Ishikawa Y, Saito M N, Ikemoto T, Takeno H, Watanabe K, Tani T
New Drug Research Department, Sumitomo Metal Industries, Kyoto, Japan.
Diabetes Res Clin Pract. 1998 Aug;41(2):101-11. doi: 10.1016/s0168-8227(98)00080-1.
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.
研究了新型口服抗糖尿病药物HQL-975对正常大鼠、链脲佐菌素诱导的糖尿病（STZD）大鼠以及遗传性胰岛素抵抗非胰岛素依赖型糖尿病（NIDDM）模型动物（KK-Ay小鼠和Zucker糖尿病脂肪大鼠，即ZDF大鼠）的降血糖作用。给KK-Ay小鼠经口给予HQL-975后，观察到血浆葡萄糖、胰岛素、甘油三酯和非酯化脂肪酸水平显著降低。使血浆葡萄糖水平降低30%的HQL-975有效剂量为每天3.1mg/kg。然而，给正常大鼠和STZD大鼠给予HQL-975后，血浆葡萄糖水平未发生改变。结果表明，HQL-975对胰岛素抵抗模型动物的糖脂代谢异常的作用比对正常和胰岛素缺乏型糖尿病动物更有效。据报道，ZDF大鼠由于胰岛素抵抗以及进一步存在β细胞胰岛素分泌缺陷而呈现严重的糖尿病状态。在此，给ZDF大鼠给予HQL-975（每天1 - 30mg/kg，共7天）；给予30mg/kg的大鼠血浆葡萄糖（18%）和脂质（41%）水平略有降低。为阐明HQL-975的作用机制，我们研究了给KK-Ay小鼠给予HQL-975对靶组织胰岛素作用的影响。给KK-Ay小鼠经口给予HQL-975（0.001%、0.003%、0.010%，共7天）后，测定肝脏糖酵解和糖异生关键酶活性。与对照组相比，葡萄糖6-磷酸酶活性降低（20 - 40%）。结果表明，HQL-975在肝脏酶调节方面增强了胰岛素作用。为研究HQL-975在肌肉和脂肪等外周组织中的作用，对用HQL-975（0.010%，共7天）处理的KK-Ay小鼠进行了使用3H-2-脱氧葡萄糖的体内葡萄糖摄取研究。基础状态下的2-脱氧葡萄糖摄取未改变，但与对照组相比，HQL-975处理使胰岛素刺激的肌肉（41 - 191%）和脂肪（46 - 88%）组织中的2-脱氧葡萄糖摄取增加。这些结果表明，HQL-975也增强了外周组织的胰岛素作用。基于这些发现，HQL-975有望用于治疗胰岛素抵抗的NIDDM患者。
