Elucidation of molecular mechanisms of beta-cell proliferation by the liver-beta cell inter-organ neuronal network

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K09816
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Tohoku University
• Principal Investigator: Imai Junta 東北大学, 医学系研究科, 准教授 (80431500)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: 膵β細胞 / インスリン / 迷走神経

Outline of Final Research Achievements

Previously, we discovered that pancreatic vagal nerve signals, elicited by liver-β cell inter-organ neuronal network, play critical roles in triggering compensatory β cell proliferation during obesity development. In this project, we explored the molecular mechanism(s) by which vagal signals enhance β cell proliferation. The FoxM1 pathway was activated in pancreatic islets of obese mice, and β cell proliferation induced by obesity was blocked in β cell specific FoxM1 knockout mice. Suppression of the neuronal network blocked activation of β cell FoxM1 and thereby suppressed β cell proliferation in obese mice. Furthermore, combined treatment of pancreatic islets with pancreatic vagus-producing factors, such as acetylcholine and PACAP/VIP, activated the FoxM1 pathway and enhanced β cell proliferation, and these effects were abolished in islets from FoxM1βKO mice. These results demonstrate how vagal signals induce compensatory β cell proliferation in obesity settings.

Free Research Field

代謝学

Academic Significance and Societal Importance of the Research Achievements

本研究は研究代表者が独自に明らかにした肝臓―膵β細胞間神経ネットワークに着想を得て、膵迷走神経による膵β細胞増殖制御の分子メカニズムを明らかにしたものである。現在のところ、膵β細胞を増量する治療法は存在せず、これは糖尿病根治療法開発が進まない大きな要因となっている。迷走神経由来因子による膵β細胞増殖機構を明らかにしたことで、世界で初めての膵β細胞増量薬の開発につながる可能性がある。