Sirt1 regulates pancreatic alpha cell proliferation and glucagon secretion

Research Project

Project/Area Number	17K16140
Research Category	Grant-in-Aid for Young Scientists (B)
Allocation Type	Multi-year Fund
Research Field	Metabolomics
Research Institution	Gunma University
Principal Investigator	Kikuchi Osamu 群馬大学, 生体調節研究所, 研究員 (40739009)
Project Period (FY)	2017-04-01 – 2019-03-31
Project Status	Completed (Fiscal Year 2018)
Budget Amount *help	¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000) Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000) Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywords	グルカゴン / Sirt1
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.
Academic Significance and Societal Importance of the Research Achievements	本研究は生体内でエネルギーセンサー分子として機能するSirt1に着目し、糖尿病で見られるグルカゴン分泌異常との関連を調べた。グルカゴン分泌細胞であるα細胞でSirt1を欠損させたマウスでは、低血糖時のグルカゴン分泌の障害が見られ、一方でα細胞量は増加した。これは糖尿病で見られるグルカゴン分泌異常と合致した結果であり、エネルギーセンサー分子Sirt1の発現低下がグルカゴン分泌異常の原因の一つであることが示唆された。この研究成果はグルカゴン分泌異常の治療薬開発につながる可能性もあり、社会的意義は大きいと考えられる。