1997 Fiscal Year Final Research Report Summary
Development of new hypoglycemic agents with a novel insulinotropic mechanism and their clinical appkicatior
| Project/Area Number |
08557060
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
内分泌・代謝学
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
SEINO Yutaka Professor, Dept.of Metab.And Clin.Nutr.Kyoto Univ.School of Med., 医学研究科, 教授 (40030986)
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| Co-Investigator(Kenkyū-buntansha) |
HORIKOSHI Hiroyoshi Principle Investigator, Biological Research Laboratories, Sankyo Company, Ltd., 第一生物研究所, 主任研究員
ISHIDA Hitoshi Associate professor, Dept.of Melab.And Clin.Nutr.Kyoto Univ.School of Med., 医学研究科, 助教授 (80212893)
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| Project Period (FY) |
1996 – 1997
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| Keywords | Pancreatic beta cells / insulin secretion / diabetes mellitus / patch clamp technique / voltage-dependent Ca^<2+> channel / intracellular calcium / oral hypoglycemic agents |
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| Research Abstract |
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.
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