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The role of Epac2A/Rap1 signaling in the protection of pancreatic beta-cell

Research Project

Project/Area Number 16K09749
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Metabolomics
Research InstitutionKobe University

Principal Investigator

TAKAHASHI Harumi  神戸大学, 医学研究科, 特命講師 (50546489)

Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords膵β細胞 / 糖尿病 / インクレチン / cAMP / Epac2 / Epac2A
Outline of Final Research Achievements

The roles of incretin/cAMP signaling and Epac2/Rap1 signaling in the protection of pancreatic β-cells were investigated. In a β-cell line, the activation of cAMP and Epac2 signaling suppressed production of reactive oxygen species (ROS) induced by alloxan and palmitate stimulations, suggesting that the role of cAMP and Epac2 signaling in the reduction of oxidative stress in pancreatic β-cells. From the generation and analyses of Epac2 deficient cell lines, we found a new isoform of Epac2 expressed in pancreatic β-cells, which may be involved in cellular functions other than insulin secretion such as the protection of β-cell against cellular stresses including oxidative stress.

Academic Significance and Societal Importance of the Research Achievements

インクレチンは食餌の摂取によって腸管から分泌され、膵β細胞からのインスリン分泌を促進するなど、糖代謝改善作用を有する。この作用を利用したインクレチン関連薬は現在2型糖尿病治療に広く用いられており、その作用機序や未知の効果を明らかにすることは臨床上の意義が大きい。また、糖尿病の病態には各種細胞ストレスなどによる膵β細胞機能の障害が深く関与しており、このような病態の解明により新規糖尿病治療法の開発にも繋がる可能性があることから本研究の意義は大きい。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (39 results)

All 2019 2018 2017 2016 2015

All Journal Article (10 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 10 results,  Open Access: 9 results,  Acknowledgement Compliant: 5 results) Presentation (29 results) (of which Int'l Joint Research: 12 results)

  • [Journal Article] Arsenic modifies serotonin metabolism through glucuronidation in pancreatic β-cells2019

    • Author(s)
      Carmean Christopher M.、Yokoi Norihide、Takahashi Harumi、Oduori Okechi S.、Kang Christie、Kanagawa Akiko、Kirkley Andrew G.、Han Guirong、Landeche Michael、Hidaka Shihomi、Katoh Miki、Sargis Robert M.、Seino Susumu
    • Journal Title

      American Journal of Physiology-Endocrinology and Metabolism

      Volume: 316 Issue: 3 Pages: E464-E474

    • DOI

      10.1152/ajpendo.00302.2018

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Activation of GLP-1 receptor signaling alleviates cellular stresses and improves beta cell function in a mouse model of Wolfram syndrome.2018

    • Author(s)
      Kondo M, Tanabe K, Amo-Shiinoki K, Hatanaka M, Morii T, Takahashi H, Seino S, Yamada Y, Tanizawa Y
    • Journal Title

      Diabetologia

      Volume: 61 Issue: 10 Pages: 2189-2201

    • DOI

      10.1007/s00125-018-4679-y

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Inhibition of SNAT5 Induces Incretin-Responsive State From Incretin-Unresponsive State in Pancreatic β-Cells: Study of β-Cell Spheroid Clusters as a Model2018

    • Author(s)
      Hashim Mahira、Yokoi Norihide、Takahashi Harumi、Gheni Ghupurjan、Okechi Oduori S.、Hayami Tomohide、Murao Naoya、Hidaka Shihomi、Minami Kohtaro、Mizoguchi Akira、Seino Susumu
    • Journal Title

      Diabetes

      Volume: 67 Issue: 9 Pages: 1795-1806

    • DOI

      10.2337/db17-1486

    • NAID

      40022150466

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Characteristics of repaglinide effects on insulin secretion.2018

    • Author(s)
      Takahashi H, Hidaka S, Seki C, Yokoi N, Seino S.
    • Journal Title

      Eur J Pharmacol.

      Volume: 828 Pages: 52-59

    • DOI

      10.1016/j.ejphar.2018.03.025

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Essential roles of aspartate aminotransferase 1 and vesicular glutamate transporters in β-cell glutamate signaling for incretin-induced insulin secretion.2017

    • Author(s)
      Murao N, Yokoi N, Honda K, Han G, Hayami T, Gheni G, Takahashi H, Minami K, Seino S.
    • Journal Title

      PLoS One.

