Characterization of alterations in glucose and insulin metabolism in Prader-Willi subjects

Abstract

Obesity is a common component of non-insulin-dependent diabetes mellitus (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. It has been assumed that the etiology for this increased rate of NIDDM is related to the morbid obesity and concomitant insulin resistance, but this remains controversial. To shed light on the glucoregulatory mechanisms in PWS, we studied both pediatric and adult PWS patients with normoglycemia. The objectives of our study were (1) to examine glucose, insulin, and C-peptide responses to oral (OGTT) and intravenous (IVGTT) glucose tolerance tests; (2) to characterize acute first- and second-phase insulin secretion during an IVGTT; (3) to assess hepatic insulin extraction (HIE) and insulin clearance (IC) in PWS subjects; and (4) to determine whether β-cell function in PWS is age-dependent. These results in PWS were compared with values obtained in age-, sex-, and body mass index (BMI)-matched non-PWS obese controls. Three groups were studied. Group I consisted of nine PWS subjects under the age of 13 years and 22 age-, sex-, weight-, and puberty stage-matched obese subjects who underwent OGTT. Group II consisted of 14 adult PWS subjects and 10 age-, weight-, and BMI-matched obese adults who underwent OGTT. Group III consisted of nine adult PWS subjects and eight age-, sex-, and weight-matched obese adults who underwent frequently sampled IVGTT (FSIVGTT). During the OGTT in the pediatric group, fasting (86 ± 3 v 89 ± 2 mg/dL), peak (144 ± 11 v 147 ± 4 mg/dL), and total area under the curve (AUC) (6,984 ± 1,320 v 6,963 ± 615 mg/dL · min) glucose levels were not significantly different in PWS versus obese children, respectively. In contrast, fasting (20 ± 6 v 37 ± 4 μU/mL), peak (114 ± 24 v 214 ± 23 • mU/mL), and total AUC (12,673 ± 2,176 v 26,734 ± 2,608 μU/mL μU/mL min) insulin levels were significantly lower in pediatric PWS. During the OGTT in the adult groups, neither fasting insulin (16.7 ± 2.8 v 13.5 ± 2.5 μU/mL) nor total AUC for insulin (10,664 ± 1,955 v 11,623 ± 1,584 μU/mL · min) were significantly different in adult PWS and obese groups. During the IVGTT in adults, both first-phase (138 ± 42 v 454 ± 102 μU/mL · min) and second-phase (295 ± 66 v 1,015 ± 231 μU/mL · min) insulin release were significantly reduced in PWS subjects despite similar glucose levels. Similarly, first-phase (8.6 ± 2.3 v 21 ± 4.6 ng/dL · min) and second-phase (47 ± 4.6 v 75 ± 14 ng/dL · min) C-peptide responses were also significantly reduced in PWS subjects. In contrast, mean HIE and IC was 33% higher in PWS subjects versus obese controls (15.4 ± 1.5 v 10.3 ± 1.6). Similarly, poststimulation HIE and IC was significantly greater (5.2 ± 0.8 v 2.4 ± 0.4) in the PWS group compared with the obese group ( P < .01). In summary, this study demonstrates that nondiabetic PWS subjects manifest (1) a reduced β-cell response to glucose stimulation, (2) a significantly increased HIE compared with obese controls, and (3) a dissociation of obesity and insulin resistance, in contrast to normal obese subjects. We conclude that glucoregulatory mechanisms are different in obese PWS versus non-PWS subjects.