The role of Epac2/Rap1 signaling in the three-dimensional construction of pancreatic islets

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07400
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Kobe University
• Principal Investigator: Takahashi Harumi 神戸大学, 医学研究科, 特命准教授 (50546489)
• Co-Investigator(Kenkyū-buntansha): 柴崎 忠雄 神戸大学, 医学研究科, 客員准教授 (00323436)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 膵島 / 膵β細胞 / Epac2 / cAMP

Outline of Final Research Achievements

Insulin secretion from pancreatic β-cell is regulated by various factors such as glucose, hormones, and neuronal signals. Three-D structure of islets is also known to be important for regulation of islet hormone secretion. In this study, the mechanisms of cell-cell interaction and cell adhesion of pancreatic islets was investigated. We focused on the role of Epac2/Rap1 signaling in cell adhesion in islets. We have found that β-cells expressed not only Epac2A, an isoform previously identified, but also a novel isoform that has similar domain structure to Epac2B which is lacking N-terminal cAMP binding domain. The results from the studies using Epac2-deficient β-cell lines, partial knockout (KO) cells in which only Epac2A is absent, and complete KO cells in which all Epac2 isoforms are ablated, suggested that Epac2A mediates mainly insulin secretion by cAMP signaling, while novel Epac2 isoform is predominantly involved in cell adhesion and cell-cell interaction in pancreatic islets.

Free Research Field

代謝内分泌学

Academic Significance and Societal Importance of the Research Achievements

本研究の成果は膵島における細胞接着および三次元構造維持のメカニズム解明に繋がるものであり、糖尿病の病態解明のみならず、新たな治療標的の発見や新規治療戦略確立の基礎となり得る。また、膵島構造の維持がインスリン分泌等の機能維持にも重要であることから、効果的な膵島形成や膵島機能維持法など、膵β細胞の再生医療や膵島移植への応用も期待できる。以上のことから臨床医学的な意義が大きい。