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

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Abstract
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.

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