Decreased insulin secretion and increased risk of type 2 diabetes associated with allelic variations of the WFS1 gene: the Data from Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study

We investigated associations of allelic variations in the WFS1 gene with insulin secretion and risk of type 2 diabetes in a general population prospective study.We studied 5,110 unrelated French men and women who participated in the prospective Data from Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study. Additional cross-sectional analyses were performed on 4,472 French individuals with type 2 diabetes and 3,065 controls. Three single nucleotide polymorphisms (SNPs) were genotyped: rs10010131, rs1801213/rs7672995 and rs734312.We observed statistically significant associations between the major alleles of the three variants and prevalent type 2 diabetes in the DESIR cohort at baseline. Cox analyses showed an association between the G-allele of rs10010131 and incident type 2 diabetes (HR 1.34, 95% CI 1.08-1.70, p = 0.007). Similar results were observed for the G-allele of rs1801213 and the A-allele of rs734312. the GGA haplotype was associated with an increased risk of diabetes as compared with the ACG haplotype (HR 1.26, 95% CI 1.04-1.42, p = 0.02). We also observed statistically significant associations of the three SNPs with plasma glucose, HbA(1c) levels and insulin secretion at baseline and throughout the study in individuals with type 2 diabetes or at risk of developing diabetes. However, no association was observed in those who remained normoglycaemic at the end of the follow-up. Associations between the three variants and type 2 diabetes were replicated in cross-sectional studies of type 2 diabetic patients in comparison with a non-diabetic control group.The most frequent haplotype at the haplotype block containing the WFS1 gene modulated insulin secretion and was associated with an increased risk of type 2 diabetes.Societe Francophone du Diabete (SFD - Alfediam)Association Diabete Risque Vasculaire (ADRV), FranceCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)INSERMCNAMTSLillyNovartis PharmaSanofi-AventisINSERM (Reseaux en Sante Publique, Interactions entre les determinants de la sante)Association Diabete Risque VasculaireFederation Francaise de CardiologieLa Fondation de FranceALFEDIAMONIVINSArdix MedicalBayer DiagnosticsBecton DickinsonCardionicsMerck SanteNovo NordiskPierre FabreRocheTopconUniv Paris 07, INSERM, Res Unit 695, F-75018 Paris, FranceFed Univ Hlth Sci Porto Alegre, Postgradut Program Hlth Sci, Porto Alegre, RS, BrazilUniversidade Federal de São Paulo, Mol Endocrinol Lab, São Paulo, BrazilAssistance Publ Hop Paris Cochin Hosp, Dept Immunol & Diabetol, Paris, FranceUniv Paris 05, UFR Med, Paris, FranceUniv Paris 07, UFR Med, Paris, FranceAssistance Publ Hop Paris Bichat Hosp, Dept Endocrinol Diabetol & Nutr, Paris, FranceInst Inter Reg Sante IRSA, La Riche, FranceINSERM, U1018, CESP, Ctr Res Epidemiol & Populat Hlth, Villejuif, FranceUniv Paris 11, UMRS 1018, Villejuif, FranceUniversidade Federal de São Paulo, Mol Endocrinol Lab, São Paulo, BrazilCAPES: 1798-09-0Web of Scienc

The common-866G > A variant in the promoter of UCP2 is associated with decreased risk of coronary artery disease in type 2 diabetic men

