| Project/Area Number |
09470100
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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 |
Hygiene
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| Research Institution | Akita University School of Medicine |
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Principal Investigator |
KOIZUMI Akio School of Medicine, Akita University, Professor, 医学部, 教授 (50124574)
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| Co-Investigator(Kenkyū-buntansha) |
WADA Yasuhiko School of Medicine, Akita University, Associate Professor, 医学部, 助教授 (10261653)
IZUMI Tetsuro Molecular and Cellular Regulation, Gunma University, Associate Professor, 生体調節研究所, 助教授 (00212952)
ITO Masaki School of Medicine, Akita University, Professor, 医学部, 教授 (40126389)
NOZAKI Junichi School of Medicine, Akita University, Research Associate, 医学部, 助手 (90302265)
KAYO Tsuyoshi School of Medicine, Akita University, Associate Professor, 医学部, 講師 (40272033)
塚田 三香子 秋田大学, 医学部, 助手 (10221409)
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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 |
¥10,100,000 (Direct Cost: ¥10,100,000)
Fiscal Year 1999: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 1998: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1997: ¥6,700,000 (Direct Cost: ¥6,700,000)
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| Keywords | Akita mouse / Insulin / Akita / Protein folding / Diabetes / Protein sorting / defects in insulin secretion / Mody / 生理的役割 / ヒト糖尿病 / 予防 / 蛋白おりたたみ / Endoplasmic reticulum / インシュリン遺伝子 / Mody4 / ホモ / 増殖 / β細胞 / 新生児糖尿病 |
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| Research Abstract |
Animal models have provided useful tools to understand the mechanisms of human diseases. In the present study, we found a mechanism of diabetes in the Akita Mouse on molecular basis. The findings in the preset study may suggest a novel mechanism for diabetes and other diseases.
The Akita mouse develops diabetes by 10 weeks of age without insulin resistance or obesity. Pathological investigations have failed to detect autoimmune insulitis at any period in the course of diabetes. Electron microscopic observation revealed proliferation of endplasmic reticulum, vacuolation of cytoplasm, ballooning of mitochondria and scarce of mature insulin granules.
The diabetes showed a autosomal dominant mode of inheritance.
Linkage analysis of this trait revealed the responsible locus at the telemere portion of chromosome 7. Sequence analyses of one of the candidate genes in this region, insulin, was shown to have a mutation [TGC(Cys)->TAC(Tyr)] and thereby disrupting a disulfide bond between 6 th Cys on the a chain and 6 the Cys on the b chain.
Several insulin mutations has been reported and has been known as insulinopathy. Clinical features of insulinopathy is commonly associated with moderate glucose intolerance and hyperinsulinmeia but do not demonstrate Mody phenotype.
In the rodents, there are 4 alleles of insulin in the diploid genome. The mutation of one insulin locus, even if it leads to a complete loss of function of insulin, would decrease insulin amounts by only 25%. Thus unless a some type of a "gain of function" mutation is postulated, it is hard to explain an early-onset overt diabetes with an autosomal dominant mode of inheritance.
The Akita mouse strain thus may be a very useful tool for investigating the pathological details associated with protein sorting and folding process.
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