METABOLIC EFFECTS OF TROGLITAZONE IN THE GOTO-KAKIZAKI RAT, A NONOBESE AND NORMOLIPIDEMIC RODENT MODEL OF NON-INSULIN-DEPENDENT DIABETES-MELLITUS

Troglitazone (TRG) is an orally active antidiabetic agent that increas es insulin sensitivity in models of non-insulin-dependent diabetes mel litus (NIDDM), subsequently reducing hyperinsulinemia and hyperglycemi a. We examined the effects of TRG on the development and severity of d iabetes in the Goto-Kakizaki (GK) rat, a spontaneous, non-obese model of NIDDM. TRG was administered at a dose of 30 mg/kg/d beginning at 4 weeks of age. TRG-treated GK rats were evaluated against Wistar and un treated GK rats at 8, 12, and 16 weeks of age. Untreated GK rats were nonketotic, normolipidemic, hyperglycemic, and had normal fasting insu lin levels compared with Wistar rats. TRG treatment decreased glycosyl ated hemoglobin levels in the GK rat independently of its effects on p lasma insulin. In untreated GK rats, intravenous glucose tolerance tes ts (IVGTTs) showed a hyperglycemic response to glucose loading with se verely impaired glucose disposal relative to Wistar controls. TRG trea tment was successful in decreasing the glucose area under the curve (A UC) (P < .03) but did not improve glucose disposal, suggesting a direc t hepatic effect. Ex vivo evaluation of hepatic glucose output (HGO) f urther supported a direct hepatic action, with 50% reduction in HGO in TRG-treated GK rats (P < .004). A euglycemic-hyperinsulinemic clamp p erformed at 16 weeks of age showed severe insulin resistance in the un treated GK rat, with a glucose infusion rate (GIR) 33% lower than in W istar rats (P < .004). TRG treatment had no effect on this insulin res istance. These results indicate that TRG selectively decreases hepatic glucose production in this unique model of NIDDM independently of its action on peripheral insulin sensitivity or hyperlipidemia. Copyright (C) 1997 by W.B. Saunders Company.