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

Research Project

Project/Area Number 19K07400
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 49010:Pathological biochemistry-related
Research InstitutionKobe 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
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膵島 / 膵β細胞 / Epac2 / cAMP / 糖尿病 / インスリン分泌
Outline of Research at the Start

膵β細胞からのインスリン分泌は生体の糖恒常性維持において重要である。本研究では、膵島の三次元構造の形成・維持の分子機構を、特にインクレチン/cAMPの下流シグナルであるEpac2/Rap1による細胞接着制御機構に焦点を当てて明らかにすることを目的とする。本研究の成果は膵島構造から見た糖尿病の病態解明のみならず、糖尿病治療薬として広く使用されるインクレチン関連薬のこれまで知られていなかった作用の解明および新たな治療戦略の確立に貢献することが期待される。

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.

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。

Report

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

    (36 results)

All 2022 2021 2020 2019

All Journal Article (8 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 7 results,  Open Access: 7 results) Presentation (28 results) (of which Int'l Joint Research: 5 results,  Invited: 5 results)

  • [Journal Article] Increased glycolysis affects β-cell function and identity in aging and diabetes2022

    • Author(s)
      Murao N, Yokoi N, Takahashi H, Hayami T, Minami Y, Seino S
    • Journal Title

      Mol Metabolism

      Volume: 55 Pages: 101014-101014

    • DOI

      10.1016/j.molmet.2021.101414

    • NAID

      120007188923

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] O-GlcNAcylation of myocyte-specific enhancer factor 2D negatively regulates insulin secretion from pancreatic β-cells2022

    • Author(s)
      Yoshida M, Yokoi N, Takahashi H, Hatano N, Hayami T, Ogawa W, Seino S
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 605 Pages: 90-96

    • DOI

      10.1016/j.bbrc.2022.03.036

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Glutamate is an essential mediator in glutamine‐amplified insulin secretion2021

    • Author(s)
      Han Guirong、Takahashi Harumi、Murao Naoya、Gheni Ghupurjan、Yokoi Norihide、Hamamoto Yoshiyuki、Asahara Shun‐ichiro、Seino Yutaka、Kido Yoshiaki、Seino Susumu
    • Journal Title

      Journal of Diabetes Investigation

      Volume: - Issue: 6 Pages: 920-930

    • DOI

      10.1111/jdi.13497

    • NAID

      120007097043

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] インスリン分泌機構-糖尿病の膵β細胞におけるGタンパク質シグナル変換の意義2021

    • Author(s)
      高橋晴美、オドゥオリ オケチ、清野 進
    • Journal Title

      医学のあゆみ

      Volume: 276(5) Pages: 364-370

    • Related Report
      2020 Research-status Report
  • [Journal Article] Tumor-like features of gene expression and metabolic profiles in enlarged pancreatic islets are associated with impaired incretin-induced insulin secretion in obese diabetes: a study of ZFDM rat.2020

    • Author(s)
      Hayami T, Yokoi N, Yamaguchi T, Honda K, Murao N, Takahashi H, Wang S, Seino Y, Kamiya H, Yabe D, Sweet IR, Mizoguchi A, Nakamura J, Seino S
    • Journal Title

      J Diabetes Investig

      Volume: - Issue: 6 Pages: 1434-1447

    • DOI

      10.1111/jdi.13272

    • Related Report
      2020 Research-status Report 2019 Research-status 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] Glutamate as intracellular and extracellular signals in pancreatic islet functions2019

    • Author(s)
      Takahashi H, Yokoi N, Seino S
    • Journal Title

      Proceedings of the Japan Academy, Series B

      Volume: 95 Issue: 6 Pages: 246-260

    • DOI

      10.2183/pjab.95.017

    • NAID

      130007662352

    • ISSN
      0386-2208, 1349-2896
    • Year and Date
      2019-06-11
    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Glucose stimulates somatostatin secretion in pancreatic δ-cells by cAMP-dependent intracellular Ca2+ release.2019

    • Author(s)
      Denwood G, Tarasov A, Salehi A, Vergari E, Ramracheya R, Takahashi H, Nikolaev VO, Seino S, Gribble F, Reimann F, Rorsman P, Zhang Q
    • Journal Title

