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 (T1/2). In contrast, pioglitazone (30 mg kg(-1) day(-1) for 15 days, p.o.) reduced T1/2, 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.
Central Pharmaceutical Research Institute, Japan Tobacco, Takatsuki, Osaka.
T
T
Shibata
K
K
Matsui
F
F
Yonemori
K
K
Wakitani
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D004041:Dietary Fats; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D000077205:Pioglitazone; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
D001786:Blood Glucose; D004041:Dietary Fats; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D007328:Insulin; D007555:Isoxazoles; D013844:Thiazoles; D045162:Thiazolidinediones; D014280:Triglycerides; C112329:JTT 501; D000077205:Pioglitazone