Development of new hypoglycemic agents with a novel insulinotropic mechanism and their clinical application

磺脲类(SU)类药物已作为口服降糖药用于治疗非胰岛素依赖型糖尿病(NIDDM)。然而，其中相当一部分已知患有SU衍生物的继发性失效，并且它们的血糖控制通常变得困难。因此，新开发的具有新机制的降糖药有望在不久的将来上市。已经观察到，NIDDM患者葡萄糖诱导的胰岛素分泌减少，但对除葡萄糖以外的促分泌剂的反应，胰岛素的释放明显增加。在本研究中，我们用膜片钳技术测量了电压依赖性钙通道(VDCC)的通道活动。NIDDMβ细胞去极化后内向钙电流显著增加。另一方面，存在一种可能性，即β细胞中过量的钙离子负荷促进了程序性死亡。然后，我们利用电通透性胰岛研究了细胞内钙离子升高后胞吐过程的变化。结果显示，在NIDDMβ细胞中，这一过程是功能性高反应的，这一证据似乎与胰岛素分泌对除葡萄糖以外的其他去极化促分泌剂的高反应以及VDCC活性的增加密切相关。因此，能够敏化钙激活的胞吐过程的药物似乎是合适的治疗药物。作为他们的候选药物之一，Pimobendan，一种心脏离子变性剂，被发现在不影响细胞内钙浓度的情况下，增强葡萄糖诱导的胰岛素释放。这类药物有望成为一种新的降血糖药物，它可以增加胰岛素的分泌，而不会导致胰岛β细胞内钙超载。

Sulfonylurea (SU) derivatives have been used as oral hypoglycemic agents for the treatment of patients with non-insulin-dependent diabetes mellitus (NIDDM). However, a considerable number of them is known to suffer from the secondary failure for SU derivatives, and their glycemic control usually becomes difficult. The newly developed hypoglycemic agents having a novel mechanism is, therefore, urged to be available in the near future. It has been observed that the glucose-induced insulin secretion is decreased in NIDDM,but that the insulin release is rather enhanced in response to the secretagogues other than glucose. In the present study, we measured the channel activity of voltage-dependent Ca^<2+> channels (VDCCs) using the patch clamp technique. The inward Ca^<2+> current was significantly increased upon depolarization in NIDDM beta cells. On the other hand, there is a possibility that excessive Ca^<2+> loading in beta cells promotes the programed death. We investigated then the alterations in exocytotic process after intracellular Ca^<2+> elevation using electrically permeabilized islets. It was revealed that the process is functionally hyperresponsive in NIDDM beta cells, and this evidence seems closely related to the hyperresponse of insulin secretion to other depolarizing secretagogues than glucose, in conjunction with the increased VDCC activity. Therefore, the agents which can sensitize the calcium activated exocytotic process seems to be suitable therapeutic drugs. As one of their candidates, pimobendan, a cardiac ionotropic agent, was found to enhance glucose-induced insulin release without affecting intracellular calcium concentrations. The agents in this category is expected to become a new hypoglycemic agent, which can augment insulin secretion without intracellular Ca^<2+> overloading in pancreatic beta cells.