ANTIOBESITY EFFECT OF DIAZOXIDE IN OBESE ZUCKER RATS

Hyperinsulinism and insulin resistance are characteristic findings in obese subjects. Obesity in both humans and experimental animals is ass ociated with a reduced number of insulin receptors and a decreased ins ulin mediated glucose disposal, whereas sensitivity to insulin's antil ipolytic action is unaltered. To evaluate the antiobesity effect of di azoxide (DZ), an inhibitor of glucose-stimulated insulin release, 7-we ek-old Zucker obese and lean rats were studied. Obese and lean rats we re grouped into OZ-treated (150 mg/kg/d) and control (C) groups. DZ-tr eated obese rats consumed similar amounts of calories per kilogram bod y weight (BW) compared with C obese animals, but gained less weight (P < .01). Postabsorptive plasma free fatty acids (FFA), cholesterol, an d triglycerides were significantly higher in obese versus lean animals (P < .01). DZ treatment reduced plasma triglyceride levels in obese a nimals (P < .001), but had no significant effect on FFA or cholesterol concentrations. Plasma glucose concentrations in the postabsorptive s tate and during glucose tolerance tests (GTTs) were significantly lowe r in DZ obese versus C obese rats (P < .01) despite a decrease in plas ma insulin concentrations in DZ-treated animals (P < .01). In contrast , DZ lean rats developed glucose intolerance (P < .05). Sensitivity an d responsiveness to the antilipolytic effect of insulin in isolated ad ipocytes were significantly decreased in OZ obese as compared with C o bese rats (P < .01). Moreover, adipocyte specific insulin receptor bin ding was increased in both OZ lean and OZ obese animals (P < .01). Thi s was accompanied by increased basal and insulin-stimulated glucose tr ansport in both genotypes (P < .01). In conclusion, DZ increased insul in receptor binding and glucose transport while decreasing hyperinsuli nemia and insulin sensitivity to the antilipolytic action of insulin. This combined effect resulted in improved glucose tolerance and a decr ease in weight gain in obese rats, implying that pharmacologic modific ation of the disturbed insulin metabolism of obesity may be therapeuti cally beneficial. Copyright (C) 1996 by W.B. Saunders Company