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-isoxazol idinedione, is a novel insulin-sensitizing agent. We investigated the trigl yceride-lowering activity of JTT-501 in a high-fat (HF) rat model. The HF r ats showed insulin resistance with elevation of fasting insulin levels and reduction of insulin-stimulated glucose oxidation. There was also a tendenc y towards increased basal insulin and triglyceride levels. Oral administrat ion of JTT-501 (3-30 mg kg(-1) day(-1) for 7 days) reduced basal triglyceri de 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 trig lyceride output rate. We conclude that JTT-501 possesses potent triglycerid e-lowering activity due to its inhibition of triglyceride secretion from th e liver and enhancement of triglyceride disposal in peripheral tissues. (C) 1999 Elsevier Science B.V. All rights reserved.