Sugiyama Y, Taketomi S, Tawada H, Meguro K, Ikeda H, Fujita T
Biology Laboratory, Takeda Chemical Industries, Ltd., Osaka, Japan.
Horm Metab Res. 1988 Mar;20(3):145-9. doi: 10.1055/s-2007-1010779.
In the perfused pancreas from normal SD rats, AD-4610 (0.01-0.1 mM) potentiated biphasic insulin secretion induced by 7.5 mM of glucose. The concentration-response curve of insulin secretion to glucose was shifted leftwards with AD-4610 (0.1 mM) without altering either the threshold concentration of glucose to induce insulin secretion or the maximal insulin response to glucose, indicating increased sensitivity of the pancreatic B-cells to glucose. On the other hand, AD-4610 was 10-fold less effective in altering insulin secretion induced by arginine and glyceraldehyde. The effect of AD-4610 on insulin secretion and glucose metabolism was compared with that of tolbutamide in vivo. AD-4610 (100 mg/kg) potentiated insulin secretion induced by an intravenous glucose load, and also accelerated glucose metabolism without altering basal insulin secretion in normal rats. On the other hand, tolbutamide (20 mg/kg) increased basal insulin secretion, but slightly decreased glucose-induced insulin secretion. In yellow KK mice with hyperglycemia, AD-4610 (10-100 mg/kg) had a dose-dependent hypoglycemic action, but tolbutamide did not. Thus, AD-4610 stimulated insulin secretion in a glucose-dependent fashion and enhanced glucose metabolism in vivo. These results suggest that AD-4610 selectively potentiates glucose-induced insulin secretion by increasing the sensitivity of pancreatic B-cells to glucose and may be useful for treating human NIDDM through a different mechanism than that of tolbutamide.
在正常SD大鼠的灌注胰腺中，AD - 4610（0.01 - 0.1 mM）增强了由7.5 mM葡萄糖诱导的双相胰岛素分泌。AD - 4610（0.1 mM）使胰岛素分泌对葡萄糖的浓度 - 反应曲线向左移动，而不改变诱导胰岛素分泌的葡萄糖阈值浓度或胰岛素对葡萄糖的最大反应，表明胰腺β细胞对葡萄糖的敏感性增加。另一方面，AD - 4610在改变精氨酸和甘油醛诱导的胰岛素分泌方面的效力低10倍。在体内将AD - 4610对胰岛素分泌和葡萄糖代谢的作用与甲苯磺丁脲进行了比较。AD - 4610（100 mg/kg）增强了静脉注射葡萄糖负荷诱导的胰岛素分泌，并且在不改变正常大鼠基础胰岛素分泌的情况下还加速了葡萄糖代谢。另一方面，甲苯磺丁脲（20 mg/kg）增加了基础胰岛素分泌，但略微降低了葡萄糖诱导的胰岛素分泌。在患有高血糖的黄色KK小鼠中，AD - 4610（10 - 100 mg/kg）具有剂量依赖性的降血糖作用，但甲苯磺丁脲没有。因此，AD - 4610以葡萄糖依赖性方式刺激胰岛素分泌并在体内增强葡萄糖代谢。这些结果表明，AD - 4610通过增加胰腺β细胞对葡萄糖的敏感性选择性地增强葡萄糖诱导的胰岛素分泌，并且可能通过与甲苯磺丁脲不同的机制用于治疗人类非胰岛素依赖型糖尿病。
