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

• Project/Area Number: 16K09749
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kobe 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: ¥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。

Research Products

• [Journal Article] Arsenic modifies serotonin metabolism through glucuronidation in pancreatic β-cells (2019)
  • 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
  • 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
  • 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 Model (2018)
  • 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
  • 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
  • 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
  • Peer Reviewed / Open Access
• [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 Issue: S1 Pages: 22-29
  • DOI: 10.1111/dom.12995
  • 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
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A novel diphenylthiosemicarbazide is a potential insulin secretagogue for anti-diabetic agent (2016)
  • 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
  • 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
  • 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
  • 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 mice (2019)
  • Author(s): Naoya Murao, Oduori S. Okechi, Kenju Shimomura, Harumi Takahashi, Norihide Yokoi, Susumu Seino
  • Organizer: 20th Servier-IGIS Symposium
  • 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
• [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
• [Presentation] The mechanism of impaired incretin responsiveness in the pancreatic islets of obese type 2 diabetes: A study of the ZFDM rat (2018)
  • Author(s): Norihide Yokoi, Tomohide Hayami, Shihomi Hidaka, Ayako Kawabata, Harumi Takahashi, Susumu Seino
  • Organizer: The 54th EASD Annual Meeting
  • 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
• [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
• [Presentation] GLP-1 receptor agonists and DPP-4 inhibitors both normalize diabetes caused by deletion of β-cell KATP_channels in mice (2018)
  • 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
• [Presentation] Enhanced Gs- and Gq-signals in β-cells contributes to normalization of glucose tolerance and insulin secretion in β-cell specific Kir6.2 (2018)
  • Author(s): Okechi S. Oduori, Kohtaro Minami, Norihide Yokoi, Harumi Takahashi, Takashi Miki, Yuko Maejima, Kenju Shimomura, Susumu Seino
  • Organizer: Keytsone symposium
  • 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
• [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
• [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.
• [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
  • 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.
• [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.
• [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.
• [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.
• [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.
  • 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.
  • 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.
• [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.
• [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
  • 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
  • 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
  • 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
  • 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
  • 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
• [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
• [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
• [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
  • Int'l Joint Research