MODIFICATION OF INSULIN-RESISTANCE BY DIAZOXIDE IN OBESE ZUCKER RATS

Hyperinsulinism, insulin resistance, and decreased number of insulin r eceptors are characteristic of obesity in both humans and experimental animals. To assess the role of insulin in developing obesity, diazoxi de (DZ), an inhibitor of glucose-stimulated insulin secretion, was adm inistered for 8 weeks to 7-week-old female Zucker rats in two concentr ations, 50 mg/kg . day (LD-DZ), and 100 mg/kg . day (HD-DZ). The obese and lean rats were divided into three subgroups: diazoxide (DZ), pair -fed (PF), and control (C) groups (n = 6 rats/subgroup-genotype). Diaz oxide-treated obese and lean animals showed significantly lower postab sorptive plasma insulin concentrations (P < 0.005) than their respecti ve obese and lean PF and C subgroups. HD-DZ obese rats consumed more c alories (P < 0.001), yet gained less weight (P < 0.05) than PF and C r ats. The plasma glucose concentrations in the postabsorptive state and during glucose tolerance tests in HD-DZ obese rats were significantly lower than those in PF and C rats (P < 0.01) despite a decrease in th eir plasma insulin concentrations (P < 0.01), whereas HD-DZ lean rats displayed a diabetic response (P < 0.01). The adipocyte-specific insul in receptor binding was dose-dependently increased in both lean and ob ese DZ animals (P < 0.01). DZ had a dual effect on insulin metabolism; it decreased insulin secretion and increased insulin receptor binding . This dual effect was associated with improved glucose tolerance and a decrease in weight gain in obese rats.