected" alleles can be defined. Application of this method confirms the predisposing effect associated with the class 1 allele of the polymorphic region 5' to the insulin gene. 1-hop neighbor's text information:Title: Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Abstract: A population association has consistently been observed between insulin-dependent diabetes mellitus (IDDM) and the "class 1" alleles of the region of tandem-repeat DNA (5' flanking polymorphism [5'FP]) adjacent to the insulin gene on chromosome 11p. This finding suggests that the insulin gene region contains a gene or genes contributing to IDDM susceptibility. However, several studies that have sought to show linkage with IDDM by testing for cosegregation in affected sib pairs have failed to find evidence for linkage. As means for identifying genes for complex diseases, both the association and the affected-sib-pairs approaches have limitations. It is well known that population association between a disease and a genetic marker can arise as an artifact of population structure, even in the absence of linkage. On the other hand, linkage studies with modest numbers of affected sib pairs may fail to detect linkage, especially if there is linkage heterogeneity. We consider an alternative method to test for linkage with a genetic marker when population association has been found. Using data from families with at least one affected child, we evaluate the transmission of the associated marker allele from a heterozygous parent to an affected offspring. This approach has been used by several investigators, but the statistical properties of the method as a test for linkage have not been investigated. In the present paper we describe the statistical basis for this "transmission test for linkage disequilibrium" (transmission/disequilibrium test [TDT]). We then show the relationship of this test to tests of cosegregation that are based on the proportion of haplotypes or genes identical by descent in affected sibs. The TDT provides strong evidence for linkage between the 5'FP and susceptibility to IDDM. The conclusions from this analysis apply in general to the study of disease associations, where genetic markers are usually closely linked to candidate genes. When a disease is found to be associated with such a marker, the TDT may detect linkage even when haplotype-sharing tests do not. 1-hop neighbor's text information:Title: T cell receptor haplotypes in families of patients with insulin-dependent diabetes mellitus. Abstract: The frequencies of Bgl 11 and BamH1 restriction fragment length polymorphisms (RFLP) of C beta, V beta 8, V beta 11 and V beta 7.2 have been defined in a healthy Australian population. Linkage disequilibrium between alleles of the T cell receptor (TCR) V beta 8 and V beta 11 gene segments has been confirmed. We have also confirmed the lack of linkage disequilibrium between either of these loci and alleles at C beta or V beta 7.2. Using RFLPs at V beta 11 and V beta 8 loci TCR beta haplotypes have been identified in five families in which the probands have insulin-dependent diabetes mellitus (IDDM). An extremely rare haplotype, marked by the higher molecular weight BamH1 allele (H, H) at each of V beta 11 and V beta 8, was found in the DR4+ DR3- probands of two families (P = 0.004). In three families in which the probands had DR3, the more common TCR haplotype LH (V beta 11, V beta 8) was found. Taken together, these data confirm that linkage disequilibrium does exist in the TCR beta locus, at least in some regions, and suggest that detailed analysis of the relationship between TCR V beta haplotypes and HLA is warranted since these RFLPs may be markers for important allelic V gene sequence variations. 2-hop neighbor's text information:Title: Susceptibility to IDDM is marked by MHC supratypes rather than individual alleles. Abstract: 107 patients with insulin-dependent diabetes mellitus (IDDM) were typed for HLA A, B, C-, and DR antigens, and for complement C4A, C4B, and Bf alleles, and the results were compared with those of a combined reference group of 332 appropriately matched healthy subjects. Supratypes (allelic combinations) were identified from the phenotype of each group, and it was shown that the frequency of several supratypes is increased in patients with IDDM, in particular supratypes (A1 Cw7) B8 C4AQ0 C4B1 BfS DR3 (P = 0.0001), (A30 Cw-) B18 C4A3 C4BQ0 BfF1 DR3 (P = 0.0003), (A2 Cw3) B62 C4AR C4B2.9 BfS DR4 (P = 0.0002), and three other supratypes including DR4. It was also shown that increases in the frequency of individual alleles are secondary to increases in supratype frequency. Moreover, supratypes appeared to interact; the presence of two relevant supratypes being particularly important. The absolute risk of IDDM was approximately 0.5 in subjects who were homozygous for B18 C4A3 C4BQ0 BfF1 DR3. We concluded that genetic susceptibility is best recognized by MHC supratypes rather than isolated alleles, and that supratype combinations make the identification of even greater disease risk possible. 2-hop neighbor's text information:Title: Association analysis of SNPs in the IL4R locus with type I diabetes. Abstract: The Type I Diabetes Genetics Consortium (T1DGC) has collected thousands of multiplex and simplex families with type I diabetes (T1D) with the goal of identifying genes involved in T1D susceptibility. These families have all been genotyped for the HLA class I and class II loci and a subset of samples has been typed for an major histocompatibility complex (MHC) single-nucleotide polymorphism (SNP) panel. In addition, the T1DGC has genotyped SNPs in candidate genes to evaluate earlier reported T1D associations. Individual SNPs and SNP haplotypes in IL4R, which encodes the alpha-chain of the IL4 and IL13 receptors, have been associated with T1D in some reports, but not in others. In this study, 38 SNPs in IL4R were genotyped using the Sequenom iPLEX Gold MassARRAY technology in 2042 multiplex families from nine cohorts. Association analyses (transmission-disequilibrium test and parental-disequilibrium test) were performed on individual SNPs and on three-SNP haplotypes. Analyses were also stratified on the high-risk HLA DR3/DR4-DQB10302 genotype. A modest T1D association in HBDI families (n=282) was confirmed in this larger collection of HBDI families (n=424). The variant alleles at the non-synonymous SNPs (rs1805011 (E400A), rs1805012 (C431R), and rs1801275 (Q576R)), which are in strong linkage disequilibrium, were negatively associated with T1D risk. These SNPs were more associated with T1D among non-DR3/DR4-DQB10302 genotypes than DR3/DR4-DQB1*0302 genotypes. This association was stronger, both in terms of odds ratio and P-values, than the initial report of the smaller collection of HBDI families. However, the IL4R SNPs and the three-SNP haplotype containing the variant alleles were not associated with T1D in the total data. Thus, in the overall families, these results do not show evidence for an association of SNPs in IL4R with T1D. I provide the content of the target node and its neighbors' information. The relation between the target node and its 1-hop neighbors, as well as between its 1-hop and 2-hop neighbors, is 'citation'. The 3 categories are: 0: Diabetes Mellitus, Experimental 1: Diabetes Mellitus, Type 1 2: Diabetes Mellitus, Type 2 Question 1: Predict the category ID (0 to 2) for each neighbor node, in the same order as they are given. Reply with the sequence of predicted IDs separated by spaces. Question 2: Based on the predicted neighbor categories from Question 1 and the content of the target scientific publication, predict the category ID (0 to 2) for the target node. Combine all answers into a single output: first the neighbor category IDs (space-separated), then the target node's category ID after a comma.	1 1 1 1,1	2	pubmed	train	183

Subsets and Splits

No community queries yet

The top public SQL queries from the community will appear here once available.