A common polymorphism in the promoter of UCP2 contributes to the variation in insulin secretion in glucose-tolerant subjects

It was reported that the common. -866G/A polymorphisin in. the promoter of the human uncoupling protein-2 (UCP2) gene, which enhances its trascriptional activity, is associated with increased mRNA,levels in human adipocytes and reduced risk of obesity, Studies in knockout mice and beta-cells indicate that UCP2 may play a role in beta-cell function. In this study, we addressed the question of whether the common -866G/A polymorphism in UCP2 gene contributes to the variation of insulin secretion in humans by genotyping 301 nondiabetic subjects who underwent an oral glucose tolerance test. Glucose-stimulated insulin secretion estimated by several indexes of beta-cell function was significantly lower carriers of the -866A/A genotype compared with -866A/G or -866G/G according to the dosage of the A allele (P = 0.002-0.05). To investigate directly whether the UCP2 -866G/A polymorphism affects human islet function, pancreatic islets isolated from two -866G/G homozygous, seven -866G/A heterozygous, and one -866A/A homozygous nondiabetic donors were studied. Islets from -866A/A homozygous had lower insulin secretion in response to glucose stimulation as compared with,-866G/G and -866G/A carriers. These results indicate that the common -866G/A polymorphism in the UCP2 gene may contribute to the biological variation of insulin secretion in humans.