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

To clarify the dose-response effects of troglitazone on insulin sensitivity and beta -cell function, we examined the effects of high-dose troglitazone (100 mg/day per animal, administered as a food admixture) on glucose and i nsulin metabolism in hyperinsulinemic Watanabe heritable hyperlipidemic (WH HL) rabbits, and compared the results with our previous results with low-do se troglitazone (10 mg/day per animal). Materials and Methods: Glucose and insulin metabolism were quantitatively characterized by a minimal model tec hnique 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 resp onse to a glucose load, improved beta -cell function as reflected by decrea sed second-phase post-hepatic insulin delivery to glucose circle divide2, a nd reduced insulin resistance as reflected by increased insulin sensitivity to glucose disposal S-i, without affecting glucose tolerance as reflected by an unchanged rate of glucose utilization Kg or insulin-independent gluco se disposal Sg. The reductions in I-b and circle divide2 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 varian ce and the Wilcoxon-Mann-Whitney test. Conclusion: In WHHL rabbits, troglit azone dose-dependently reduced hyperinsulinemia, improved beta -cell functi on, and increased insulin sensitivity.