OBJECTIVE-Uncoupling protein 2 (UCP2) is a physiological downregulator of reactive oxygen species generation and plays an antiatherogenic role in the vascular wall. A common variant in the UCP2 promoter (-866G>A) modulates mRNA expression, with increased expression associated with the A allele. We investigated association of this variant with coronary artery disease (CAD) in two cohorts of type 2 diabetic subjects.RESEARCH DESIGN and METHODS-We studied 3,122 subjects from the 6-year prospective Non-Insulin-Dependent Diabetes, Hypertension, Microalbuminuria, Cardiovascular Events, and Ramipril (DIABHYCAR) Study (14.9% of CAD incidence at follow-up). An independent, hospital-based cohort of 335 men, 52% of whom had CAD, was also studied.RESULTS-We observed an inverse association of the A allele with incident cases of CAD in a dominant model (hazard risk 0.88 [95% CI 0.80-0.96]; P = 0.006). Similar results were observed for baseline cases of CAD. Stratification by sex confirmed an allelic association with CAD in men, whereas no association was observed in women. All CAD phenotypes considered-myocardial infarction, angina pectoris, coronary artery bypass graft (CABG), and sudden death-contributed significantly to the association. Results were replicated in a cross-sectional study of an independent cohort (odds ratio 0.47 [95% CI 0.25-0.89]; P = 0.02 for a recessive model).CONCLUSIONS-The A allele of the -866G>A variant of UCP2 was associated with reduced risk of CAD in men with type 2 diabetes in a 6-year prospective study. Decreased risk of myocardial infarction, angina pectoris, CABG, and sudden death contributed individually and significantly to the reduction of CAD risk. This association was independent of other common CAD risk factors.INSERM, Fac Med Xavier Bichat, U695, F-75018 Paris, FranceCochin Hosp, AP HP, Dept Immunol & Diabetol, Paris, FranceUniv São Paulo, Lab Cellular & Mol Endocrinol, São Paulo, BrazilUniversidade Federal de São Paulo, Mol Endocrinol Lab, São Paulo, BrazilFed Fac Fdn Med Sci Porto Alegre, Post Grad Program Med Sci, Porto Alegre, RS, BrazilHop La Pitie Salpetriere, Dept Cardiol, AP HP, Paris, FranceUniv Paris 07, Paris, FranceUniv Paris 05, Paris, FranceUniversidade Federal de São Paulo, Mol Endocrinol Lab, São Paulo, BrazilWeb of Scienc

Relation of the Mediterranean diet with the incidence of gestational diabetes

Background/objectives: Some studies document relationships of the incidence of gestational diabetes mellitus (GDM) with individual components of the diet, but studies exploring relationships with patterns of eating are lacking. This observational study aimed to explore a possible relationship between the incidence of GDM and the Mediterranean diet (MedDiet) pattern of eating. Subjects/methods: In 10 Mediterranean countries, 1076 consecutive pregnant women underwent a 75-g OGTT at the 24th-32nd week of gestation, interpreted both by the ADA-2010 and the International Association of the Diabetes and Pregnancy Study Groups (IADPSG)-2012 criteria. The dietary habits were assessed by a previously validated questionnaire and a Mediterranean Diet Index (MDI) was computed, reflecting the degree of adherence to the MedDiet pattern of eating: a higher MDI denoting better adherence. Results: After adjustment for age, BMI, diabetes in the family, weight gain and energy intake, subjects with GDM, by either criterion, had lower MDI (ADA-2010, 5. 8 vs 6. 3, P=0. 028; IADPSG-2012, 5. 9 vs 6. 4, P<0. 001). Moreover, the incidence of GDM was lower in subjects with better adherence to the MedDiet (higher tertile of MDI distribution), 8. 0% vs 12. 3%, OR=0. 618, P=0. 030 by ADA-2010 and 24. 3% vs 32. 8%, OR=0. 655, P=0. 004 by IADPSG-2012 criteria. In subjects without GDM, MDI was negatively correlated with both fasting plasma glucose and AUC glucose, P<0. 001 for both. Conclusions: Adherence to a MedDiet pattern of eating is associated with lower incidence of GDM and better degree of glucose tolerance, even in women without GDM. The possibility to use MedDiet for the prevention of GDM deserves further testing with intervention studies.peer-reviewe

