| 1. |
- Andersen, Mette K., et al.
(författare)
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Latent Autoimmune Diabetes in Adults Differs Genetically From Classical Type 1 Diabetes Diagnosed After the Age of 35 Years
- 2010
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Ingår i: Diabetes Care. - American Diabetes Association. - 0149-5992. ; 33:9, s. 2062-2064
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE- We studied differences between patients with latent autoimmune diabetes in adults (LADA), type 2 diabetes, and classical type 1 diabetes diagnosed after age 35 years. RESEARCH DESIGN AND METHODS- Polymorphisms in HLA-DQB1, INS, PTPN22, and CTLA4 were genotyped in patients with LADA (n = 213), type 1 diabetes diagnosed at >35 years of age (T1D(>35y); n = 257) or <20 years of age (T1D(<20y); n = 158), and type 2 diabetes. RESULTS- Although patients with LADA had an increased frequency of HLA-DQB1 and PTPN22 risk genotypes and alleles compared with type 2 diabetic subjects, the frequency was significantly lower compared with T1D(>35y) patients. Genotype frequencies, measures of insulin secretion, and metabolic traits within LADA differed according to GAD antibody (GADA) quartiles, but even the highest quartile differed from type 1 diabetes. Having two or more risk genotypes was associated with lower C-peptide concentrations in LADA. CONCLUSIONS- LADA patients differed genetically and phenotypically from both T1D(>35y) and type 2 diabetic patients in a manner dependent on GADA levels.
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| 2. |
- Bakhtadze, Ekaterine, et al.
(författare)
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Common variants in the TCF7L2 gene help to differentiate autoimmune from non-autoimmune diabetes in young (15-34 years) but not in middle-aged (40-59 years) diabetic patients.
- 2008
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Ingår i: Diabetologia. - Springer. - 0012-186X. ; 51:12, s. 2224-2232
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Type 1 diabetes in children is characterised by autoimmune destruction of pancreatic beta cells and the presence of certain risk genotypes. In adults the same situation is often referred to as latent autoimmune diabetes in adults (LADA). We tested whether genetic markers associated with type 1 or type 2 diabetes could help to discriminate between autoimmune and non-autoimmune diabetes in young (15-34 years) and middle-aged (40-59 years) diabetic patients. METHODS: In 1,642 young and 1,619 middle-aged patients we determined: (1) HLA-DQB1 genotypes; (2) PTPN22 and INS variable-number tandem repeat (VNTR) polymorphisms; (3) two single nucleotide polymorphisms (rs7903146 and rs10885406) in the TCF7L2 gene; (4) glutamic acid decarboxylase (GAD) and IA-2-protein tyrosine phosphatase-like protein (IA-2) antibodies; and (5) fasting plasma C-peptide. RESULTS: Frequency of risk genotypes HLA-DQB1 (60% vs 25%, p = 9.4x10(-34); 45% vs 18%, p = 1.4 x 10(-16)), PTPN22 CT/TT (34% vs 26%, p = 0.0023; 31% vs 23%, p = 0.034), INS VNTR class I/I (69% vs 53%, p = 1.3 x 10(-8); 69% vs 51%, p = 8.5 x 10(-5)) and INS VNTR class IIIA/IIIA (75% vs 63%, p = 4.3 x 10(-6); 73% vs 60%, p = 0.008) was increased in young and middle-aged GAD antibodies (GADA)-positive compared with GADA-negative patients. The type 2 diabetes-associated genotypes of TCF7L2 CT/TT of rs7903146 were significantly more common in young GADA-negative than in GADA-positive patients (53% vs 43%; p = 0.0004). No such difference was seen in middle-aged patients, in whom the frequency of the CT/TT genotypes of TCF7L2 was similarly increased in GADA-negative and GADA-positive groups (55% vs 56%). CONCLUSIONS/INTERPRETATION: Common variants in the TCF7L2 gene help to differentiate young but not middle-aged GADA-positive and GADA-negative diabetic patients, suggesting that young GADA-negative patients have type 2 diabetes and that middle-aged GADA-positive patients are different from their young GADA-positive counterparts and share genetic features with type 2 diabetes.
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| 3. |
- Fagerholm, E., et al.
