Actions of the novel oral antidiabetic agent HQL-975 in insulin-resistant non-insulin-dependent diabetes mellitus model animals.

The hypoglycemic effects of a novel oral antidiabetic agent HQL-975, were studied in normal rats, streptozotocin-induced diabetic (STZD) rats and genetically insulin-resistant non-insulin-dependent diabetes mellitus (NIDDM) model animals, KK-Ay mice and Zucker diabetic fatty (ZDF) rats. After the dietary administration of HQL-975 to KK-Ay mice, significant decreases in plasma glucose, insulin, triglyceride and non-esterified fatty acid levels were observed. The effective dosage of HQL-975 to decrease the plasma glucose level by 30% was 3.1 mg/kg per day. However, the plasma glucose level was not altered after the administration of HQL-975 in normal and STZD rats. The results suggest that HQL-975 is more effective against the abnormalities of glucose and lipid metabolism of insulin-resistant model animals than in that of normal and insulin-deficient diabetic animals. It is reported that ZDF rats indicate a severely diabetic state as a result of insulin resistance and further the presence of beta-cell insulin secretory defects. Here, HQL-975 (1-30 mg/kg per day for 7 days) was administered to ZDF rats; slight decreases in the plasma glucose (18%) and lipids (41%) levels were observed in the rats given 30 mg/kg. To clarify the action mechanism of HQL-975, we studied the effects of HQL-975 administration on the insulin action of target tissues in KK-Ay mice. After the dietary administration of HQL-975 (0.001, 0.003, 0.010% for 7 days) to KK-Ay mice, hepatic glycolytic and gluconeogenic key enzyme activities were measured. The glucose 6-phosphatase activity was decreased (20-40%) as compared with control. The results suggest that HQL-975 enhances the insulin action in hepatic enzyme regulation. To investigate the actions of HQL-975 in peripheral tissues such as muscle and adipose, an in vivo glucose uptake study using 3H-2-deoxyglucose was performed in KK-Ay mice treated with HQL-975 (0.010% for 7 days). The 2-deoxyglucose uptake of the basal state was not altered, but the insulin-stimulated 2-deoxyglucose uptake in muscle (41-191%) and adipose (46-88%) tissues was increased by the HQL-975 treatment as compared with control. These results suggest that HQL-975 also enhances the insulin action of peripheral tissues. Based on these findings, HQL-975 is expected to be useful for treatment of insulin-resistant patients with NIDDM.