| Project/Area Number |
25860754
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Metabolomics
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| Research Institution | Yokohama City University |
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Principal Investigator |
SHIRAKAWA JUN 横浜市立大学, 医学(系)研究科(研究院), 客員研究員 (70625532)
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| Project Period (FY) |
2013-04-01 – 2015-03-31
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| Project Status |
Completed (Fiscal Year 2014)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2013: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
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| Keywords | 膵β細胞 / 糖尿病 / アポトーシス / 小胞体ストレス / 2型糖尿病 / 炎症 / グルコキナーゼ |
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| Outline of Final Research Achievements |
Glucokinase upregulates insulin receptor substrate 2 (IRS-2) expression in beta-cells, but the role of glucokinase and IRS-2 in ER stress has been unclear. In this study, we investigated the impact of glucokinase activation by glucokinase activator (GKA) on ER stress in beta-cells. GKA administration improved beta-cell apoptosis in Akita mice, a model of ER stress-mediated diabetes. IRS-2-deficient islets were vulnerable, but bIRS-2-Tg islets were resistant to ER stress-induced apoptosis. Meanwhile, GKA regulated the expressions of C/EBP homologous protein (CHOP) and other ER stress-related genes in an IRS-2-independent fashion in islets. GKA suppressed the expressions of CHOP and Bcl2-associated X protein (Bax) and protected against beta-cell apoptosis under ER stress in an ERK1/2-dependent, IRS-2-independent manner. Taken together, GKA ameliorated ER stress-mediated apoptosis by harmonizing IRS-2 upregulation and the IRS-2-independent control of apoptosis in beta-cells.
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