| Project/Area Number |
19K08970
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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 | Gunma University |
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Principal Investigator |
Kikuchi Osamu 群馬大学, 生体調節研究所, 研究員 (40739009)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | グルカゴン / Sirt1 / 膵α細胞 / 糖尿病 |
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| Outline of Research at the Start |
近年、糖尿病発症の原因としてグルカゴン分泌異常が重要視されている。申請者は糖尿病におけるグルカゴン分泌異常の発症機序としてSirt1に着目し、「エネルギーセンサー分子であるSirt1の高血糖曝露下での発現・活性の低下がα細胞におけるグルカゴン分泌異常を引き起こす」という仮説を立てた。本研究では①LC-MS/MSによる高特異性グルカゴン濃度測定法、②グルコースクランプ法、③セルソーターを用いた単離α細胞の回収という3つの手法を用いて、膵α細胞特異的Sirt1遺伝子改変マウスの表現型解析を行うことで仮説の検証をし、糖尿病発症に伴うグルカゴン分泌異常の機序の解明を目指す。
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| Outline of Final Research Achievements |
Sirt1, known as an energy sensor, regulates pancreatic β cell proliferation and insulin secretion However, the roles of Sirt1 in α cells are still unclear. Thus, we investigated the roles of Sirt1 in α cell proliferation and glucagon secretion.
We generated α cell specific Sirt1 knockout(αSKO) mice. α cell mass in αSKO mice was significantly increased compared to the control mice. Although recovery from insulin-induced hypoglycemia was impaired in αSKO mice due to decreased plasma glucagon secretion. Hyperinsulinemic-hypoglycemic clamp revealed that αSKO mice have lower hepatic glucose production (HGP) and lower plasma glucagon concentration than the control mice at 60 min after insulin injection. However, at 120 min after insulin injection, HGP and plasma glucagon concentration were rather increased in αSKO mice compared to the control mice. These results suggest that Sirt1 inhibits α cell proliferation, whereas accelerates glucagon secretion in α cells.
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| Academic Significance and Societal Importance of the Research Achievements |
近年、糖尿病病態におけるグルカゴンの役割は重要視されつつある。糖尿病で見らえるグルカゴン分泌異常のメカニズムの一部を解明した本研究の学術的意義は大きい。また、グルカゴンをターゲットとした糖尿病治療薬の分子標的としてSirt1やその下流因子を同定出来たことは社会的な意義も大きい。
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