Quantification of the effects of troglitazone on insulin sensitivity and beta-cell function in Watanabe heritable...

Troglitazone is a newly developed antidiabetic drug that has been shown to improve insulin resistance and hyperinsulinemia both in diabetic animal models and in patients with non-insulin-dependent diabetes mellitus. The Watanabe heritable hyperlipidemic (WHHL) rabbit, an animal model of familial hypercholesterolemia, is characterized by hyperinsulinemia, which reflects insulin resistance. In this study to determine the effects of troglitazone on glucose and insulin metabolism in WHHL rabbits, we quantified the rate of glucose utilization (glucose tolerance index [Kg]), sensitivity of first-phase posthepatic insulin secretion to glucose (phi1), sensitivity of second-phase posthepatic insulin secretion to glucose (phi2), insulin sensitivity to glucose disposal ([Si] inversely related to insulin resistance), insulin-independent glucose disposal (glucose effectiveness [Sg]), and rate of insulin clearance (Ki) by incorporating our previously reported two-compartment model of a glucose/insulin system with the glucose disappearance model of Bergman. Galvin insulin sensitivity (GIS) was also computed for comparison with Bergman Si. When troglitazone was administered as a food admixture (24 mg/d per animal) for 6 months, it did not significantly affect beta-cell function as measured by phi2, glucose tolerance as measured by Kg, or Sg, but increased both Si and Ki and reduced phi1, leading to a decreased plasma insulin response during the intravenous glucose tolerance test (IVGTT). Si was strongly and significantly correlated with GIS. These data indicate that in WHHL rabbits, troglitazone improves insulin sensitivity and posthepatic insulin clearance without affecting beta-cell function or glucose tolerance.