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

• Published in: European journal of pharmacology 1999-05, Vol.373 (1), p.85-91
• Main Authors: Shibata, Tsutomu, Matsui, Kenichi, Yonemori, Fumihiko, Wakitani, Korekiyo
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Blood Glucose - drug effects; Blood Glucose - metabolism; Body Weight - drug effects; Dietary Fats; General and cellular metabolism. Vitamins; Hypoglycemic Agents - pharmacology; Hypolipidemic Agents - pharmacology; Insulin - blood; Insulin Resistance; Insulin-sensitizing agent; Isoxazoles - pharmacology; JTT-501; Male; Medical sciences; Pharmacology. Drug treatments; Pioglitazone; Rats; Rats, Sprague-Dawley; Thiazoles - pharmacology; Thiazolidinediones; Triglyceride; Triglycerides - blood; Triglycerides - metabolism
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(99)00256-3

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.