| Project/Area Number |
09671048
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
内分泌・代謝学
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| Research Institution | Kyorin University (1998-1999)
Kyoto University (1997) |
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Principal Investigator |
ISHIDA Hitoshi Professor, Third Department of Internal Medicine, Kyorin University, 医学部, 教授 (80212893)
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| Co-Investigator(Kenkyū-buntansha) |
NAGAMATSU Shinya Associate Professor, Second Department of Biochemistry, Kyorin University, 医学部, 助教授 (80231489)
清野 裕 京都大学, 医学研究科, 教授 (40030986)
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| Project Period (FY) |
1997 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 1999: ¥300,000 (Direct Cost: ¥300,000)
Fiscal Year 1998: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1997: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Keywords | diabetes mellitus / insulin secrction / intraccllular calcium / SNARE protcins / calmodulin / cyclic AMP / ATP-sensitive KィイD1+ィエD1 channel / voltage-dependent calcium channel / 電位依存性Ca^<2+>チャネル / 細胞内情報伝達系 / バッチクランプ法 / 膵β細胞 / 電位依存性CA^<2+>チャネル / ブドウ糖 / 細胞内Ca^<2+>濃度 / パッチクランプ法 |
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| Research Abstract |
In order to elucidate the molecular mechanism of impairment of glucose-induced insulin secretion in type 2 diabetes mellitus, we examined the altered expression of SNARE proteins (syntaxin 1A and SNAP-25), which are known to play an important role on exocytolic process of insulin secretary granules as sensor molecules for the intracellular CaィイD12+ィエD1 elevation and metabolic signals derived from glucose, in diabetic GK (Goto-Kakizaki) rats. Immunoblot analysis revealed that protein levels of syntaxin 1A and SNAP-25 in GK rat islets decreased to 〜60% of the levels in control rat islets. Restoration of these proteins to normal levels in GK rats was achieved via the recombinant adenovirus-mediated gene transduction system. Glucose-stimulated insulin release from Adex 1CA syntaxin 1A and Adex 1CA SNAP-25-infected GK rat islets increased up to those from normal rat islets. The decreased expression of SNARE proteins is at least in part the defect responsible for impaired insulin secretion. For the screening of the agents, which can augment the CaィイD12+ィエD1 sensitivity of exocytotic mechanism of insulin secretory granules, pimobendan and JTT-608 were examined. Both of them increased the glucose-induced insulin secretion dose-dependently. Using electrically permeabilized rat pancreatic islets, they augmented the sensitivity for intracellular CaィイD12+ィエD1 elevation to trigger the exocytosis. It is revealed that pimobendan can exhibit its effect by in part activating CaィイD12+ィエD1/calmodulin dependent protein kinase II, and that JTT-608 can do it by inhibiting phosphodiesterase activity to increase intracellular cAMP levels. Accordingly, these agents would become novel therapeutic means for the treatment of impaired insulin secretion in type 2 diabetes mellitus.
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