Bernard Zinman

In a recent report of large-scale association analysis, a type 2 diabetes susceptibility locus near HNF1A was identified in predominantly European descent populations. A population-specific G319S polymorphism in HNF1A was previously identified in Aboriginal Canadians who have a high prevalence of type 2 diabetes. We aimed to investigate the association of the HNF1A G319S polymorphism with incident type 2 diabetes and to assess whether clinical risk variables for type 2 diabetes influence the association in an Aboriginal population.

Background: C-reactive protein (CRP), a biomarker of inflammation, has been associated with increased risk of developing cardiovascular disease. Common variants of the hepatocyte nuclear factor 1A (HNF1A) gene encoding HNF-1α have been associated with plasma CRP in predominantly European Caucasian samples. HNF1A might therefore have an impact on vascular disease and diabetes risk that is mediated by CRP. In an Aboriginal Canadian population, a private polymorphism, HNF1A G319S, was associated with increased prevalence of type 2 diabetes. However, it has not been investigated whether this association is mediated by CRP. We aimed to investigate whether CRP was mediating the association between HNF1A G319S and type 2 diabetes in an Aboriginal Canadian population with a high prevalence of diabetes. Methods: A total of 718 individuals who participated in a diabetes prevalence and risk factor survey were included in the current analysis. Participants were genotyped for HNF1A G319S. Fasting plasma samples were analyzed for CRP. Fasting plasma glucose and a 75-g oral glucose tolerance test were obtained to determine type 2 diabetes. Results: The prevalence rate of type 2 diabetes was 17.4% (125/718) using the 1999 World Health Organization definition and was higher among S319 allele carriers compared to G/G homozygotes (p < 0.0001). Among participants without type 2 diabetes, CRP levels were higher among G/G homozygotes (1.64 [95% confidence interval 1.35-2.00] mg/l) than in S319 carriers (1.26 [1.04-1.54] mg/l) (p = 0.009) after adjustment for age, sex, 2-h post-load glucose, waist circumference, and serum amyloid A. CRP levels were elevated among those with diabetes after similar adjustment (4.39 [95% confidence interval 3.09-6.23] and 4.44 [3.13-6.30] mg/L, respectively), and no significant difference in CRP was observed between S319 carriers and non-carriers (p = 0.95). Conclusions: CRP levels were lower in S319 allele carriers of the HNF1A gene compared to non-carriers among individuals without diabetes, but this difference was not present among those with diabetes, who uniformly had elevated CRP levels. Therefore, while HNF1A appears to influence CRP concentrations in the non-diabetic state, chronic elevation of CRP is unlikely mediating the association between the HNF1A polymorphism and the high prevalence of type 2 diabetes in this Aboriginal population.

Background: The rs9939609 T>A single-nucleotide polymorphism (SNP) in the FTO gene has previously been found to be associated with obesity in European Caucasian samples. The objective of this study is to examine whether this association extends to metabolic syndrome (MetS) and applies in non-Caucasian samples. Methods: The FTO rs9939609 SNP was genotyped in 2121 subjects from four different non-Caucasian geographical ancestries. Subjects were classified for the presence or absence of MetS according to the International Diabetes Federation (IDF) and National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) III definitions. Results: Carriers of ≥ 1 copy of the rs9939609 A allele were significantly more likely to have IDF-defined MetS (35.8%) than non-carriers (31.2%), corresponding to a carrier odds ratio (OR) of 1.23 (95% confidence interval [CI] 1.01 to 1.50), with a similar trend for the NCEP ATP III-defined MetS. Subgroup analysis showed that the association was particularly strong in men. The association was related to a higher proportion of rs9939609 A allele carriers meeting the waist circumference criterion; a higher proportion also met the HDL cholesterol criterion compared with wild-type homozygotes. Conclusion: Thus, the FTO rs9939609 SNP was associated with an increased risk for MetS in this multi-ethnic sample, confirming that the association extends to non-Caucasian population samples.

