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

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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.