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

• 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
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 膵β細胞 / インスリン / 迷走神経 / 糖尿病 / 肥満症

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.

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。

Research Products

• [Journal Article] Regulation of compensatory β-cell proliferation by inter-organ networks from the liver to pancreatic β-cells (2018)
  • Author(s): Imai J
  • Journal Title: Endocrine Journal Volume: 65 Issue: 7 Pages: 677-684
  • DOI: 10.1507/endocrj.EJ18-0241
  • NAID: 130007420731
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed
• [Journal Article] Selective insulin resistance with differential expressions of IRS-1 and IRS-2 in human NAFLD livers. (2018)
  • Author(s): Honma M, Sawada S, Ueno Y, Murakami K, Yamada T, Gao J, Kodama S, Izumi T, Takahashi K, Tsukita S, Uno K, Imai J, Kakazu E, Kondo Y, Mizuno K, Kawagishi N, Shimosegawa T, Katagiri H.
  • Journal Title: Int J Obes (Lond). Volume: 印刷中 Issue: 9 Pages: 1544-1555
  • DOI: 10.1038/s41366-018-0062-9
  • Peer Reviewed / Open Access
• [Journal Article] 肝臓ー膵β細胞間神経ネットワークによるβ細胞制御の分子機構 (2018)
  • Author(s): 今井淳太
  • Journal Title: Islet Equality Volume: 7 Pages: 16-19
• [Journal Article] Olfactory receptors are expressed in pancreatic beta-cells and promote glucose-stimulated insulin secretion. (2018)
  • Author(s): Munakata Y, Yamada T, Imai J, Takahashi K, Tsukita S, Shirai Y, Kodama S, Asai Y, Sugisawa T, Chiba Y, Kaneko K, Uno K, Sawada S, Hatakeyama H, Kanzaki M, Miyazaki JI, Oka Y, Katagiri H
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 1499-1499
  • DOI: 10.1038/s41598-018-19765-5
  • Peer Reviewed / Open Access
• [Journal Article] Serum cystatin C level is associated with carotid arterial wall elasticity in subjects with type 2 diabetes mellitus: A potential marker of early-stage atherosclerosis. (2018)
  • Author(s): Kaneko R, Sawada S, Tokita A, Honkura R, Tamura N, Kodama S, Izumi T, Takahashi K, Uno K, Imai J, Yamada T, Miyachi Y, Hasegawa H, Kanai H, Ishigaki Y, Katagiri H
  • Journal Title: Diabetes Research and Clinical Practice Volume: 139 Pages: 43-51
  • DOI: 10.1016/j.diabres.2018.02.003
  • Peer Reviewed / Open Access
• [Journal Article] 中枢―臓器連関による膵β細胞制御機構ー肝臓ー膵β細胞間神経ネットワークー (2018)
  • Author(s): 今井淳太、片桐秀樹
  • Journal Title: 最新医学 Volume: 73 Pages: 30-36
• [Journal Article] Neuronal signals regulate obesity induced beta-cell proliferation by FoxM1 dependent mechanism. (2017)
  • Author(s): Yamamoto J, Imai J, Izumi T, Takahashi H, Kawana Y, Takahashi K, Kodama S, Kaneko K, Gao J, Uno K, Sawada S, Asano T, Kalinichenko VV, Susaki EA, Kanzaki M, Ueda HR, Ishigaki Y, Yamada T, Katagiri H
  • Journal Title: Nature Communications Volume: 8 Issue: 1 Pages: 1930-1930
  • DOI: 10.1038/s41467-017-01869-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] インスリン抵抗性時に膵β細胞増殖を制御する肝臓由来シグナル (2017)
  • Author(s): 今井淳太
  • Journal Title: 肝胆膵 Volume: 75 Pages: 905-910
• [Journal Article] 糖尿病とピロリ菌感染 (2017)
  • Author(s): 今井淳太、片桐秀樹
  • Journal Title: Diabetes Frontier Volume: 28 Pages: 427-431
• [Journal Article] Ｂ型インスリン抵抗症：インスリン受容体抗体による糖尿病 (2017)
  • Author(s): 今井淳太
  • Journal Title: 月刊糖尿病 Volume: 9 Pages: 74-79
• [Presentation] Regulation of pancreatic beta-cells by vagal nerve signals (2018)
  • Author(s): 今井淳太、山本淳平、井泉知仁、片桐秀樹
  • Organizer: 第91回日本内分泌学会
  • Invited
• [Presentation] Regulation of Compensatory Beta-cell Proliferation by Vagal Nerve Signals (2018)
  • Author(s): Imai J
  • Organizer: 2018 Asia Islet Biology&Incretin Symposium
  • Int'l Joint Research / Invited
• [Remarks] 東北大学大学院医学系研究科 糖尿病代謝内科学分野
  • URL: http://www.diabetes.med.tohoku.ac.jp/