Impact of TCF7L2 rs7903146 on insulin secretion and action in young and elderly Danish twins

Objective: We investigated the regulation and metabolic effects of TCF7L2 gene expression in human sc fat and skeletal muscle and the impact of the TCF7L2, rs7903146, T-allele on gene expression and measures of glucose metabolism including insulin secretion and peripheral and hepatic insulin action. Research Design and Methods: The rs7903146 was genotyped in 1) a population-based sample of 587 twins (55-64 yr) with glucose tolerance ranging from normal to type 2 diabetes and 2) a population of 196 nondiabetic young (22-31 yr) and elderly (57-66 yr) twins. All subjects underwent oral glucose tolerance tests, and population 2 was additionally examined with iv glucose tolerance tests and hyperinsulinemic, euglycemic clamps. Results: Elderly T-allele carriers had decreased plasma insulin responses and lower disposition index, whereas insulinogenic index was similar between genotype groups. Elderly nondiabetic T-allele carriers had increased peripheral insulin sensitivity (P = 0.03). Young T-allele carriers had impaired hepatic insulin sensitivity (P = 0.04) independent of plasma insulin levels. TCF7L2 gene expression in skeletal muscle and adipose tissue was not explained by genotype, sex, aerobic capacity, birth, or adult anthropometry and was not associated with in vivo glucose metabolism. Conclusions: The rs7903146 T-allele associates with hepatic insulin resistance and diminished glucose-stimulated plasma insulin secretion. Our study does not provide evidence of a role of TCF7L2 gene expression in sc fat tissue and muscle tissue in the regulation of glucose homeostasis. This suggests that the primary defect of rs7903146 T-allele carriers is impairment of insulin secretion rather than a defect in insulin action in peripheral tissues.