      Volume: 12 Issue: 11 Pages: e0187213-e0187213

    • DOI

      10.1371/journal.pone.0187213

    • NAID

      120006373802

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] β-cell signaling and insulin secretagogues: a path for improved diabetes therapy2017

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

      Diabetes Obes Metab

      Volume: 印刷中 Issue: S1 Pages: 22-29

    • DOI

      10.1111/dom.12995

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] β-cell signaling and insulin secretagogues: a path for improved diabetes therapy.2017

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

      Diabetes Obes Metab

      Volume: 印刷中

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] A novel diphenylthiosemicarbazide is a potential insulin secretagogue for anti-diabetic agent2016

    • Author(s)
      Sugawara k, Honda K, Reien Y, Yokoi N, Seki C, Takahashi H, Minami K, Mori I, Matsumoto A, Nakaya H, Seino S
    • Journal Title

      PLoS One

      Volume: 11 Issue: 10 Pages: e0164785-e0164785

    • DOI

      10.1371/journal.pone.0164785

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Beta-cell gulutamate signaling: Its role in incretin-induced insulin secretion.2016

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

      J Diabet Investig

      Volume: 7 Issue: S1 Pages: 38-43

    • DOI

      10.1111/jdi.12468

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Structure and functional roles of Epac2 (Rapgef4)2015

    • Author(s)
      Sugawara K, Shibasaki T, Takahashi H, Seino S
    • Journal Title

      Gene

      Volume: 505 Issue: 2 Pages: 577-583

    • DOI

      10.1016/j.gene.2015.09.029

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Presentation] Enhanced beta-cell Gq signaling underlies improved insulin secretion and glucose tolerance by GLP-1 in beta-cell-specific Kir6.2 knockout diabetic mice2019

    • Author(s)
      Naoya Murao, Oduori S. Okechi, Kenju Shimomura, Harumi Takahashi, Norihide Yokoi, Susumu Seino
    • Organizer
      20th Servier-IGIS Symposium
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 肥満2型糖尿病における肥大膵島は未分化細胞や癌細胞に類似した代謝様式に変化し、インクレチン応答性障害を呈する2019

    • Author(s)
      速水 智英, 横井 伯英, 本田 洸平, 高橋 晴美, 神谷 英紀, 溝口 明, 中村 二郎,  清野 進
    • Organizer
      第33回糖尿病・肥満動物学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 肥満2型糖尿病では肥大した膵島における糖代謝異常とO-GlcNAc化の亢進がインクレチン応答性インスリン分泌障害を引き起こす2018

    • Author(s)
      横井 伯英、速水 智英、吉田 舞、高橋 晴美、清野 進
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] The mechanism of impaired incretin responsiveness in the pancreatic islets of obese type 2 diabetes: A study of the ZFDM rat2018

    • Author(s)
      Norihide Yokoi, Tomohide Hayami, Shihomi Hidaka, Ayako Kawabata, Harumi Takahashi, Susumu Seino
    • Organizer
      The 54th EASD Annual Meeting
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 膵β細胞のインクレチン応答性獲得におけるアミノ酸トランスポーターSNAT5の役割2018

    • Author(s)
      マヒラ アシム、横井伯英、グプルジャン ゲニ、金川章子、星川律子、高橋晴美、清野進
    • Organizer
      第61回日本糖尿病学会年次学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] グルタミン-グルタミン酸シグナルによるインスリン分泌増強機構の解明2018

    • Author(s)
      韓 桂栄、横井 伯英 グプルジャン ゲニ、村尾 直哉、高橋晴美、清野 裕、木戸 良明、清野 進
    • Organizer
      第61回日本糖尿病学会年次学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] GLP-1 receptor agonists and DPP-4 inhibitors both normalize diabetes caused by deletion of β-cell KATP_channels in mice2018

    • Author(s)
      Oduori S. Okechi, Harumi Takahashi, Norihide Yokoi, Kohtaro Minami, Yuko Maejima, Kenju Shimomura, Susumu Seino
    • Organizer
      第61回日本糖尿病学会年次学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Enhanced Gs- and Gq-signals in β-cells contributes to normalization of glucose tolerance and insulin secretion in β-cell specific Kir6.22018

