JTT-501 is a new oral
hypoglycemic agent that is reported to be effective in
insulin-resistant diabetic animal models by improving
insulin resistance. It also improves
hypertriglyceridemia. We investigated the mechanism of the reversal of
hypertriglyceridemia in two types of obese animals using
JTT-501. In Zucker fatty obese rats, an animal model of genetic
obesity, fasting plasma
triglyceride and
glucose significantly decreased after a single daily oral dose of
JTT-501 (100 mg/kg) for 7 days. In ventromedial hypothalamus (VMH)-lesioned obese rats, an animal model of nongenetic
obesity, fasting plasma
triglycerides significantly decreased but fasting plasma
glucose levels remained unchanged
after treatment with this agent. In Sprague-Dawley (SD) rats, fasting plasma
triglyceride and
glucose levels remained unchanged. The JTT-501-treated Zucker fatty and VMH-lesioned obese rats showed a decrease in
insulin, but it was not significant, while the treated SD rats showed a significant decrease in
insulin. Postheparin plasma
lipoprotein lipase (LPL) increased significantly in treated Zucker fatty obese and SD rats, but did not change in VMH-lesioned obese rats. The hepatic
triglyceride secretion rate (TGSR) did not change in any species treated with
JTT-501. There was a negative correlation between postheparin plasma LPL and plasma
triglyceride levels in Zucker fatty obese rats, while no such correlation was observed in VMH-lesioned obese or SD rats. The fractional catabolic rate (FCR) for plasma
triglyceride was increased significantly by
JTT-501 in both Zucker fatty and VMH-lesioned obese rats. These results suggest that
JTT-501 decreases plasma
triglycerides mainly by increasing postheparin plasma LPL in Zucker fatty obese rats, while it ameliorates an impairment in the ability of adipose tissue to remove
triglyceride from the circulation in VMH-lesioned obese rats.