Triglyceride-lowering effect of a novel insulin-sensitizing agent, JTT-501

JTT-501, 4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-3, 5-isoxazolidinedione, is a novel insulin-sensitizing agent. We investigated the triglyceride-lowering activity of JTT-501 in a high-fat (HF) rat model. The HF rats showed insulin resistance with elevation of fasting insulin levels and reduction of insulin-stimulated glucose oxidation. There was also a tendency towards increased basal insulin and triglyceride levels. Oral administration of JTT-501 (3–30 mg kg −1 day −1 for 7 days) reduced basal triglyceride levels dose dependently with a minimum effective dose of 3 mg kg −1 day −1. Furthermore, regarding triglyceride metabolism, JTT-501 (30 mg kg −1 day −1 for 15 days, p.o.) decreased hepatic triglyceride output rate and serum triglyceride half-life ( T 1/2). In contrast, pioglitazone (30 mg kg −1 day −1 for 15 days, p.o.) reduced T 1/2, but did not affect hepatic triglyceride output rate. We conclude that JTT-501 possesses potent triglyceride-lowering activity due to its inhibition of triglyceride secretion from the liver and enhancement of triglyceride disposal in peripheral tissues.