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

TCF7L2 Variant rs7903146 Affects the Risk of Type 2 Diabetes by Modulating Incretin Action Dennis T. Villareal 1 , Heather Robertson 1 , Graeme I. Bell 2 , Bruce W. Patterson 1 , Hung Tran 1 , Burton Wice 1 and Kenneth S. Polonsky 1 1 Department of Medicine, Washington University School of Medicine, St. Louis, Missouri; 2 Departments of Medicine and Human Genetics, The University of Chicago, Chicago, Illinois. Corresponding author: Kenneth S. Polonsky, polonsky{at}wustl.edu . Abstract OBJECTIVE Common variants in the gene TCF7L2 confer the largest effect on the risk of type 2 diabetes. The present study was undertaken to increase our understanding of the mechanisms by which this gene affects type 2 diabetes risk. RESEARCH DESIGN AND METHODS Eight subjects with risk-conferring TCF7L2 genotypes (TT or TC at rs7903146) and 10 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 ± 15 × 10 9 min −1 ; P = 0.01) in the group of subjects with risk-conferring TCF7L2 genotypes compared with control subjects. 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 glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) responses to oral glucose. The ISR response to intravenous glucose over a physiologic glucose concentration range (5–9 mmol/l) was similar between groups. CONCLUSIONS The TCF7L2 variant rs7903146 appears to affect risk of type 2 diabetes, 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 type 2 diabetes. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in a