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