Pregnant women with an abnormal screening glucose challenge test (GCT) but without gestational diabetes mellitus (GDM) on subsequent oral glucose tolerance test (OGTT) are at increased risk of delivering macrosomic and large for gestational age (LGA) neonates. We thus sought to evaluate the maternal constitutional and biochemical factors that determine infant birth weight in this patient population. Women with an abnormal GCT were evaluated at the time of their OGTT in late pregnancy. This analysis was restricted to Caucasian women without GDM (N = 86). Maternal demographic and biochemical factors were evaluated in relation to infant birth weight and LGA. After adjustment for length of gestation, birth weight was positively associated with pre-pregnancy body mass index (BMI) (r = 0.31, p = 0.0063) and negatively correlated with maternal serum levels of the insulin-sensitizing protein adiponectin (r = -0.30, p = 0.0084). On multiple linear regression analysis, pre-pregnancy BMI and weight gain in pregnancy were positive independent determinants of infant birth weight, while family history of diabetes emerged as a negative independent correlate. Logistic regression analysis confirmed that pre-pregnancy BMI was a positive predictor of LGA (odds ratio (OR) = 1.25, 95% confidence interval (CI) 1.05-1.49), whereas family history of diabetes was again identified as a negative determinant (OR = 0.10, 95% CI 0.02-0.59). In contrast, neither measures of glycemia nor insulin resistance/sensitivity were independently associated with birth weight or LGA. In pregnant women with an abnormal GCT but without GDM, pre-gravid maternal obesity predicts increased infant birth weight, whereas family history of diabetes is independently associated with decreased infant size.

Background: Common polymorphisms in the promoter of the APOC3 gene have been associated with hypertriglyceridemia and may impact on phenotypic expression of the metabolic syndrome (MetS). The rs7566605 marker, located near the INSIG2 gene, has been found to be associated with obesity, making it also a potential genetic determinant for MetS. The objective of this study is to examine the APOC3 -455T>C and the INSIG2 rs7566605 polymorphisms as potential genetic determinants for MetS in a multi-ethnic sample. Methods: Subjects were genotyped for both the APOC3 -455T>C and INSIG2 rs7566605 polymorphisms, and classified for the presence or absence of MetS (NCEP ATP III and IDF definitions). The total study population included 2675 subjects (≥18 years of age) from six different geographical ancestries. Results: For the overall study population, the prevalence of MetS was 22.6% (NCEP ATP III definition). Carriers of ≥1 copy of APOC3 -455C were more likely to have MetS (NCEP ATP III definition) than noncarriers (carrier odds ratio 1.73, 95% CI 1.40 to 2.14, adjusting for age and study group). The basis of the association was related not only to a higher proportion of -455C carriers meeting the triglyceride and high-density lipoprotein cholesterol criteria, but also the blood pressure criteria compared with wild-type homozygotes. Plasma apo C-III concentrations were not associated with APOC3 -455T>C genotype. The INSIG2 rs7566605 polymorphism was not associated with MetS or measures of obesity. Conclusion: Meta-analysis of the sample of multiple geographic ancestries indicated that the functional -455T>C promoter polymorphism in APOC3 was associated with an approximately 2-fold increased risk of MetS, whereas the INSIG2 rs7566605 polymorphism was not associated with MetS.

Exenatide therapy is effective in combination with metformin or sulfonylureas for treating type 2 diabetes. Thiazolidinediones (TZDs) also are commonly used, but the efficacy of exenatide with a TZD has not been reported. To compare the effects of exenatide versus placebo on glycemic control. Placebo run-in, randomized, double-blind, placebo-controlled trial conducted from May 2004 to August 2005. 49 sites in Canada, Spain, and the United States. 233 (exenatide group, n = 121; placebo group, n = 112) patients with type 2 diabetes that was suboptimally controlled with TZD treatment (with or without metformin). Mean (+/-SE) baseline glycated hemoglobin A1c level was 7.9% +/- 0.1%. Subcutaneous abdominal injections of 10 microg of exenatide or placebo twice daily, added to a TZD (with or without metformin) for 16 weeks. The primary outcome was change from baseline in hemoglobin A1c level. Other outcomes were fasting serum glucose level, body weight, self-monitored blood glucose level, and any adverse events. Exenatide treatment reduced hemoglobin A(1c) level (mean difference, -0.98% [95% CI, -1.21% to -0.74%]), serum fasting glucose level (mean difference, -1.69 mmol/L [-30.5 mg/dL] [CI, -2.22 to -1.17 mmol/L {-40.0 to -21.1 mg/dL}]), and body weight (mean difference, -1.51 kg [CI, -2.15 to -0.88 kg]). Sixteen percent of patients in the exenatide group and 2% of patients in the placebo group discontinued treatment because of adverse events. In the exenatide group, 40% (n = 48) of patients experienced nausea (mostly mild [n = 21] or moderate [n = 19]), 13% experienced vomiting, and 11% experienced hypoglycemia. In the placebo group, 15% of patients experienced nausea, 1% experienced vomiting, and 7% experienced hypoglycemia. Combinations with TZDs and sulfonylureas were not tested. Trial duration was relatively short. Only 71% and 86% of patients in the exenatide and placebo groups, respectively, completed the study. Exenatide therapy improved glycemic control, reduced body weight, and caused gastrointestinal symptoms more than placebo in patients with type 2 diabetes that was suboptimally controlled with TZD therapy. ClinicalTrials.gov registration number: NCT00099320. For more information on exenatide click here.