      J Gen Physiol

      Volume: 151(9) Issue: 9 Pages: 1094-1115

    • DOI

      10.1085/jgp.201912351

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 細胞内NAD代謝の変容が膵β細胞老化を制御する2021

    • Author(s)
      村尾 直哉、横井 伯英、高橋 晴美、清野 進
    • Organizer
      第64回日本糖尿病学会年次学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Gs/Gq signaling switch in diabetic β-cells2021

    • Author(s)
      高橋晴美、オドゥオリ オケチ、村尾直哉、清野 進
    • Organizer
      第64回日本糖尿病学会年次学術集会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] インスリン分泌の分子機構の解明と今後の展望2021

    • Author(s)
      高橋晴美、清野 進
    • Organizer
      第64回日本糖尿病学会年次学術集会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Metabolic Shift to Cytosolic NAD Production Regulates β-cell Function in Aging and Diabetes2021

    • Author(s)
      Naoya Murao, Norihide Yokoi, Harumi Takahashi, Susumu Seino
    • Organizer
      第64回日本糖尿病学会年次学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] インクレチン応答性インスリン分泌障害に関与する候補タンパク質の同定2021

    • Author(s)
      吉田 舞、横井伯英、波多野直哉、速水智英、高橋晴美、小川 渉、清野 進
    • Organizer
      第64回日本糖尿病学会年次学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Improvements of hyperglycemia and insulin secretion by chronic imeglimin treatment in an obese diabetes model KK-Ay mice2021

    • Author(s)
      権 映月、高橋晴美、村尾直哉、清野 進
    • Organizer
      第64回日本糖尿病学会年次学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 細胞内NAD代謝の変容が膵β細胞老化を制御する -SAMP1, SAMR1系統を用いた検討-2021

    • Author(s)
      村尾直哉,横井伯英,高橋晴美,清野 進
    • Organizer
      第36回老化促進モデルマウス(SAM)学会学術大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 新規Epac2アイソフォームの膵β細胞機能における役割2020

    • Author(s)
      高橋晴美、藤原結花、堰 千紘、横井伯英、清野 進
    • Organizer
      第63回日本糖尿病学会年次学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] グルタミンによるインスリン分泌増強機構の解明2020

    • Author(s)
      韓 桂栄、高橋晴美、村尾直哉、ゲニ グプルジャン、太田新菜、浜本芳之、清野 裕、横井伯英、木戸良明、清野 進
    • Organizer
      第63回日本糖尿病学会年次学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] 耐糖能ならびに膵β細胞機能の加齢性変化の解明2020

    • Author(s)
      村尾直哉、横井伯英、速水智英、高橋晴美、清野 進
    • Organizer
      第63回日本糖尿病学会年次学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] 肥満糖尿病の膵島における、タンパク質のO-結合型糖鎖修飾に関連したインクレチン応答性障害の機序の解明2020

    • Author(s)
      吉田 舞,横井伯英,速水智英,高橋晴美,小川 渉,清野 進
    • Organizer
      第63回日本糖尿病学会年次学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] SGLT阻害剤の全身の糖代謝に及ぼす作用の解明2020

    • Author(s)
      横井伯英、高橋晴美、清野 進
    • Organizer
      第63回日本糖尿病学会年次学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] 耐糖能および膵β細胞機能の加齢性変化の解明 -SAMP1, SAMR1, B6J系統を用いた検討-2020

    • Author(s)
      村尾直哉,横井伯英,高橋晴美,清野 進
    • Organizer
      第35回老化促進モデルマウス(SAM)学会学術大会
    • Related Report
      2020 Research-status Report
  • [Presentation] SGLT2阻害薬が全身の糖代謝に及ぼす影響の検討2020

    • Author(s)
      横井伯英、高橋晴美、清野 進
    • Organizer
      第34回日本糖尿病・肥満動物学会年次学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] 膵島機能の加齢性変化の解明-B6マウスならびに老化促進モデルマウスを用いた検討-2020