Analysis of KLF transcription factor family gene variants in type 2 diabetes

<p>Abstract</p> <p>Background</p> <p>The Krüppel-like factor (<it>KLF</it>) family consists of transcription factors that can activate or repress different genes implicated in processes such as differentiation, development, and cell cycle progression. Moreover, several of these proteins have been implicated in glucose homeostasis, making them candidate genes for involvement in type 2 diabetes (T2D).</p> <p>Methods</p> <p>Variants of nine <it>KLF </it>genes were genotyped in T2D cases and controls and analysed in a two-stage study. The first case-control set included 365 T2D patients with a strong family history of T2D and 363 normoglycemic individuals and the second set, 750 T2D patients and 741 normoglycemic individuals, all of French origin. The SNPs of six <it>KLF </it>genes were genotyped by Taqman^®SNP Genotyping Assays. The other three <it>KLF </it>genes (KLF2, -15 and -16) were screened and the identified frequent variants of these genes were analysed in the case-control studies.</p> <p>Results</p> <p>Three of the 28 SNPs showed a trend to be associated with T2D in our first case-control set (P < 0.10). These SNPs, located in the <it>KLF2, KLF4 </it>and <it>KLF5 </it>gene were then analysed in our second replication set, but analysis of this set and the combined analysis of the three variants in all 2,219 individuals did not show an association with T2D in this French population. As the <it>KLF2</it>, -15 and -16 variants were representative for the genetic variability in these genes, we conclude they do not contribute to genetic susceptibility for T2D.</p> <p>Conclusion</p> <p>It is unlikely that variants in different members of the <it>KLF </it>gene family play a major role in T2D in the French population.</p

Genetic and Functional Assessment of the Role of the rs13431652-A and rs573225-A Alleles in the G6PC2 Promoter That Are Strongly Associated With Elevated Fasting Glucose Levels

OBJECTIVE Genome-wide association studies have identified a single nucleotide polymorphism (SNP), rs560887, located in a G6PC2 intron that is highly correlated with variations in fasting plasma glucose (FPG). G6PC2 encodes an islet-specific glucose-6-phosphatase catalytic subunit. This study examines the contribution of two G6PC2 promoter SNPs, rs13431652 and rs573225, to the association signal. RESEARCH DESIGN AND METHODS We genotyped 9,532 normal FPG participants (FPG <6.1 mmol/l) for three G6PC2 SNPs, rs13431652 (distal promoter), rs573225 (proximal promoter), rs560887 (3rd intron). We used regression analyses adjusted for age, sex, and BMI to assess the association with FPG and haplotype analyses to assess comparative SNP contributions. Fusion gene and gel retardation analyses characterized the effect of rs13431652 and rs573225 on G6PC2 promoter activity and transcription factor binding. RESULTS Genetic analyses provide evidence for a strong contribution of the promoter SNPs to FPG variability at the G6PC2 locus (rs13431652: β = 0.075, P = 3.6 × 10−35; rs573225 β = 0.073 P = 3.6 × 10−34), in addition to rs560887 (β = 0.071, P = 1.2 × 10−31). The rs13431652-A and rs573225-A alleles promote increased NF-Y and Foxa2 binding, respectively. The rs13431652-A allele is associated with increased FPG and elevated promoter activity, consistent with the function of G6PC2 in pancreatic islets. In contrast, the rs573225-A allele is associated with elevated FPG but reduced promoter activity. CONCLUSIONS Genetic and in situ functional data support a potential role for rs13431652, but not rs573225, as a causative SNP linking G6PC2 to variations in FPG, though a causative role for rs573225 in vivo cannot be ruled out

Secretory granule neuroendocrine protein 1 (SGNE1) genetic variation and glucose intolerance in severe childhood and adult obesity

<p>Abstract</p> <p>Background</p> <p>7B2 is a regulator/activator of the prohormone convertase 2 which is involved in the processing of numerous neuropeptides, including insulin, glucagon and pro-opiomelanocortin. We have previously described a suggestive genetic linkage peak with childhood obesity on chr15q12-q14, where the 7B2 encoding gene, <it>SGNE1 </it>is located. The aim of this study is to analyze associations of <it>SGNE1 </it>genetic variation with obesity and metabolism related quantitative traits.</p> <p>Methods</p> <p>We screened <it>SGNE1 </it>for genetic variants in obese children and genotyped 12 frequent single nucleotide polymorphisms (SNPs). Case control analyses were performed in 1,229 obese (534 children and 695 adults), 1,535 individuals with type 2 diabetes and 1,363 controls, all French Caucasians. We also studied 4,922 participants from the D.E.S.I.R prospective population-based cohort.</p> <p>Results</p> <p>We did not find any association between <it>SGNE1 </it>SNPs and childhood or adult obesity. However, the 5' region SNP -1,701A>G associated with higher area under glucose curve after oral glucose tolerance test (p = 0.0005), higher HOMA-IR (p = 0.005) and lower insulinogenic index (p = 0.0003) in obese children. Similar trends were found in obese adults. SNP -1,701A>G did not associate with risk of T2D but tends to associate with incidence of type 2 diabetes (HR = 0.75 95%CI [0.55–1.01]; p = 0.06) in the prospective cohort.</p> <p>Conclusion</p> <p><it>SGNE1 </it>genetic variation does not contribute to obesity and common forms of T2D but may worsen glucose intolerance and insulin resistance, especially in the background of severe and early onset obesity. Further molecular studies are required to understand the molecular bases involved in this process.</p

The genetic susceptibility to type 2 diabetes may be modulated by obesity status: implications for association studies

<p>Abstract</p> <p>Background</p> <p>Considering that a portion of the heterogeneity amongst previous replication studies may be due to a variable proportion of obese subjects in case-control designs, we assessed the association of genetic variants with type 2 diabetes (T2D) in large groups of obese and non-obese subjects.</p> <p>Methods</p> <p>We genotyped <it>RETN</it>, <it>KCNJ11</it>, <it>HNF4A</it>, <it>HNF1A</it>, <it>GCK</it>, <it>SLC30A8</it>, <it>ENPP1</it>, <it>ADIPOQ</it>, <it>PPARG</it>, and <it>TCF7L2 </it>polymorphisms in 1,283 normoglycemic (NG) and 1,581 T2D obese individuals as well as in 3,189 NG and 1,244 T2D non-obese subjects of European descent, allowing us to examine T2D risk over a wide range of BMI.</p> <p>Results</p> <p>Amongst non-obese individuals, we observed significant T2D associations with <it>HNF1A </it>I27L [odds ratio (OR) = 1.14, <it>P </it>= 0.04], <it>GCK </it>-30G>A (OR = 1.23, <it>P </it>= 0.01), <it>SLC30A8 </it>R325W (OR = 0.87, <it>P </it>= 0.04), and <it>TCF7L2 </it>rs7903146 (OR = 1.89, <it>P </it>= 4.5 × 10^-23), and non-significant associations with <it>PPARG </it>Pro12Ala (OR = 0.85, <it>P </it>= 0.14), <it>ADIPOQ </it>-11,377C>G (OR = 1.00, <it>P </it>= 0.97) and <it>ENPP1 </it>K121Q (OR = 0.99, <it>P </it>= 0.94). In obese subjects, associations with T2D were detected with <it>PPARG </it>Pro12Ala (OR = 0.73, <it>P </it>= 0.004), <it>ADIPOQ </it>-11,377C>G (OR = 1.26, <it>P </it>= 0.02), <it>ENPP1 </it>K121Q (OR = 1.30, <it>P </it>= 0.003) and <it>TCF7L2 </it>rs7903146 (OR = 1.30, <it>P </it>= 1.1 × 10^-4), and non-significant associations with <it>HNF1A </it>I27L (OR = 0.96, <it>P </it>= 0.53), <it>GCK </it>-30G>A (OR = 1.15, <it>P </it>= 0.12) and <it>SLC30A8 </it>R325W (OR = 0.95, <it>P </it>= 0.44). However, a genotypic heterogeneity was only found for <it>TCF7L2 </it>rs7903146 (<it>P </it>= 3.2 × 10^-5) and <it>ENPP1 </it>K121Q (<it>P </it>= 0.02). No association with T2D was found for <it>KCNJ11</it>, <it>RETN</it>, and <it>HNF4A </it>polymorphisms in non-obese or in obese individuals.</p> <p>Conclusion</p> <p>Genetic variants modulating insulin action may have an increased effect on T2D susceptibility in the presence of obesity, whereas genetic variants acting on insulin secretion may have a greater impact on T2D susceptibility in non-obese individuals.</p