Background and Aim: The T allele of TCF7L2 rs7903146 is a common genetic variant associated with type 2 diabetes. The mechanisms underlying this association are not fully understood, but diminished incretin-induced insulin secretion has been suggested. We undertook this study to evaluate the effect of the TCF7L2 rs7903146 T allele on the incretin effect in normal glucose tolerant individuals and patients with type 2 diabetes.
Methods: The incretin effect was assessed by relating the difference in integrated beta cell secretory responses to oral glucose tolerance test (OGTT) and isoglycemic intravenous glucose infusion (IIGI) to the response during OGTT in 36 normal glucose tolerant individuals (of whom 12 had the risk-conferring variant rs7903146 (TC/TT)) and 20 patients with type 2 diabetes (10 with TC/TT). Homeostatic model assessment (HOMA) was used to estimate insulin resistance.
Results: No differences in incretin effect estimates between risk allele carriers and non-carriers in the two groups were observed. Normal glucose tolerant individuals with rs7903146 displayed higher C-peptide levels in the fasting state (P=0.029) as well as during OGTT (P=0.029) and IIGI (P=0.015) compared to normal glucose tolerant non-carriers. Normal glucose tolerant risk allele carriers were more insulin resistant compared to normal glucose tolerant non-carriers (P=0.042). No detectable differences in glucose metabolism were found between risk allele carriers and non-carriers in the type 2 diabetes group.
Conclusions: The TCF7L2 rs7903146 T allele was not associated with reduced incretin effect in these relatively small cohorts of normal glucose tolerant individuals and patients with type 2 diabetes. Insulin resistance rather than beta cell secretory defects distinguished the normal glucose tolerant risk allele carriers examined here, from the normal glucose tolerant non-carriers.
D.S. Mathiesen: None. A.B. Lund: None. K.B. Hansen: None. A. Junker: None. T. Idorn: Employee; Self; Novo Nordisk A/S. M. Hornum: None. A. Jonsson: None. T. Hansen: None. T. Vilsbøll: None. J.I. Bagger: None. F.K. Knop: Advisory Panel; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi. Consultant; Self; Amgen Inc., Carmot Therapeutics, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Norgine, Novo Nordisk A/S.
Novo Nordisk Foundation (NNF17OC0029370)