121-OR: Insulin Clearance Is an Independent Determinant of ß-Cell Cell Function in Obese Youths

Background: Hyperinsulinemia results from β-cell ompensatory adaptation to insulin resistance and reduced insulin clearance. We examined the relationship between hepatic/peripheral insulin clearance and β-cell function in lean and obese insulin sensitive (IS) and insulin resistant (IR) adolescents. Methods: A 2-step euglycemic hyperinsulinemic clamp and an hyperglycemic clamp were performed in 153 youths (73F, 14.4±3.3y) to evaluate hepatic (MCR1) and peripheral (MCR2) insulin clearance, β-cell function (DI cpep ) and insulin sensitivity. Participants were grouped as:non-Obese NGT (nOb-NGT, n=23), obese NGT-IS (Ob-NGT-IS, n=47), obese NGT-IR (Ob-NGT-IR, n=47), and obese IGT (Ob-IGT, n=36). IS and IR were defined according to the median M (glucose disposal) from euglycemic clamp. Effect of MCR1-2, sex, age, BMI, Tanner stage, fasting/2h-glucose, ethnicity on DI cpep was estimated by multivariate regression model. Results: IS, MCR1/MCR2 did not differ between nOb-NGT and Ob-NGT-IS. MCR1 was lower in Ob-NGT-IR and Ob-IGT than nOb-NGT, while MCR2 only declined in the Ob-IGT. (upper panels) MCR1 and MCR2 were the sole determinants of DI cpep (p0.006 and p0.015), as confirmed by ~50% reduction in DI cpep of the lowest tertiles of MCR1 and MCR2. (lower panels). Conclusion: In obese adolescents, lower MCR1 and MCR2 are independently associated with a blunted β-cell function thus playing a key role in youth onset T2D. Disclosure A. Galderisi: None. D. Trico: None. C. Giannini: None. N. Santoro: None. S. Caprio: None. R. Weiss: Consultant; Self; Medtronic MiniMed, Inc. 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)