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Mechanism of proliferation, differentiation, and dedifferentiation of pancreatic beta-cells induced by local signals

Research Project

Project/Area Number 19K07281
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 48020:Physiology-related
Research InstitutionChiba University

Principal Investigator

MIKI Takashi  千葉大学, 大学院医学研究院, 教授 (50302568)

Co-Investigator(Kenkyū-buntansha) 李 恩瑛  千葉大学, 大学院医学研究院, 助教 (60583424)
波多野 亮  千葉大学, 大学院医学研究院, 助教 (60521713)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords糖尿病 / 膵島再生 / 膵β細胞 / 前駆細胞 / インスリン / 再生 / 幹細胞 / 脱分化
Outline of Research at the Start

糖尿病患者では進行性に膵β細胞の量と機能の低下が進行する。従って膵β細胞の再生促進は糖尿病の根治治療となり得る。申請者らは活発な膵島再生を誘導可能な膵島再生マウスと膵β細胞の脱分化を誘導できる擬膵島移植マウスを樹立し、レーザーキャプチャーマイクロダイセクション法(LCM法)を用いた再生膵島の遺伝子発現解析法を確立した。本研究では、これらの動物モデルと実験系を組み合わせて、局所環境の変化により惹起される膵β細胞の増殖・分化・脱分化の制御機構の解明を目指す。

Outline of Final Research Achievements

Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia, and deterioration of pancreatic beta-cells both in quantity and in quality is central to its pathophysiology. By contrast, mass and function of beta-cells are known to be unaltered throughout live in healthy subjects. Therefore, medical intervention to recover their mass and function can be its radical therapy. However, its precise mechanism remains unknown. In the present study, we elucidated the mechanism of beta-cell regeneration by using our murine model of beta-cell ablation. As a result, we found that beta-cell reduction triggers the proliferation of the residual beta-cells, and that the mode of beta-cell regeneration differs depending on the local cellular circumstances during regeneration. Notably, alteration in cellular arrangement inside the islets triggers the active, repetitive cell proliferation of a small number of beta-cells through de-differentiation, proliferation, and re-differentiation.

Academic Significance and Societal Importance of the Research Achievements

膵島再生は糖尿病の根治治療となり得るが、実際の生体で、膵β細胞が膵島再生を担うだけの十分な再生能を有しているのか。どの様な方法で再生を人為的に誘導できるのかなど、基本的な疑問が未解決である。正常状態での膵島量の制御機構と、膵β細胞の増殖機構を解明することは、これらの課題を解決する上で、不可欠な学術的な基盤である。今回の結果は、成体のマウスにおいては反復して細胞分裂が可能な膵β細胞が存在することが示され、膵島再生による糖尿病の根治治療の可能性を指示する結果となった。また、再生誘導法の違いにより異なった機序の再生が惹起されることが示された点も重要な成果であると考えている。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (33 results)

All 2022 2021 2020 2019 Other

All Int'l Joint Research (5 results) Journal Article (7 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 7 results,  Open Access: 6 results) Presentation (18 results) (of which Int'l Joint Research: 3 results,  Invited: 6 results) Book (1 results) Remarks (2 results)

  • [Int'l Joint Research] ケンブリッジ大学/オクスフォード大学(英国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] トロント大学(カナダ)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] Cambridge大学/Oxford大学(英国)

    • Related Report
      2020 Research-status Report
  • [Int'l Joint Research] University of Toronto(カナダ)

    • Related Report
      2019 Research-status Report
  • [Int'l Joint Research] Cambridge University(英国)

    • Related Report
      2019 Research-status Report
  • [Journal Article] GPR52 accelerates fatty acid biosynthesis in a ligand-dependent manner in hepatocytes and in response to excessive fat intake in mice2021

    • Author(s)
      Wada, M., Yukawa, K., Ogasawara, H. Suzawa, K., Maekawa, T., Yamamoto, Y., Ohta, T., Lee, E., Miki, T.
    • Journal Title

      iScience

      Volume: 24 Issue: 4 Pages: 102260-102260

    • DOI

      10.1016/j.isci.2021.102260

    • NAID

      120006997059

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Lack of Brain Insulin Receptor Substrate-1 Causes Growth Retardation, With Decreased Expression of Growth Hormone?Releasing Hormone in the Hypothalamus2021

