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

Troglitazone is a new orally active hypoglycemic agent that has been shown to reduce insulin resistance and hyperinsulinemia in both diabetic animal models and non-insulin-dependent diabetes mellitus (NIDDM) subjects. To determine whether this drug could prevent the development of fructose-induced insulin resistance and related abnormalities, we studied the effects of troglitazone on the insulin resistance induced by fructose feeding in rats. Normal male Sprague-Dawley rats were fed a high-fructose diet for 3 weeks with and without troglitazone as a food admixture (0.2%) or were fed normal chow to serve as a control group. In vivo insulin resistance was measured by the euglycemic hyperinsulinemic clamp technique at two different insulin infusion rates, 29 (submaximal stimulation) and 290 (maximal stimulation) pmol.kg(-1).min(-1). Fructose feeding markedly reduced submaximal glucose disposal rate (GDR) (113.8 +/- 8.3 vs. 176.0 +/- 5.6 mu mol.kg(-1).min(-1), P < 0.05) and maximal GDR (255.9 +/- 5.6 vs. 313.6 +/- 10.5 mu mol.kg(-1).min(-1), P < 0.05), reduced the suppressibility of submaximal hepatic glucose production (HGP; 45.5 +/- 5.0 vs. 11.7 +/- 5.0 mu mol.kg(-1) .min(-1), P < 0.05), and resulted in hypertriglyceridemia and hypertension. Troglitazone treatment completely restored the GDR (submaximal 158.2 +/- 5.6, maximal 305.3 +/- 6.1 mu mol. kg(-1).min(-1)) and submaximal HGP (9.4 +/- 2.8 mu mol. kg(-1).min(-1)) to control levels and also normalized the elevated plasma triglyceride concentration and systolic blood pressure levels in fructose-fed rats. These results suggest that troglitazone treatment could completely prevent the insulin resistance, hypertension, and hypertriglyceridemia induced by a diet high in fructose and that the drug might prove useful in the treatment and/or prevention of nonhyperglycemic insulin-resistant states as well as in the treatment of established NIDDM.