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

新型促胰岛素机制降糖药的研制及其临床应用

• 批准号: 08557060
• 负责人: SEINO Yutaka
• 金额: $ 6.02万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08557060/
• 关键词: Pancreatic beta cells; insulin secretion; diabetes mellitus; patch clamp technique; voltage-dependent Ca^<2+> channel; intracellular calcium; oral hypoglycemic agents

The effect of metabolic inhibition on the blocking of beta cell ATP-sensitive K^+ channels (K_<ATP> channels) by glibenclamide was investigated using patch-clamp technique. Inhibition of K_<ATP> channels by glibenclamide was attenuated in the cell-attached mode under metabolic inhibition induced by 2,4-dinitrophenol. Under a low concentration (0.1muM) of ATP applied in the inside-out mode, K_<ATP> channel activity was not fully abolished even when a high dose of glibenclamide was applied, in contrast to the dose-dependent and complete K_<ATP> channel inhibition under 10muM ATP.On the other hand, cibenzoline, a class Ia antiarrhythmic agent, inhibits K_<ATP> channel activity in a dose-dependent manner, and completely blocks it even under metabolic inhibition. In sulfonylurea receptor (SUR1)-and inward rectifier K^+ channel (Kir6.2)-expressed proteins, cibenzoline binds directly to Kir6.2, unlike glibenclamide. Thus, K_<ATP> channel inhibition by glibenclamide is impaired under the condition of decreased intracellular ATP in pancreatic beta cells, probably due to a defect in signal transmission between SUR1 and Kir6.2 downstream of the site of sulfonylurea binding to SUR1.

采用膜片钳技术研究了代谢抑制对格列本脲阻断β细胞ATP敏感的K^+通道（K_<ATP>通道）的影响。在2,4-二硝基苯酚诱导的代谢抑制下，格列本脲对K_<ATP>通道的抑制作用在细胞附着模式下减弱。在低浓度（0.1 μ m）由内而外的ATP模式下，即使使用高剂量的格列本脲，K_<ATP>通道活性也没有完全消除，而在10μ m的ATP模式下，K_<ATP>通道的抑制是剂量依赖性的、完全的。另一方面，Ia类抗心律失常药物苯并喹啉抑制K_<ATP>通道活性呈剂量依赖性，即使在代谢抑制下也能完全阻断该通道。在磺酰脲受体（SUR1）和向内整流K^+通道（Kir6.2）表达的蛋白中，与格列本脲不同，苯并啉直接与Kir6.2结合。因此，在胰腺β细胞胞内ATP减少的情况下，格列本脲对K_<ATP>通道的抑制作用受损，这可能是由于磺酰脲与SUR1结合位点下游的SUR1与Kir6.2之间的信号传递存在缺陷。

项目成果

T.Miura et al.: "A comparative study of high-fat diet containing fish oil or lard on blood glucose in genetically diabetic (db//db) mice." J Nurt Sci Vitaminol. 43. 225-231 (1997)

T.Miura 等人：“一项含有鱼油或猪油的高脂饮食对遗传性糖尿病 (db//db) 小鼠血糖影响的比较研究。”

J.Fujita,et al.: "Elevated erythrocyte sodium-lithium counterrtansport activity correlates with increased intracellular sodium and free calcium-ion concentration in type 2 diabetes." Diatebec Medicine. 13. 53-58 (1996)

J.Fujita 等人：“2 型糖尿病中红细胞钠锂反转运活性升高与细胞内钠离子和游离钙离子浓度增加相关。”

J.Fujita, et al.: "Nisoldipine blocks the increase of intracellular free calcium-ion concentration associated with celevated sodium-lithium ounter transport activity in erythrocytes in patients with NIDDM." Diabetic Med. 14. 499-502 (1997)

J.Fujita 等人：“尼索尔地平可阻止 NIDDM 患者红细胞内游离钙离子浓度的增加，该浓度与红细胞钠锂反转运活性升高相关。”

M.Nishimura et al.: "Necessity of endogenous GTP derived from glucose-6-phosphate for insulin secretion augmented by glucose under protein kinase A activation" Biochem.Biophys.Res.Commun.(in press).

M.Nishimura 等人：“在蛋白激酶 A 激活下，葡萄糖-6-磷酸衍生的内源性 GTP 对于胰岛素分泌的必要性”Biochem.Biophys.Res.Commun.（出版中）。

S.Fujimoto et al.: "The novel insulinotropic mechanism of pimobendan : direct enhancement of the exocytotic process of insulin secretory granules by increased Ca^<2+> sensitivity in β cells." Endocrinology. (in press).

S. Fujimoto 等人：“匹莫苯丹的新型促胰岛素机制：通过增加 β 细胞中的 Ca^2+ 敏感性来直接增强胰岛素分泌颗粒的胞吐过程（正在出版）。”