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

  1. Dennis T. Villareal1,
  2. Heather Robertson1,
  3. Graeme I. Bell2,
  4. Bruce W. Patterson1,
  5. Hung Tran1,
  6. Burton Wice1 and
  7. Kenneth S. Polonsky1
  1. 1Department of Medicine, Washington University School of Medicine, St. Louis, Missouri;
  2. 2Departments of Medicine and Human Genetics, The University of Chicago, Chicago, Illinois.
  1. Corresponding author: Kenneth S. Polonsky, polonsky{at}


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 × 109 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.


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    • Received August 11, 2009.
    • Accepted November 8, 2009.
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  1. Diabetes vol. 59 no. 2 479-485
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