QUANTIFICATION OF THE EFFECTS OF TROGLITAZONE ON INSULIN SENSITIVITY AND BETA-CELL FUNCTION IN WATANABE HERITABLE HYPERLIPIDEMIC RABBITS - A MINIMAL MODEL ANALYSIS

Troglitazone is a newly developed antidiabetic drug that has been show n to improve insulin resistance and hyperinsulinemia both in diabetic animal models and in patients with non-insulin-dependent diabetes mell itus. The Watanabe heritable hyperlipidemic (WHHL) rabbit, an animal m odel of familial hypercholesterolemia, is characterized by hyperinsuli nemia, which reflects insulin resistance. In this study to determine t he effects of troglitazone on glucose and insulin metabolism in WHHL r abbits, we quantified the rate of glucose utilization (glucose toleran ce index [Kg]), sensitivity of first-phase posthepatic insulin secreti on to glucose (Phi(1)), sensitivity of second-phase posthepatic insuli n secretion to glucose (Phi(2)), insulin sensitivity to glucose dispos al ([S-i] inversely related to insulin resistance), insulin-independen t glucose disposal (glucose effectiveness [S-g]), and rate of insulin clearance (K-i) by incorporating our previously reported two-compartme nt model of a glucose/insulin system with the glucose disappearance mo del of Bergman. Galvin insulin sensitivity (GIS) was also computed for comparison with Bergman S-i. When troglitazone was administered as a food admixture (24 mg/d per animal) for 6 months, it did not significa ntly affect beta-cell function as measured by Phi(2), glucose toleranc e as measured by K-g, or S-g, but increased both S-i and K-i and reduc ed Phi(1), leading to a decreased plasma insulin response during the i ntravenous glucose tolerance test (IVGTT). S-i was strongly and signif icantly correlated with GIS. These data indicate that in WHHL rabbits, troglitazone improves insulin sensitivity and posthepatic insulin cle arance without affecting beta-cell function or glucose tolerance. Copy right (C) 1997 by W.B. Saunders Company.