2022 Fiscal Year Final Research Report
Evaluatiion of the effect of Japanese type 2 diabetes susceptibility gene GCN2 on pancreatic beta cell function.
| Project/Area Number |
20K08906
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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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| Review Section |
Basic Section 54040:Metabolism and endocrinology-related
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| Research Institution | Kobe University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
木戸 良明 神戸大学, 保健学研究科, 教授 (10335440)
堀 裕一 神戸大学, 保健学研究科, 教授 (80248004)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Keywords | GCN2 / 膵β細胞 / mTORC1活性 |
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| Outline of Final Research Achievements |
EIF2AK4, which encodes the amino acid deficiency-sensing protein GCN2, has been implicated as a susceptibility gene for type 2 diabetes in the Japanese population. However, the mechanism by which GCN2 affects glucose homeostasis is unclear.
l-Asparaginase, which is expressed downstream of GCN2, was found to bind 14-3-3 and thereby to inhibit its binding to the T1462 phosphorylation site of TSC2 and contribute to TSC2 activation and mTORC1 inactivation upon TSC2 dephosphorylation.
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| Free Research Field |
糖尿病
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| Academic Significance and Societal Importance of the Research Achievements |
日本人2型糖尿病患者とGCN2のSNPとの関連が報告されており、日本人2型糖尿病患者に近い生理的な動態としてβGCN2-/-マウスを用いた解析を行った。本研究において、高脂肪食負荷下では、インスリン需要が増大し、膵β細胞におけるインスリン合成が亢進しアミノ酸濃度が減少することにより、GCN2のリン酸化が惹起され、mTORC1活性の調整がSestrin2やL-asparaginaseを介して行われる新たなメカニズムの存在が示唆された。
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