TCF7L2 variant rs7903146 affects the risk of type 2 diabetes by modulating incretin action.

Diabetes
Dennis T VillarealKenneth S Polonsky

Abstract

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. 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. beta-cell responsivity to oral glucose was 50% lower (47 +/- 4 vs. 95 +/- 15 x 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 pep...Continue Reading

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Methods Mentioned

BETA
X-ray
ELISA
Genotyping
Assay
pharmacotherapy

Software Mentioned

SigmaPlot
SPSS

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