Effects of the novel oral antidiabetic agent HQL-975 on glucose and lipid metabolism in diabetic db/db mice.
The antidiabetic effects of 3-¿4-[2-(5-methyl-2-phenyl-oxazol-4- yl)ethoxy]phenyl¿-2S-propylamino-propionic acid (CAS 185679-16-7, HQL-975), a novel oral agent, on a genetically obese non-insulin-dependent diabetes mellitus (NIDDM) model (db/db mice) were examined. HQL-975 administration (3.7-34.1 mg/kg/d for 7 days) decreased the levels of plasma glucose, triglyceride, total cholesterol, non-esterified fatty acid and insulin in the mice. In an intraperitoneal glucose tolerance test (IPGTT), HQL-975 administration decreased the fasting plasma glucose level and improved the glucose tolerance in the mice. The HQL-975 administration also significantly increased the glycogenesis and lipogenesis from 14C-glucose in liver, but did not alter the glycogenesis in the diaphragm or the lipogenesis in adipose tissues at 2 h after the glucose loading. In the HQL-975-treated db/db mice, the radioactivity of 14C-glucose incorporated into hepatic glycogen was higher than that incorporated into hepatic total lipids. After the administration of HQL-975 (34.1 mg/kg/d for 7 days) to db/db mice, the hepatic hexokinase and fatty acid synthetase activities were significantly increased, the glycogen synthase I activity was increased but not significantly, and the glucose-6-phosphatase and the phosphoenolpyruvate carboxykinase activities were decreased. These results suggest that HQL-975 increases the hepatic glucose utilization and decreases the hepatic glucose production. Since hepatic glycogenesis is regulated by glucose itself but not by insulin in normoglycemic ICR mice, HQL-975 is thought to enhance the effect of glucose on the stimulation of hepatic glycogenesis. It is concluded that the enhancement of the hepatic glucose utilization played an important role in the hypoglycemic action of HQL-975.