The TCF7L2 Variant rs7903146 Affects the Risk of Youth-Onset Type 2 Diabetes by Reducing the Incretin Effect on Insulin Secretion

Background: Common variants of the transcription factor-7-like-2 gene (TCF7L2) have been implicated in the progression of prediabetes to T2D. We explored the effect of the rs7903146 variant on the incretin effect in youths with dysglycemia. Methods: 5 carriers with the risk-genotype of TCF7L2 (TT at the rs7903146, 14.4±2.3y, BMI 34.7±6.4kg/m2) and 5 with the wild type genotype CC (16.2±1.9y, BMI 36.8±6.0kg/m2) underwent a 3-hour OGTT followed, a week later, by an isoglycemic intravenous glucose infusion (IVGTT), designed to match the plasma glucose concentrations during the OGTT. The incretin effect was measured as 100*(SROGTT-SRIVGTT)/SROGTT where SR was the secretion rate of c-peptide. Results: As shown in the Figure, the plasma glucose profile in the OGTT and IVGTT were well matched in both groups. The increase in SR during the OGTT compared to IVGTT was significantly lower in the carriers of the TT compared to CC genotype (ΔiAUCc-peptide 1281±688.6 vs. 5632±1604 pmol/L*min, p < 0.025). Thus, relative to the control group, carriers of the TT-risk genotype had a significant reduction of the incretin effect (TT 0% [-11.74, 16.84], CC: +35% [12.05, 55.71]; p <0.018). Conclusion: The TCF7L2 variant rs7903146 impairs the incretin effect in obese youths carrying the risk-genotype (TT), suggesting a causative mechanism for the association of this variant with progression to T2D. Disclosure A. Galderisi: None. B. Pierpont: None. D. D'Alessio: Consultant; Self; Intarcia Therapeutics, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S. N. Santoro: None. S. Caprio: None.