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

• Published in: Diabetes (New York, N.Y.) Vol. 59; no. 2; pp. 479 - 485
• Main Authors: VILLAREAL, Dennis T, ROBERTSON, Heather, BELL, Graeme I, PATTERSON, Bruce W, TRAN, Hung, WICE, Burton, POLONSKY, Kenneth S
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01-02-2010
• Subjects: Biological and medical sciences; Blood Glucose - metabolism; Body Composition; C-Peptide - blood; Diabetes; Diabetes Mellitus, Type 2 - epidemiology; Diabetes Mellitus, Type 2 - genetics; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Genetic aspects; Genetic Variation; Genotype; Genotype & phenotype; Glucose; Glucose Tolerance Test; Humans; Incretins - physiology; Insulin; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - physiology; Male; Medical sciences; Original; Peptide hormones; Peptides; Physiological aspects; Plasma; Reference Values; Research design; Risk Assessment; Risk Factors; TCF Transcription Factors - genetics; Transcription Factor 7-Like 2 Protein; Transcription factors; Type 2 diabetes; Endocrinopathy; Type 2 diabetes; Variant; Incretin; Metabolic diseases; Risk factor
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db09-1169

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 accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received August 11, 2009.
Accepted November 8, 2009.
© 2010 by the American Diabetes Association.