    • Author(s)
      Hayashi Takanori、Kubota Tetsuya、Mariko Inoue、Takamoto Iseki、Aihara Masakazu、Sakurai Yoshitaka、Wada Nobuhiro、Miki Takashi、Yamauchi Toshimasa、Kubota Naoto、Kadowaki Takashi
    • Journal Title

      Diabetes

      Volume: 70 Issue: 8 Pages: 1640-1653

    • DOI

      10.2337/db20-0482

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Lecithin Inclusion by α-Cyclodextrin Activates SREBP2 Signaling in the Gut and Ameliorates Postprandial Hyperglycemia2021

    • Author(s)
      Lee Eunyoung、Zhang Xilin、Noda Tomoe、Miyamoto Junki、Kimura Ikuo、Tanaka Tomoaki、Sakurai Kenichi、Hatano Ryo、Miki Takashi
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Issue: 19 Pages: 10796-10796

    • DOI

      10.3390/ijms221910796

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Gs/Gq signaling switch in β cells defines incretin effectiveness in diabetes2020

    • Author(s)
      Oduori Okechi S.、Murao Naoya、Shimomura Kenju、Takahashi Harumi、Zhang Quan、Dou Haiqiang、Sakai Shihomi、Minami Kohtaro、Chanclon Belen、Guida Claudia、Kothegala Lakshmi、Tol? Johan、Maejima Yuko、Yokoi Norihide、Minami Yasuhiro、Miki Takashi、Rorsman Patrik、Seino Susumu
    • Journal Title

      Journal of Clinical Investigation

      Volume: 130 Issue: 12 Pages: 6639-6655

    • DOI

      10.1172/jci140046

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Deficiency of lysyl hydroxylase 2 in mice causes systemic endoplasmic reticulum stress leading to early embryonic lethality2019

    • Author(s)
      笠松厚志
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 512 Issue: 3 Pages: 486-491

    • DOI

      10.1016/j.bbrc.2019.03.091

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Gut microbiota confers host resistance to obesity by metabolizing dietary polyunsaturated fatty acids2019

    • Author(s)
      Miyamoto J, Igarashi M, Watanabe K, Karaki SI, Mukouyama H, Kishino S, Li X, Ichimura A, Irie J, Sugimoto Y, Mizutani T, Sugawara T, Miki T, Ogawa J, Drucker DJ, Arita M, Itoh H, Kimura I
    • Journal Title

      Nat Commun

      Volume: 10 Issue: 1 Pages: 1-15

    • DOI

      10.1038/s41467-019-11978-0

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Diet-Induced Obese Mice and Leptin-Deficient Lepob/ob Mice Exhibit Increased Circulating GIP Levels Produced by Different Mechanisms2019

    • Author(s)
      Lee Eunyoung、Miedzybrodzka Emily L.、Zhang Xilin、Hatano Ryo、Miyamoto Junki、Kimura Ikuo、Fujimoto Kosuke、Uematsu Satoshi、Rodriguez-Cuenca Sergio、Vidal-Puig Antonio、Gribble Fiona M.、Reimann Frank、Miki Takashi
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 20 Issue: 18 Pages: 4448-4448

    • DOI

      10.3390/ijms20184448

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 腸内細菌叢と宿主の代謝クロストーク2022

    • Author(s)
      三木隆司、李恩瑛、芳川隼登、波多野亮、宮本潤基、木村郁夫
    • Organizer
      第99回日本生理学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] グルコースとcAMPによるインスリン分泌の調節機構2021

    • Author(s)
      三木隆司
    • Organizer
      第94回日本内分泌学会年次学術集会
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 膵β細胞傷害モデルマウスを用いた膵島再生機構の解析2021

    • Author(s)
      波多野亮, 張錫麟, 馬玉潔, 陳雪, 李恩瑛, 金田篤志, 三木 隆司
    • Organizer
      日本薬学会大会第141回年会
    • Related Report
      2021 Annual Research Report 2020 Research-status Report
  • [Presentation] Investigation of molecular mechanisms in pancreatic β cell regeneration using β-cell-specific injured mice2021

    • Author(s)
      波多野亮、張 錫麟、馬 玉潔、陳 雪、李 恩瑛、金田篤志、三木隆司
    • Organizer
      第126回 日本解剖学会総会・全国学術集会第98回 日本生理学会大会合同大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Adult murine pancreatic b cells retain repetitive proliferation capacity in a diphtheria toxin mediated β cell ablation model2021

    • Author(s)
      Xue Chen, Xilin Zhang, Ryo Hatano, Yujie Ma, Atsushi Kaneda, Eunyong Lee, Takashi Miki
    • Organizer
      第94回日本生化学会大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Regulation of fatty acid biosynthesis in liver through GPR52 signaling.2021

