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


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.
Villareal
Dennis T
DT
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
Robertson
Heather
H
Bell
Graeme I
GI
Patterson
Bruce W
BW
Tran
Hung
H
Wice
Burton
B
Polonsky
Kenneth S
KS
D001786:Blood Glucose / Q000378:metabolism; D001823:Body Composition; D002096:C-Peptide / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology* / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D005951:Glucose Tolerance Test; D006801:Humans; D054795:Incretins / Q000502:physiology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008297:Male; D012016:Reference Values; D018570:Risk Assessment; D012307:Risk Factors; D051820:TCF Transcription Factors / Q000235:genetics*; D058118:Transcription Factor 7-Like 2 Protein
D001786:Blood Glucose; D002096:C-Peptide; D054795:Incretins; D007328:Insulin; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein