TCF7L2 Variant rs7903146 Affects the Risk of Type 2 Diabetes by Modulating Incretin Action

Abstract

Background. Common variants in the gene TCF7L2 confer the largest effect on the risk of T2D. The present study was undertaken to increase our understanding of the mechanisms by which this gene affects T2D risk.

Research methods. Eight subjects with risk-conferring TCF7L2 genotypes (TT or TC at rs7903146) and ten-matched subjects with wild-type genotype (CC) underwent 5-h oral glucose tolerance test (OGTT), isoglycemic intravenous glucose infusion, and graded glucose infusion (GGI). Mathematical modeling was used to quantify insulin-secretory profiles during OGTT and glucose infusion protocols. The incretin effect was assessed from ratios of the insulin secretory rates (ISR) during oral and isoglycemic glucose infusions. Dose-response curves relating insulin secretion to glucose concentrations were derived from the GGI.

Results. β-cell responsivity to oral glucose was 50% lower (47±4 vs. 95±15x10⁹ min⁻¹; P=0.01) in the group of subjects with risk-conferring TCF7L2 genotypes compared with controls. The incretin effect was also reduced by 30% (32±4 vs. 46±4%; P=0.02) in the at-risk group. The lower incretin effect occurred despite similar GIP and GLP-1 responses to oral glucose. The ISR response over a physiologic glucose concentration range (5–9 mmol/L) was similar between groups.

Conclusions. The TCF7L2 variant rs7903146 appears to affect risk of T2D, at least in part, by modifying the effect of incretins on insulin secretion. This is not due to reduced secretion of GLP-1 and GIP but rather due to the effect of TCF7L2 on the sensitivity of the β-cell to incretins. Treatments that increase incretin sensitivity may decrease the risk of T2D.