New pathogenesis of diabetes mellitus : Role of endoplasmic reticulum stress mediated apoptosis on pancreatic β-cells
| Project/Area Number |
14370339
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | Kumamoto University |
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Principal Investigator |
ARAKI Eiichi Kumamoto University, Department of Medicine, Professor, 大学院・医学薬学研究部, 教授 (10253733)
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| Co-Investigator(Kenkyū-buntansha) |
NISHIKAWA Takeshi Kumamoto University, Department of Medicine, Investigator, 大学院・医学薬学研究部, 助手 (70336212)
SAKAKIDA Michiharu Kumamoto University, Department of Medicine, Associate Professor, 大学院・医学薬学研究部, 助教授 (50170577)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥14,900,000 (Direct Cost: ¥14,900,000)
Fiscal Year 2003: ¥7,200,000 (Direct Cost: ¥7,200,000)
Fiscal Year 2002: ¥7,700,000 (Direct Cost: ¥7,700,000)
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| Keywords | Endoplasmic reticulum stress / Apoptosis / Diabetes mellitus / CHOP / Akita mouse / OLETF rat / pancreatic β-cell / MIN6 |
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| Research Abstract |
Accumulating evidences suggest that disturbance of endoplasmic function leads to cell death through apoptosis mechanism. This study was undertaken to reveal the role of endoplasmic reticulum stress in the pathogenesis of diabetes.
The Akita mouse is a diabetic model mouse with a missense mutation in insulin 2 gene. This mutation may cause a heavy conformational change of insulin, and disturb endoplasmic reticulum function. The mRNAs of endoplasmic reticulum chaperone Bip and apoptosis factor CHOP were induced in the pancreas of Akita mouse at early stage of diabetes. Disruption of the CHOP gene in the heterozygous Akita mouse could protect β-cells from apoptosis, which delayed the onset of diabetes. Over expression of the mutant insulin in MIN6 cells, a mouse β-cell line, induced CHOP expression and led to apoptosis.
These results suggested that endoplasmic reticulum overload in β-cells can cause endoplasmic reticulum stress and leads to apoptosis via CHOP induction in vivo.
The endoplasmic reticulum stress was also evaluated in the type 2 diabetic model rat (OLETF) and control rat (LETO). The OLETF rat showed higher body weight, blood glucose, serum insulin concentration than those of LETO rat after 12 weeks of age. The OLETF rat showed higher expression of Bip and CHOP mRNAs in the β-cells than those in LETO rat.
These results suggested that the pathway of endoplasmic reticulum stress mediated β-cell apoptosis was involved in the pathogenesis of diabetes in OLETF rat.
This study suggests the importance of endoplasmic reticulum stress in the cause of diabetes.
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Report
(3 results)
Research Products
(14 results)
