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

Diabetes. 2010 Feb;59(2):479-85. doi: 10.2337/db09-1169. Epub 2009 Nov 23.


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: 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 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 beta-cell to incretins. Treatments that increase incretin sensitivity may decrease the risk of type 2 diabetes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blood Glucose / metabolism
  • Body Composition
  • C-Peptide / blood
  • Diabetes Mellitus, Type 2 / epidemiology*
  • Diabetes Mellitus, Type 2 / genetics*
  • Female
  • Genetic Variation*
  • Genotype
  • Glucose Tolerance Test
  • Humans
  • Incretins / physiology*
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / physiology
  • Male
  • Reference Values
  • Risk Assessment
  • Risk Factors
  • TCF Transcription Factors / genetics*
  • Transcription Factor 7-Like 2 Protein


  • Blood Glucose
  • C-Peptide
  • Incretins
  • Insulin
  • TCF Transcription Factors
  • TCF7L2 protein, human
  • Transcription Factor 7-Like 2 Protein