Pathophysiological analyses of functional subtypes in pancreatic alpha-cells

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08511
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Osaka University
• Principal Investigator: Kawamori Dan 大阪大学, 医学部附属病院, 准教授 (50622362)
• Co-Investigator(Kenkyū-buntansha): 松岡 孝昭 大阪大学, 医学系研究科, 准教授 (10379258)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: グルカゴン / 糖尿病 / GLP-1 / DPP-4 / ストレス応答 / 膵α細胞

Outline of Final Research Achievements

In this research project, we aimed to validate a hypothesis; the pancreatic α-cells exhibit different subtypes, and a functional shift of α-cells contributes to the pathophysiological exacerbation of diabetes via excessive glucagon secretion together with impaired intra-islet effects of GLP-1. Using an in vitro model of α-cells by glucagon-secreting InR1G cells, we confirmed an excessive glucagon secretion by 12-h chronic high-glucose load to the cells while GLP-1 secretion was not. On the other hand, we picked up an incretin-degradation enzyme DPP-4 as a candidate responsible for the alteration of glucagon and GLP-1 secretion since 24-h glucose load to the cells significantly and reproducibly upregulated DPP-4 gene expression. The results of the project indicated the significance of pancreatic α-cell functions including various hormone secretions, which may lead us to the development of new therapeutic approach to diabetes targeting α-cells.

Free Research Field

糖尿病学

Academic Significance and Societal Importance of the Research Achievements

大きな社会健康問題である糖尿病では、様々な治療アプローチが可能な一方、その病態の多様性から最適な治療法選択と疾患コントロールに難渋することも少なくない。本研究成果は、糖尿病病態を「グルカゴン分泌異常と膵α細胞機能変容」という新たな視点から捉えた新規治療標的の同定につながるものとして、糖尿病学における学術的意義のみならず、将来の治療法開発に向けた研究基盤としての社会的意義を有するものと考えられる。