JTT-501, a novel oral antidiabetic agent, improves insulin resistance in genetic and non-genetic insulin-resistant models.

We investigated whether JTT-501 (4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-3,5-isoxazolidinedione) would improve insulin resistance in genetic (Zucker fatty rats) and non-genetic (high-fat fed rats) rodent models of obesity. JTT-501 (10–100 mg kg−1 day−1) was administered orally to Zucker fatty rats for 7–21 days. In the high-fat fed rat model, JTT-501 (100 mg kg−1 day−1) was administered orally for 7 days. In both models, JTT-501 improved metabolic abnormalities by enhancing insulin action during the glucose tolerance test and the euglycaemic-hyperinsulinaemic clamp study. In ex vivo assays, JTT-501 ameliorated the impaired insulin-sensitive glucose oxidation and lipid synthesis in peripheral tissues. Furthermore, JTT-501 enhanced insulin receptor autophosphorylation in hindlimb muscle. JTT-501 reduced serum leptin concentrations in both models, but did not affect body weight or epididymal fat weight. Our observations indicate that JTT-501 improves the metabolic abnormalities in both genetic and non-genetic insulin-resistant models by enhancing insulin action in peripheral tissues. These effects of JTT-501 are due, at least in part, to enhanced insulin receptor autophosphorylation. In addition, JTT-501 is able to reduce serum leptin concentrations in hyperleptinaemia of the insulin-resistant model. We expect JTT-501 to show promise for treating non-insulin dependent diabetes mellitus patients with insulin resistance.