Effects of high-dose troglitazone on insulin sensitivity and β-cell function in watanabe heritable hyperlipidemic rabbits

To clarify the dose-response effects of troglitazone on insulin sensitivity and β-cell function, we examined the effects of high-dose troglitazone (100 mg/day per animal, administered as a food admixture) on glucose and insulin metabolism in hyperinsulinemic Watanabe heritable hyperlipidemic (WHHL) rabbits, and compared the results with our previous results with low-dose troglitazone (10 mg/day per animal). Materials and Methods: Glucose and insulin metabolism were quantitatively characterized by a minimal model technique as reported previously. Results: When troglitazone was administrated at a high dose for 6 months, it reduced hyperinsulinemia as reflected by a reduced basal (steady-state) insulin concentration Ib and the insulin response to a glucose load, improved β-cell function as reflected by decreased second-phase post-hepatic insulin delivery to glucose O2, and reduced insulin resistance as reflected by increased insulin sensitivity to glucose disposal Si, without affecting glucose tolerance as reflected by an unchanged rate of glucose utilization Kg or insulin-independent glucose disposal Sg. The reductions in Ib and O2 and the increases in Si in WHHL rabbits treated with a high dose of troglitazone were greater (p<0.05) than those observed in WHHL rabbits treated with a low dose of troglitazone, as assessed by a two-way repeated measures analysis of variance and the Wilcoxon-Mann-Whitney test. Conclusion: In WHHL rabbits, troglitazone dose-dependently reduced hyperinsulinemia, improved β-cell function, and increased insulin sensitivity.