Insulin resistance and 'beta'-cell function in severe obesity: effect of weight loss after gastric bypass

Author(s)

Daniela Miguel Marin

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas
• Defense date: 2007-07-31

Examining board members

Sarah Monte Alegre; Dora Maria Grassi Kassisse; Walkyria de Paula Pimenta; Mario José Abdalla Saad; José Barreto Campello Carvalheira

• Advisor: Sarah Monte Alegre

Abstract

The objectives are to evaluate the contribution of insulin resistance and impaired ß-cell function to glucose tolerance in severely obese subjects and the effect of massive weight loss by Roux-en-Y Gastric bypass, RGB-Y, on the adaptation of insulin secretion to insulin resistance (IR). Euglycemic hyperinsulinemic clamp (3h at 240pmol/min.m-2) with indirect calorimetry, IV glucose tolerance test and an OGTT were performed in 32 severe obese subjects (17NGT, 11IGT and 6type 2 diabetic ¿ OB-T2D) and in 10 controls. Insulin sensitivity, Mvalue, was calculated from the glucose infusion rate of the clamp. Total (T-ISR) and fasting insulin secretion rate (f-ISR) were evaluated by C-peptide deconvolution and ß-cell glucose sensitivity (ß-GS) as dose-response curve ISR-to-glucose. Disposition index was calculated as ISRxMvalue. 14 patients (11OB-NGT and 3OB-IGT) were re-evaluated post-surgery after weight stabilization (~18 months). Obese subjects were insulin resistant for oxidative, nonoxidative and whole body glucose disposal (OB-T2D, OB-IGT and OB-NGT were ~30%, 60% and 43% of CT). The acute insulin response (AIR: 0-10min-IVGTT) was higher in OB-NGT than in CT and in other obese groups (CT 5378±590; OB-NGT 9363±895; OB-IGT 6544±558 and OB-T2D 3893±622 pmol.min-1.m-2x10min), T-ISR was elevated in all obese groups (CT 20.2±1.9; OB-NGT 39.2±3.6; OB-IGT 39.2±2.5 and OB-T2D 37.1±4.5 nmol.min-1.m-2x60min) while ß-GS was decreased in OB-IGT and -T2DM but not in -NGT as compared to CT (OB-T2D -4±3; OB-IGT 31±4; OB-NGT 56±6 and CT 43±6 pmol.min-1.m-2.mM-1). The disposition index was reduced in OB-IGT and -T2DM but not in -NGT. After weight loss (BMI 30.2±1.2kg.m-2), f-ISR (from 148±12 to 83±12 pmol.min-1.m-2, p<0.05) and insulin sensitivity (from 30±4 to 50±5µmol.kg-1.min-1, p<0.05) changed to normal values. The time-course evidenced a significant decrease in T-ISR, and an unchanged AIR. ß-GS increased to levels higher than CT (from 43±7 to 75±10 pmol.min-1.m-2.mM-1). The disposition index, similar to the CT group, after weight loss increased to values higher than in CT. T2D and IGT severe obese subjects show a progressive deterioration of glucose homeostasis, despite increased insulin secretion. This can be explained as an impairment of ß-cell function for the prevailing IR. RGB-Y weight loss normalized IR and improved ß-cell function in IGT and NGT obese to levels higher than in lean CT (AU)