    • Author(s)
      村尾直哉、横井伯英、速水智英、高橋晴美、清野 進
    • Organizer
      第34回日本糖尿病・肥満動物学会年次学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] 肥満糖尿病の膵島におけるインクレチン応答性障害の発症機序2020

    • Author(s)
      速水智英、横井伯英、吉田 舞、本田洸平、高橋晴美、神谷英紀、溝口 明、中村二郎、清野 進
    • Organizer
      第34回日本糖尿病・肥満動物学会年次学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] 新規Epac2アイソフォームの同定とその膵β細胞機能における役割2020

    • Author(s)
      高橋晴美、藤原結花、堰 千紘、横井伯英、清野 進
    • Organizer
      第93回日本薬理学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] Role of glutamate signaling in insulin secretion.2019

    • Author(s)
      Norihide Yokoi, Harumi Takahashi, Susumu Seino
    • 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] 肥満糖尿病における膵島機能不全の機序の解明2019

    • Author(s)
      吉田 舞, 横井伯英, 速水智英, 川畑綾子, 高橋晴美, 小川渉, 清野 進
    • Organizer
      第62回日本糖尿病学会年次学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] 膵β細胞に発現する新たなEpac2アイソフォームとその特異的な役割2019

    • Author(s)
      高橋晴美、藤原結花、堰 千紘、横井伯英、清野 進
    • Organizer
      第62回日本糖尿病学会年次学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] Enhanced β-cell Gq signal underlies improved insulin secretion and glucose tolerance by GLP-1 in Kir6.2 KO diabetic mice.2019

    • Author(s)
      Okechi S Oduori,Kenju Shimomura,Harumi Takahashi,Shihomi Hidaka,Naoya Murao,Norihide Yokoi,Susumu Seino
    • Organizer
      第62回日本糖尿病学会年次学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] 新規インスリン分泌促進薬シード化合物の同定とその作用機序の解明2019

    • Author(s)
      村尾直哉、菅原健二、Okechi S Oduori、Christopher M Carmean、横井伯英、高橋晴美、清野 進
    • Organizer
      第62回日本糖尿病学会年次学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] Role of glutamine/glutamate signaling in insulin secretion.2019

    • Author(s)
      Guirong Han, Harumi Takahashi, Norihide Yokoi, Ghupurjan Gheni, Naoya Murao, Yutaka Seino, Yoshiyuki Hamamoto, Yoshiaki Kido, Susumu Seino
    • Organizer
      The 11th Scientific Meeting of the AASD in conjunction with The 62nd Annual Meeting of the Japan Diabetes Society
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Tumor-like metabolic feature of enlarged pancreatic islets underlies incretin unresponsiveness in obese type 2 diabetes.2019

    • Author(s)
      Tomohide Hayami, Norihide Yokoi, Kohei Honda, Harumi Takahashi, Hideki Kamiya, Akira Mizoguchi, Jiro Nakamura, Susumu Seino
    • Organizer
      The 11th Scientific Meeting of the AASD in conjunction with The 62nd Annual Meeting of the Japan Diabetes Society
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Role of Noc2 in incretin exocytosis2019

    • Author(s)
      Harumi Takahashi
    • Organizer
      2019 Asia Islet Biology & Incretin Symposium
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] How can we improve insulin secretion of diabetic-beta-cells?2019

    • Author(s)
      Susumu Seino, Naoya Murao, Harumi Takahashi, Okechi S Oduori
    • Organizer
      International Diabetes Federation Congress 2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Age-associated changes of glucose tolerance and pancreatic islet function in mice.2019

    • Author(s)
      Naoya Murao, Norihide Yokoi, Tomohide Hayami, Okechi S Oduori, Yingyue Quan, Harumi Takahashi, Susumu Seino
    • Organizer
      International Diabetes Federation Congress 2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Elucidation of genetic factors and pathogenesis of obese diabetes: Study of ZFDM rat.2019

    • Author(s)
      Norihide Yokoi, Tomohide Hayami, Mai Yoshida, Harumi Takahashi, Yukio Taniguchi, Susumu Seino
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Research-status Report

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

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