ACTIONS OF THE NOVEL ORAL ANTIDIABETIC AGENT HQL-975 IN GENETICALLY-OBESE DIABETIC DB DB MICE/

The hypoglycemic effect of the novel oral agent zol-4-yl)-ethoxy]-phen yl}-2S-propylamino-propionic acid (HQL-975) was examined in db/db mice with genetically obese non-insulin dependent diabetes mellitus (NIDDM ). The oral administration of HQL-975 at 3.5 and 35.3 mg/kg/d for 7 d decreased the plasma glucose level of these mice in a dose-dependent m anner. HQL-975 also significantly decreased the plasma triglyceride, t otal cholesterol, non-esterified fatty acid and insulin levels. In the oral glucose tolerance test, HQL-975-treated mice showed improved glu cose tolerance and decreased endogenous insulin secretion. HQL-975 inc reased glycemic response to exogenous insulin in the mice. In the HQL- 975-treated db/db mice adipocytes, the glucose uptake, insulin binding , and GLUT4 expression were increased compared with those in untreated db/db mice adipocytes. These results indicate that HQL-975 improved i nsulin action in db/db mice through receptor and post-receptor effects . In conclusion, HQL-975 is a new oral antidiabetic agent with a hypog lycemic effect which is associated with an insulin-sensitizing effect. This agent may therefore be effective for the treatment of NIDDM.