HQL-975 (3-{4-12-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxyl-phenyl}-2S- propylamino-propionic acid) is a new oral antidiabetic agent which has been shown to be effective in insulin-resistant diabetic animals. In the present study, we examined the effects of HQL-975 on glucose utilization and insulin action in KK-Ay mice with genetically obese non-insulin diabetes. (1) Dietary administration of HQL-975 (19 mg/kg/d for 7 d) improved hyperglycemia, hyperlipidemia and hyperinsulinemia in the mice. (2) The HQL-975-treated mice showed enhanced net glucose utilization, that is, glucose was significantly incorporated into total lipids in the white adipose tissue (WAT) and liver, and into glycogen in the diaphragm for the last 24 h of the drug administration period. (3) Treatment improved the decreased stimulative action of insulin in the epididymal WAT and the agent increased insulin-stimulated lipogenesis from both glucose and acetate. (4) Treatment also increased the activity of lipogenic enzymes such as glycerol-3-phosphate dehydrogenase and fatty acid synthetase. (5) In vitro exposure of WAT to HQL-975 enhanced lipogenesis in the presence of insulin. From these findings, we conclude that HQL-975 improves glucose utilization of KK-Ay mice through the enhancement of insulin action, which is associated with its lipogenic effects.

1998-08-01·Diabetes Research and Clinical Practice3区 · 医学

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

3区 · 医学

Article

作者: Hidekazu Takeno ; Masahiko Nagumo Isao Saito ; Yuji Ishikawa ; Tomoyuki Ikemoto ; Kazubiro Watanabe ; Tadato Tani

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.

1998-03-01·Arzneimittel-Forschung

Effects of the novel oral antidiabetic agent HQL-975 on glucose and lipid metabolism in diabetic db/db mice.

Article

作者: Ishikawa, Y ; Watanabe, K ; Takeno, H ; Tani, T

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.

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