Breakdown of MafA regulatory system leading to b-cell failure during type 2 diabetes progression
| Project/Area Number |
16K09763
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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 | Yokohama City University |
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Principal Investigator |
Kataoka Kohsuke 横浜市立大学, 生命医科学研究科, 准教授 (20262074)
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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 |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | 糖尿病 / 遺伝子発現調節 / 細胞内シグナル伝達 / 膵β細胞 / 遺伝子発現制御 / シグナル伝達 / 膵島β細胞 / タンパク質リン酸化 |
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| Outline of Final Research Achievements |
During progression of type 2 diabetes, pancreatic islet b-cells gradually lose their ability to secrete insulin in response to glucose. Loss or decrease of MafA transcription factor has been thought be responsible for the b-cell dysfunction. Here, we identified a intracellular system regulating MafA protein function and stability.
We found that an amino acid-related compound Taurine activates WNK kinase in b-cells, thereby maintains MafA protein levels. We also found that basal level autophagy is required for maintaining mafA mRNA transcription. Furthermore, glucocorticoid and related compounds inhibit ability of MafA-Beta2-HNF1b transcription factors to synergistically activate glut2 gene transcription. As Glut2 (glucose transporter 2) is an essential component of glucose-stimulated insulin secretion in b-cells, this mechanism may explain how steroids suppress b-cell function.
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| Academic Significance and Societal Importance of the Research Achievements |
２型糖尿病において、膵島β細胞の機能が次第に低下してインスリン分泌が減少してしまう問題について、その分子機構の解明を、β細胞の機能に必須な転写調節因子MafAに注目することによって行った。
MafAのタンパク質量を一定レベルに保つβ細胞内のシグナル伝達の仕組みを一部あきらかにした。また、mafA mRNAの発現レベルの維持には、意外なことにオートファジーが関係することを見出した。また当初の目的とは異なるが、MafAを対象とすることによって、ステロイドの副作用としてβ細胞の機能が低下する仕組みの一端を解明することもできた。
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Report
(4 results)
Research Products
(7 results)
