1317-P: Static, but Nondynamic, ß-Cell Responsiveness to Glucose Is Affected by the Risk Variant rs7903146 of TCF7L2 and Associated with a Delayed Time-to-Glucose-Peak in Obese Youths

Abstract

Background: Beta-cell function can be dissected into a dynamic component, estimating the immediate secretion after glucose change, and a static component representing the insulin secreted at any given glucose level. We evaluated their clinical and genetic determinants as well as their effect on glucose time to peak in obese youths. Methods: A 3hOGTT was performed in 630 obese youths (374F, 13.6±3.1y, 33.3±7.5kg/m2); dynamic (DId) and static (DIs) components of beta-cell function were estimated by the oral minimal model. Participants were genotyped for the rs7903146 of TCF7L2 and grouped into 3 tertiles for DId and DIs. Effect of sex, BMI, age, ethnicity and TCF7L2 on DIs/DId was estimated by multivariate regression model. Results: Lower DId, as well as DIs, were associated with higher BMI and 2h-glucose, while fasting glucose was increased in the lower DIs tertile. The risk genotype (TT) for the TCF7L2 and the BMI, were both associated to a lower DIs (p<0.01), while TCF7L2 did not affect DId (p=0.22). Glucose time to peak>30min was more likely in the lower DIs, without a difference among the DId tertiles (Figure). Conclusion: The risk variant of TCF7L2 is associated with a blunted DIs, in the absence of an effect on the DId, and accompanied by a delayed glucose time to peak. The role of TCF7L2 in the incretin response might be responsible for this effect. Disclosure A. Galderisi: None. D. Trico: None. C. Dalla Man: None. S. Siebel: None. N. Santoro: None. B. Pierpont: None. C. Cobelli: None. S. Caprio: None. Funding National Institutes of Health (R01DK085577-01, R01HD40787, R01HD28016, P30DK045735, K12DK094714-02, R01DK111038-01A1); Robert E. Leet and Clara Guthrie Patterson Trust; European Medical International Framework (EMIF115372)