The elucidation of the mechanisms underlying beta cell dedifferentiation and plasticity in diabetes
| Project/Area Number |
16K09752
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | Yamaguchi University |
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Principal Investigator |
TANABE Katsuya 山口大学, 医学部附属病院, 講師 (00397994)
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| Co-Investigator(Kenkyū-buntansha) |
谷澤 幸生 山口大学, 大学院医学系研究科, 教授 (00217142)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 糖尿病 / 膵β細胞 / 小胞体ストレス / 脱分化 / Wolfram症候群 / インスリン / 膵β細胞不全 / WFS1 / Wfs1 |
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| Outline of Final Research Achievements |
Insulin deficiency is thought to be caused by both pancreatic β cell dysfunction and decreased β cell mass. β cell loss is associated with augmented ER and oxidative stresses in Wolfram syndrome. In the Wfs1 deficient mice, β cells become dedifferentiated and revert to endocrine progenitor-like cells. This appears after nursing, independently of hyperglycemia, and becomes more apparent along with diabetes progression. Wfs1 deficient islets demonstrated decreased ATP production due to impaired glucose catabolism. This was corrected by genetic inhibition of Txnip. Importantly, ablation of Txnip prevented β cell dedifferentiation and maintained glucose homeostasis associated with preserved beta cell mass in the Wfs1 deficient mice. Thus, these finding provide new insights into molecular mechanisms underlying β cell loss in diabetes related to cellular stresses, such as Wolfram syndrome.
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| Academic Significance and Societal Importance of the Research Achievements |
Wfs1欠損マウスはβ細胞脱分化を明瞭に示し、β細胞以外の因子、例えば高血糖の関与を排除できるため、このマウスで示される脱分化の分子病態が、他のマウスモデルやヒトでの脱分化と膵β細胞機能不全の病態解明を促進するとともに膵β細胞の生物学への理解を一層深める。WFS1遺伝子はWolfram症候群の原因遺伝子であるが、2型糖尿病遺伝子としても認知されており、両疾患でのβ細胞不全の成因について共通する部分も多い。そのため、本研究はWolfram症候群のみならず2型糖尿病のβ細胞の病態理解や進展阻止に向けた治療法開発への貢献が期待できる。
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Report
(4 results)
Research Products
(19 results)
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[Book] 月刊 糖尿病2017
Author(s)
田部勝也、松永仁恵、椎木幾久子、谷澤幸生
Total Pages
9
Publisher
医学出版
ISBN
9784287820988
Related Report
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[Book] 月刊 糖尿病2017
Author(s)
椎木幾久子、田部勝也、谷澤幸生
Total Pages
9
Publisher
医学出版
ISBN
9784287820971
Related Report
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