(författare)
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SNP in the genome-wide association study hotspot on chromosome 9p21 confers susceptibility to diabetic nephropathy in type 1 diabetes
- 2012
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Ingår i: Diabetologia. - Springer. - 0012-186X. ; 55:9, s. 2386-2393
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Tidskriftsartikel (refereegranskat)abstract
- Parental type 2 diabetes mellitus increases the risk of diabetic nephropathy in offspring with type 1 diabetes mellitus. Several single nucleotide polymorphisms (SNPs) that predispose to type 2 diabetes mellitus have recently been identified. It is, however, not known whether such SNPs also confer susceptibility to diabetic nephropathy in patients with type 1 diabetes mellitus. We genotyped nine SNPs associated with type 2 diabetes mellitus in genome-wide association studies in the Finnish population, and tested for their association with diabetic nephropathy as well as with severe retinopathy and cardiovascular disease in 2,963 patients with type 1 diabetes mellitus. Replication of significant SNPs was sought in 2,980 patients from three other cohorts. In the discovery cohort, rs10811661 near gene CDKN2A/B was associated with diabetic nephropathy. The association remained after robust Bonferroni correction for the total number of tests performed in this study (OR 1.33 95% CI 1.14, 1.56, p = 0.00045, p (36tests) = 0.016). In the meta-analysis, the combined result for diabetic nephropathy was significant, with a fixed effects p value of 0.011 (OR 1.15 95% CI 1.02, 1.29). The association was particularly strong when patients with end-stage renal disease were compared with controls (OR 1.35 95% CI 1.13, 1.60, p = 0.00038). The same SNP was also associated with severe retinopathy (OR 1.37 95% CI 1.10, 1.69 p = 0.0040), but the association did not remain after Bonferroni correction (p (36tests) = 0.14). None of the other selected SNPs was associated with nephropathy, severe retinopathy or cardiovascular disease. A SNP predisposing to type 2 diabetes mellitus, rs10811661 near CDKN2A/B, is associated with diabetic nephropathy in patients with type 1 diabetes mellitus.
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| 4. |
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| 5. |
- Ronnback, Mats, et al.
(författare)
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Complex Relationship Between Blood Pressure and Mortality in Type 2 Diabetic Patients. A Follow-Up of the Botnia Study.
- 2006
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Ingår i: Hypertension. - American Heart Association. - 1524-4563. ; 47:Dec 27, s. 168-173
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Tidskriftsartikel (refereegranskat)abstract
- The presence of hypertension aggravates the high cardiovascular risk in type 2 diabetic patients. Pulse pressure is a marker of arterial stiffness and constitutes a risk factor for cardiovascular mortality. This study examines the relationship between different blood pressure indices and mortality in a cohort of type 2 diabetic patients. A total of 1294 type 2 diabetic patients with a median age of 69.1 years participated in the Botnia Study from 1990 to 1997. In 2004, after a median follow-up of 9.5 years, data on mortality was collected from the national population registry and hospital records. Systolic and diastolic blood pressure correlated negatively with mortality after adjustment for other risk factors. The association between low systolic and diastolic blood pressure and mortality was pronounced in patients with previous cardiovascular disease. A U-shaped association between pulse pressure and mortality was observed in elderly patients. These observations could be linked to arterial stiffness and heart failure. Low blood pressure in high-risk patients is likely to be a marker of poor health rather than the cause of mortality. The results suggest that the role of blood pressure as a risk marker in elderly type 2 diabetic patients with cardiovascular disease needs to be reevaluated.
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| 6. |
- Sandholm, Niina, et al.
(författare)
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New susceptibility loci associated with kidney disease in type 1 diabetes
- 2012
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Ingår i: PLOS Genetics. - San Francisco, USA : Public Library of Science, PLOS. - 1553-7404. ; 8:9, s. e1002921
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Tidskriftsartikel (refereegranskat)abstract
- Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genomewide association studies (GWAS) of T1D DN comprising similar to 2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2 x 10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0 x 10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-beta 1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1 x 10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.
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| 7. |
- Abdul-Ghani, Muhammad A., et al.
(författare)
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Fasting Versus Postload Plasma Glucose Concentration and the Risk for Future Type 2 Diabetes Results from the Botnia Study
- 2009
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Ingår i: Diabetes Care. - American Diabetes Association. - 0149-5992. ; 32:2, s. 281-286
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE - The purpose of this study was to assess the efficacy of the postload plasma glucose concentration in predicting future risk of type 2 diabetes, compared with prediction models based oil measurement. of the fasting plasma glucose (FPG) concentration. RESEARCH DESIGN AND METHODS - A total of 2,442 subjects from the Botnia Study, who were free Of type 2 diabetes at baseline, received an oral glucose tolerance test (OGTT) at baseline and after 7-8 years of follow-up. Future risk for type 2 diabetes was assessed with area under the receiver-operating characteristic curve for prediction models based up measurement of the FPG concentration 1) with or without a 1-h plasma glucose concentration during the OGTT and 2) with or without the metabolic syndrome. RESULTS - Prediction models based on measurement of the FPG concentration were weak predictors for the risk of Future type 2 diabetes. Addition of a 1-h plasma glucose Concentration markedly enhanced prediction Of the risk of future type 2 diabetes. A cut point of 155 mg/dl for the 1-h plasma glucose concentration during the OGTT and presence Of the metabolic syndrome were used to Stratify subjects in each glucose tolerance group into low, intermediate, and high risk for future type 2 diabetes. CONCLUSIONS - The plasma glucose concentration at 1 h during the OGTT is a Strong predictor of future risk for type 2 diabetes and adds to the prediction power of models based on measurements made during the fasting state. A plasma glucose cut point of 155 mg/dl Plus the Adult Treatment Panel III criteria for the metabolic syndrome can be used to stratify nondiabetic subjects into low-, intermediate-, and high-risk groups.
