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) ra ts and genetically insulin-resistant non-insulin-dependent diabetes me llitus (NIDDM) model animals, KK-Ay mice and Zucker diabetic fatty (ZD F) rats. After the dietary administration of HQL-975 to KK-Ay mice, si gnificant decreases in plasma glucose, insulin, triglyceride and non-e sterified 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 administ ration of HQL-975 in normal and STZD rats. The results suggest that HQ L-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 i ndicate a severely diabetic state as a result of insulin resistance an d further the presence of beta-cell insulin secretory defects. Here, H QL-975 (1-30 mg/kg per day for 7 days) was administered to ZDF rats; s light decreases in the plasma glucose (18%) and lipids (41%) levels we re observed in the rats given 30 mg/kg. To clarify the action mechanis m 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 admi nistration of HQL-975 (0.001, 0.003, 0.010% for 7 days) to KK-Ay mice, hepatic glycolytic and gluconeogenic key enzyme activities were measu red. The glucose 6-phosphatase activity was decreased (20-40%) as comp ared with control. The results suggest that HQL-975 enhances the insul in action in hepatic enzyme regulation. To investigate the actions of HQL-975 in peripheral tissues such as muscle and adipose, an in vivo g lucose uptake study using H-3-2-deoxyglucose was performed in KK-Ay mi ce 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-deox yglucose uptake in muscle (41-191%) and adipose (46-88%) tissues was i ncreased by the HQL-975 treatment as compared with control. These. res ults suggest that HQL-975 also enhances the insulin action of peripher al tissues. Based on these findings, HQL-975 is expected to be useful for treatment of insulin-resistant patients with NIDDM. (C) 1998 Publi shed by Elsevier Science Ireland Ltd. All rights reserved.