    • Author(s)
      Okechi S. Oduori, Kohtaro Minami, Norihide Yokoi, Harumi Takahashi, Takashi Miki, Yuko Maejima, Kenju Shimomura, Susumu Seino
    • Organizer
      Keytsone symposium
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 肥満糖尿病におけるインクレチン応答性インスリン分泌障害機序の解明2018

    • Author(s)
      速水 智英, 横井 伯英, マヒラ アシム, 高橋 晴美, 清野 進
    • Organizer
      第39回日本肥満学会
    • Related Report
      2018 Annual Research 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-オミクス解析による検討-2018

    • Author(s)
      速水 智英, 横井 伯英, 日高志保美, 川畑綾子, グプルジャン ゲニ, マヒラ アシム, 高橋 晴美, 神谷 英紀, 清野 裕, 中村 二郎, 清野 進
    • Organizer
      61回日本糖尿病学会年次学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] ZFDMラットにおけるインクレチン応答性インスリン分泌障害機序―オミクス解析による検討.2018

    • Author(s)
      速水 智英、横井 伯英、本田 洸平、マヒラ アシム、高橋 晴美、清野 進.
    • Organizer
      第32回日本糖尿病・肥満動物学会年次学術集会.
    • Related Report
      2017 Research-status Report
  • [Presentation] Beta-cell specific KATP Channel knockout mouse: diabetes, impaired insulin secretion and enhanced incretin signalling.2017

    • Author(s)
      Oduori O, Minami K, Takahashi H, Yokoi N, Herrera PL, Shimomura K, Seino S
    • Organizer
      18th Servier-IGIS Symposium
    • Place of Presentation
      St. Jean-Cap-Ferrat, France
    • Year and Date
      2017-03-25
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Insulin secretagogues and their signaling mechanisms.2017

    • Author(s)
      Harumi Takahashi, Kenji Sugawara, Norihide Yokoi, Susumu Seino.
    • Organizer
      第60回日本糖尿病学会年次学術集会.
    • Related Report
      2017 Research-status Report
  • [Presentation] Incretin and beta-cell metabolic signaling.2017

    • Author(s)
      横井 伯英、村尾 直哉、高橋 晴美、清野 進.
    • Organizer
      第60回日本糖尿病学会年次学術集会.
    • Related Report
      2017 Research-status Report
  • [Presentation] インクレチン応答性インスリン分泌増強機構の解明:インスリン顆粒内グルタミン酸の役割.2017

    • Author(s)
      グプルジャン ゲニ、横井 伯英、波多野 直哉、韓 桂栄、高橋 晴美、清野 進.
    • Organizer
      第60回日本糖尿病学会年次学術集会.
    • Related Report
      2017 Research-status Report
  • [Presentation] 膵β細胞間相互作用によるインクレチン応答性獲得に関与する分子の同定.2017

    • Author(s)
      マヒラ アシム、横井伯英、星川律子、グプルジャン ゲニ、高橋晴美、清野進.
    • Organizer
      第60回日本糖尿病学会年次学術集会.
    • Related Report
      2017 Research-status Report
  • [Presentation] Approaches to identification of novel small molecules that can be insulin secretagogues.2017

    • Author(s)
      Harumi Takahashi, Kenji Sugawara, Kohei Honda, Norihide Yokoi, Ichiro Mori, Haruaki Nakaya, Susumu Seino.
    • Organizer
      2nd Joint Meeting of the EASD Islet Study Group & Beta Cell Workshop.
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Impaired insulin secretion and severe glucose intolerance caused by deleting β-cell specific KATP channels.2017

    • Author(s)
      Okechi S. Oduori, Kohtara Minami, Norihide Yokoi, Harumi Takahashi, Yuko Maejima, Kenju Shimomura, Pedro Luis Herrera, Susumu Seino.
    • Organizer
      The 9th Scientific Meeting of Asian Association for the Study of Diabetes.
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] グルタミンによるインスリン分泌増強機構の解明.2017

    • Author(s)
      韓 桂栄、グプルジャン ゲニ、横井 伯英、村尾 直哉、高橋 晴美、清野 裕、清野 進.
    • Organizer
      第60回日本糖尿病学会年次学術集会.
    • Related Report
      2017 Research-status Report
  • [Presentation] 膵β細胞間相互作用によるインクレチン応答性獲得に関与する新規分子の同定.2017