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| 8. |
- Abdul-Ghani, Muhammad A., et al.
(författare)
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Minimal Contribution of Fasting Hyperglycemia to the Incidence of Type 2 Diabetes in Subjects With Normal 2-h Plasma Glucose
- 2010
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Ingår i: Diabetes Care. - American Diabetes Association. - 0149-5992. ; 33:3, s. 557-561
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE - To assess the relative contribution of increased fasting and postload plasma glucose concentrations to the incidence of type 2 diabetes in subjects with a normal 2-h plasma glucose concentration. RESEARCH DESIGN AND METHODS - A total of 3,450 subjects with 2-h plasma glucose concentration < 140 mg/dl at baseline were followed up in the San Antonio Heart Study (SAHS) and the Botnia Study for 7-8 years. The incidence of type 2 diabetes at follow-up was related to the fasting, 1-h, and 2-h plasma glucose concentrations. RESULTS - in subjects with 2-h plasma glucose < 140 mg/dl, the incidence of type 2 diabetes increased with increasing fasting plasma glucose (FPG) and 1-h and 2-h plasma glucose concentrations. In a multivariate logistic analysis, after adjustment for all diabetes risk factors, the FPG concentration was a Strong predictor Of type 2 diabetes in both the SAHS and the Botnia Study (P < 0.0001). However, when the 1-h plasma glucose, but not 2-h plasma glucose, concentration was added to the model, FPG concentration was no longer a significant predictor of type 2 diabetes in both Studies (NS). When subjects were matched for the level of 1-h plasma glucose concentration, the incidence Of type 2 diabetes markedly increased with the increase in 1-h plasma glucose, but the increase in FPG was not associated with a significant increase in the incidence of type 2 diabetes. CONCLUSIONS - An increase in postload glycemia in the normal range is associated with an increase in the incidence of type 2 diabetes. After controlling for 1-h plasma glucose concentration, the increase in FPG concentration is not associated with an increase in the incidence of type 2 diabetes.
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| 9. |
- Abdul-Ghani, Muhammad A., et al.
(författare)
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The shape of plasma glucose concentration curve during OGTT predicts future risk of type 2 diabetes
- 2010
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Ingår i: Diabetes/Metabolism Research and Reviews. - Wiley InterScience. - 1520-7552. ; 26:4, s. 280-286
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Tidskriftsartikel (refereegranskat)abstract
- Background The aim of the study is to assess the relationship between the shape of plasma glucose concentration during the OGTT and future risk for T2DM. Methods 2445 non-diabetic subjects from the Botnia study received an OGTT at baseline and after 7-8 years of follow-up. Results NGT and IFG subjects who returned their plasma glucose concentration following an ingested glucose load below FPG within 60 min had increased insulin sensitivity, greater insulin secretion and lower risk for future T2DM compared to NGT and IFG subjects whose post-load plasma glucose concentration required 120 min or longer to return their plasma glucose level to FPG level. IGT subjects who had a lower plasma glucose concentration at 1-h compared to 2-h during oGrr had greater insulin sensitivity, better beta cell function and lower risk for future T2DM. Conclusions These data suggest that the shape of glucose curve can be utilized to assess future risk for T2DM. Copyright (C) 2010 John Wiley & Sons, Ltd.
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| 10. |
- Abdul-Ghani, Muhammad A., et al.
(författare)
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Two-Step Approach for the Prediction of Future Type 2 Diabetes Risk
- 2011
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Ingår i: Diabetes Care. - Amer Diabetes Assoc. - 0149-5992. ; 34:9, s. 2108-2112
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE-To develop a model for the prediction of type 2 diabetes mellitus (T2DM) risk on the basis of a multivariate logistic model and 1-h plasma glucose concentration (1-h PG). RESEARCH DESIGN AND METHODS-The model was developed in a cohort of 1,562 non-diabetic subjects from the San Antonio Heart Study (SAHS) and validated in 2,395 nondiabetic subjects in the Botnia Study. A risk score on the basis of anthropometric parameters, plasma glucose and lipid profile, and blood pressure was computed for each subject. Subjects with a risk score above a certain cut point were considered to represent high-risk individuals, and their 1-h PG concentration during the oral glucose tolerance test was used to further refine their future T2DM risk. RESULTS-We used the San Antonio Diabetes Prediction Model (SADPM) to generate the initial risk score. A risk-score value of 0.065 was found to be an optimal cut point for initial screening and selection of high-risk individuals. A 1-h PG concentration >140 mg/dL in high-risk individuals (whose risk score was >0.065) was the optimal cut point for identification of subjects at increased risk. The two cut points had 77.8, 77.4, and 44.8% (for the SAHS) and 75.8, 71.6, and 11.9% (for the Botnia Study) sensitivity, specificity, and positive predictive value, respectively, in the SAHS and Botnia Study. CONCLUSIONS-A two-step model, based on the combination of the SADPM and 1-h PG, is a useful tool for the identification of high-risk Mexican-American and Caucasian individuals. Diabetes Care 34:2108-2112, 2011
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