The frequent UCP2 −866G>A polymorphism protects against insulin resistance and is associated with obesity: a study of obesity and related metabolic traits among 17 636 Danes

CONTEXT: Uncoupling protein 2 (UCP2) is involved in regulating ATP synthesis, generation of reactive oxygen species and glucose-stimulated insulin secretion in β-cells. Polymorphisms in UCP2 may be associated with obesity and type 2 diabetes mellitus. OBJECTIVE: To determine the influence of a functional UCP2 promoter polymorphism (−866G>A, rs659366) on obesity, type 2 diabetes and intermediary metabolic traits. Furthermore, to include these and previously published data in a meta-analysis of this variant with respect to its impact on obesity and type 2 diabetes. DESIGN: We genotyped UCP2 rs659366 in a total of 17 636 Danish individuals and established case–control studies of obese and non-obese subjects and of type 2 diabetic and glucose-tolerant subjects. Meta-analyses were made in own data set and in publicly available data sets. Quantitative traits relevant for obesity and type 2 diabetes were analysed within separate study populations. RESULTS: We found no consistent associations between the UCP2 −866G-allele and obesity or type 2 diabetes. Yet, a meta-analysis of data from 12 984 subjects showed an association with obesity (GA vs GG odds ratio (OR) (95% confidence interval (CI)): 0.894(0.826–0.968) P =0.00562, and AA vs GG OR(95% CI): 0.892(0.800–0.996), P =0.0415. Moreover, a meta-analysis for type 2 diabetes of 15 107 individuals showed no association. The −866G-allele was associated with elevated fasting serum insulin levels ( P =0.002) and HOMA insulin resistance index ( P =0.0007). Insulin sensitivity measured during intravenous glucose tolerance test in young Caucasian subjects ( n =377) was decreased in carriers of the GG genotype ( P =0.05). CONCLUSIONS: The UCP2 −866G-allele is associated with decreased insulin sensitivity in Danish subjects and is associated with obesity in a combined meta-analysis.