CHARACTERIZATION OF EARLY ALTERATIONS IN GLUCOSE HOMEOSTASIS, INSULIN SECRETION, AND HEPATIC INSULIN EXTRACTION IN NONDIABETIC OBESE PRADER-WILLI SUBJECTS AND HEALTHY OBESE CONTROLS SUBJECTS. † 576

Abstract

Obesity is a common component of NIDDM and plays an important role in the development of insulin resistance and hyperinsulinemia. Prader-Willi Syndrome(PWS) has been associated with morbid obesity and an increased propensity for early development of NIDDM. In order to shed light on the glucoregulatory mechanisms in PWS, we studied pediatric and adult PWS with normoglycemia. The objectives of this study were 1) to examine glucose (glu), insulin (ins) and c-peptide (cpep) responses to OGTT and IVGTT 2) to characterize first and second phases ins secretion 3) to assess hepatic ins extraction (HIE) in PWS subjects and 4) to determine whether beta cell function in PWS is age-dependent.. Group I consisted of 9 pediatric (PED) PWS and 22 age-, weight- and puberty stage-matched obese subjects who had OGTT. Group II consisted of 14 adult (AD) PWS and 10 age-, weight-, and BMI-matched obese AD who had OGTT. Group III consisted of 9 AD PWS and 8 age- and weight-matched obese AD who had FSIVGTT. During the OGTT in the PED group, glu levels were not significantly (sig) different in PWS vs. obese children. In contrast, the fasting, (20±6 vs. 37±4uU/ml), peak (114±24 vs. 214±23uU/ml) and total AUC for ins (12,673±2176 vs. 26,734±2608uU/ml × min) were sig lower in the PED PWS. During the OGTT in the AD groups, ins levels were not sig different in the AD PWS and obese groups. During IVGTT in AD, both the first (138±42 vs. 454±102uU/ml × min) and second (295±66 vs. 1015±231uU/ml × min) phase ins release were sig reduced in the PWS. Similarly, first and second phase cpep responses were also sig reduced in the PWS. In contrast, the mean HIE was 33% higher in PWS vs. obese group(15.4±1.5 vs. 10.3±1.6). Similarly, the post-stimulation HIE was sig greater (5.2±0.8 vs. 2.4±0.4) in the PWS group when compared to obese group. In summary, PWS manifest a) reduced β-cell responses b) increased HIE and c) a dissociation of obesity and ins resistance in contrast to obese subjects. Increased ins sensitivity as well as enhanced HIE appear to be compensatory mechanisms for the reduced β-cell function in PWS.