Prediabetes and type 2 diabetes in obese youths are associated with a reduced incretin effect. Herein, we investigated the metabolic and genetic determinants of incretin effect in obese youths with normal and impaired glucose tolerance. We studied 35 obese youth (15.8±2.4y, BMI 39.9±6.1kg/m2, NGT/IGT 18/17, F/M 18/17). All participants were genotyped for the TCF7L2 rs7903146 variant and underwent: A) 180-minutes OGTT and a matched iso-glycemic intravenous glucose tolerance test (iso-IVGTT) to estimate the incretin effect, by modelling of C-peptide secretion (SR), and insulin sensitivity (SI) by the oral minimal model; B) a hyperglycemic clamp with arginine stimulation to estimate insulin secretion independently from the oral phase. Incretin effect was measured as (SROGTT-SRiso-IVGTT)/SROGTT. Insulin clearance (CL) was computed as SROGTT-[Vx insulin]/AUCInsulin-OGTT. Determinants of the Incretin effect were assessed by multivariate logistic regression.Insulin clearance (p=0.004), T allele for TCF7L2 (p=0.018) and 2-h glucose (p=0.035) were independent determinants of the incretin effect (Figure A), with an increase in insulin clearance associated with greater incretin effect (Figure B). Lower insulin clearance, higher 2-h glucose and the risk-genotype of TCF7L2 rs7903146 are associated with a lower incretin effect in obese adolescents with prediabetes.


A. Galderisi: None. S. Samuels: None. B. Pierpont: None. C. Dalla Man: Research Support; Self; Sanofi-Aventis Deutschland GmbH. N. Santoro: None. S. Caprio: None.


National Institutes of Health (R01DK111038); Patterson Foundation

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at