    • Author(s)
      Mitsuo Wada, Kayo Yukawa, Hiroyuki Ogasawara, Koichi Suzawa, Tatsuya Maekawa, Yoshihisa Yamamoto, Takeshi Ohta, Eunyoung Lee, Takashi Miki
    • Organizer
      第98回日本生理学会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] Investigation of molecular mechanisms in pancreatic β cell regeneration using β-cell-specific injured mice.2021

    • Author(s)
      Ryo Hatano, Xillin Zhang, Chen Xue, Eunyoung Lee, Atsushi Kaneda, Takashi Miki
    • Organizer
      第98回日本生理学会大会
    • Related Report
      2020 Research-status Report
  • [Presentation] レーザーマイクロダイセクション法による膵島再生の分子機構の解明2020

    • Author(s)
      張錫麟、波多野亮、李恩瑛、金田篤志、三木隆司
    • Organizer
      第63回日本糖尿病学会年次学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] 膵β細胞再生の分子機構2020

    • Author(s)
      三木隆司、波多野亮、張錫麟、陳雪、馬玉潔、金田篤志、李恩瑛
    • Organizer
      令和2年度生理研研究会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] エズリンの腎近位尿細管における膜タンパク質の局在制御と溶質再吸収調節機構2020

    • Author(s)
      波多野亮、高山実樹子、川口高徳、福富俊之、木村徹、櫻井裕之、李恩瑛、三木隆司、浅野真司
    • Organizer
      第97回日本生理学会大会
    • Related Report
      2019 Research-status Report
  • [Presentation] 足場タンパク質エズリンの腎近位尿細管再吸収機能制御について2020

    • Author(s)
      波多野亮、高山実樹子、川口高徳、福富俊之、木村徹、櫻井裕之、三木隆司、浅野真司
    • Organizer
      日本薬学会第139年会
    • Related Report
      2019 Research-status Report
  • [Presentation] 脂肪組織の代謝シグナルによる糖調節機構2019

    • Author(s)
      李恩瑛、三木隆司
    • Organizer
      第62回日本糖尿病学会年次学術集会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] 腸内分泌細胞における糖感知の分子機構2019

    • Author(s)
      三木隆司
    • Organizer
      第249回生理学会東京談話会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] istinct mechanism for the elevation of plasma glucose-dependent insulinotropic polypeptide by high-fat-diet and by leptin-deficiency2019

    • Author(s)
      Eun-Young Lee, Xilin Zhang, Junki Miyamoto, Ikuo Kimura, Ryo Hatano, Takashi Miki
    • Organizer
      54th EASD Annual Meeting
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Ezrin regulates multiple solutes reabsorption via the regulation of membrane protein localization in the proximal tubules2019

    • Author(s)
      Hatano R, Kawaguchi K, Miki T, Asano S
    • Organizer
      ASN Kidney Week 2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] 腸管内の栄養素感知とインクレチン分泌制御2019

    • Author(s)
      三木隆司、李恩瑛、宮本潤基、木村郁夫
    • Organizer
      生体機能と創薬シンポジウム2019/日本薬学会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] 肥満における高GIP血症の発症機序2019

    • Author(s)
      李恩瑛、張錫麟、宮本潤基、木村郁夫、波多野亮、三木隆司
    • Organizer
      第62回日本糖尿病学会年次学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] 腎近位尿細管溶質再吸収制御におけるエズリンの新たな役割について2019

    • Author(s)
      波多野亮、高山実樹子、川口高徳、福富俊之、木村徹、櫻井裕之、三木隆司、浅野真司
    • Organizer
      第249回生理学会東京談話会
    • Related Report
      2019 Research-status Report
  • [Book] ギャノング生理学 原書26版2022

    • Author(s)
      岡田 泰伸、佐久間 康夫、岡村 康司
    • Total Pages
      910
    • Publisher
      丸善出版
    • ISBN
      9784621307083
    • Related Report
      2021 Annual Research Report
  • [Remarks] 千葉大学大学院医学研究院代謝生理学研究室ホームページ

    • URL

      https://www.m.chiba-u.ac.jp/class/physiol/

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
  • [Remarks] 千葉大学大学院医学研究院代謝生理学ホームページ

    • URL

      https://www.m.chiba-u.ac.jp/class/physiol/

    • Related Report
      2019 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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