METABOLIC EFFECTS OF TROGLITAZONE ON FAT-INDUCED INSULIN-RESISTANCE IN THE RAT

Troglitazone is a new orally active hypoglycemic agent that has been s hown to ameliorate insulin resistance and hyperinsulinemia in both dia betic animal models and non-insulin-dependent diabetes mellitus (NIDDM ) subjects. To determine whether this drug could prevent the developme nt of diet-induced insulin resistance and related abnormalities, we st udied its effect on insulin resistance induced by high-fat feeding in rats. Normal male Sprague-Dawley rats were fed a high-fat diet for 3 w eeks with and without troglitazone as a food mixture (0.2%) or were fe d normal chow. In vivo insulin action was measured using a euglycemic- hyperinsulinemic clamp at two different insulin infusion rates, 4 (sub maximal stimulation) and 40 (maximal stimulation) mU/kg/min. Fat feedi ng markedly reduced the submaximal glucose disposal rate ([GDR], 26.4 +/- 1.3 v 37.5 +/- 1.4 mg/kg/min. P <.01) and maximal GDR (55.9 +/- 1. 3 v 64.5 +/- 1.3 mg/kg/min, P <.05), reduced the suppressibility of su bmaximal hepatic glucose production ([HGP], 3.2 +/- 0.9 v 1.5 +/- 0.5 mg/kg/min, P <.05), and resulted in hyperlipidemia. Troglitazone treat ment did not affect any of these parameters. Insulin resistance induce d by fat feeding is the first experimental model in which troglitazone failed to correct or partially correct the insulin resistance. Copyri ght (C) 1995 by W.B. Saunders Company