    • Author(s)
      マヒラ アシム、横井伯英、グプルジャン ゲニ、星川律子、高橋晴美、清野進.
    • Organizer
      第40回日本分子生物学学会年会.
    • Related Report
      2017 Research-status Report
  • [Presentation] Trans-S-1-propenyl-l-cysteine sulfoxide from Allium cepa, onions, has appreciable antidiabetic potential in streptozotocin-induced diabetic mice.2016

    • Author(s)
      Oduori S. O, Sugawara K, Yoshida S, Takahashi H, Yokoi N, Nakayama M, Seino S
    • Organizer
      The 11th IDF-WPR Congress and 8th AASD Scientific Meeting
    • Place of Presentation
      Taipei, Taiwan
    • Year and Date
      2016-10-28
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Deletion of β-cell specific KATP channels causes severe glucose intolerance with impaired insulin secretion and enhanced incretin secretion.2016

    • Author(s)
      O.S. Oduori, K. Minami, N. Yokoi, Y. Maejima, H. Takahashi, P.L. Herrera, K. Shimomura, S. Seino
    • Organizer
      52nd Annual Meeting of the European Association for the Study of Diabetes
    • Place of Presentation
      Munich, Germany
    • Year and Date
      2016-09-15
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Mechanisms of the induction of incretin/cAMP responsiveness in insulin secretion: study by pseudoislets.2016

    • Author(s)
      M. Hashim, N. Yokoi, G. Gheni, R. Hoshikawa, H. Takahashi, S. Seino
    • Organizer
      52nd Annual Meeting of the European Association for the Study of Diabetes
    • Place of Presentation
      Munich, Germany
    • Year and Date
      2016-09-13
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Roles of KATP channels in brain-islet axis.2016

    • Author(s)
      Susumu Seino, Harumi Takahashi
    • Organizer
      21st EASD-Hagedorn Oxford Workshop
    • Place of Presentation
      Oxford, UK
    • Year and Date
      2016-08-07
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Antidiabetic effect of a sulfur compound trans-S-1-propenyl-l-cysteine sulfoxide from Allium cepa.2016

    • Author(s)
      Okechi OS, Sugawara K, Takahashi H, Yokoi N, Nakayama M, Seino S
    • Organizer
      The 76th scientific sessions of the American Diabetes Association
    • Place of Presentation
      New Orleans, USA
    • Year and Date
      2016-06-10
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] 膵β細胞間相互作用によるインクレチン応答性獲得機構の解明 -偽膵島を用いた検討-2016

    • Author(s)
      マヒラ アシム、横井 伯英、グプルジャン ゲニ、星川律子、高橋晴美、清野進
    • Organizer
      第59回日本糖尿病学会年次学術集会
    • Place of Presentation
      京都
    • Year and Date
      2016-05-21
    • Related Report
      2016 Research-status Report
  • [Presentation] Antidiabetic effect of a sulfur compound, trans-S-1-propenyl-l-cysteine sulfoxide, in Allium cepa.2016

    • Author(s)
      Oduori OS, Sugawara K, Honda K, Takahashi H, Yokoi N, Nakayama M, Seino S
    • Organizer
      第59回日本糖尿病学会年次学術集会
    • Place of Presentation
      京都
    • Year and Date
      2016-05-20
    • Related Report
      2016 Research-status Report
  • [Presentation] レパグリニドとインクレチンによるインスリン分泌動態の解析2016

    • Author(s)
      髙橋晴美、日高志保美、堰 千紘、清野 進
    • Organizer
      第59回日本糖尿病学会年次学術集会
    • Place of Presentation
      京都
    • Year and Date
      2016-05-19
    • Related Report
      2016 Research-status Report
  • [Presentation] Chronic Arsenic Exposure Impairs Pancreatic Function.2016

    • Author(s)
      Carmean CM, Kirkley AG, Yokoi N, Hoshikawa R, Honda K, Gheni G, Sugawara K, Takahashi H, Sargis RM, Seino S
    • Organizer
      17th International Group on Insulin Secretion Conference
    • Place of Presentation
      St. Jean-Cap-Ferrat, France
    • Year and Date
      2016-04-05
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research

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Published: 2016-04-21   Modified: 2020-03-30  

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