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Involvement of DAG metabolism in beta-cell dysfunction during type 2 diabetes

Research Project

Project/Area Number 17K01857
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Applied health science
Research InstitutionUniversity of Shizuoka

Principal Investigator

Kaneko Yukiko  静岡県立大学, 薬学部, 講師 (00381038)

Co-Investigator(Kenkyū-buntansha) 石川 智久  静岡県立大学, 薬学部, 教授 (10201914)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords糖尿病 / 膵β細胞 / インスリン分泌 / ジアシルグリセロール / ジアシルグリセロールキナーゼ / インスリン / 糖脂肪毒性 / シグナル伝達 / 脂質
Outline of Final Research Achievements

The intracellular DAG level is strictly controlled, primarily by DAG kinase (DGK), an enzyme catalyzing the conversion of DAG to phosphatidic acid. We have previously shown a crucial role of DGK in GSIS. Of the 10 known DGK isoforms, we focused on type-I DGK isoforms (i.e., DGKα, DGKγ), which are activated by Ca2+. We investigated the effects of DAG accumulated via the reduced activity of type I DGKs on insulin secretion. DAG accumulation through declined type I DGK activity shows a dual effect on insulin secretion depending on the degree of accumulation; a mild DAG accumulation induces a PKC-dependent stimulatory effect on insulin secretion, whereas an excessive DAG accumulation suppresses it in a PKC-independent manner, possibly via attenuation of VDCC activity. Moreover, glucose tolerance was reduced in type I DGK knockout mice. Thus, type I DGKs are likely to play a pivotal role in maintaining appropriate insulin secretion by optimizing DAG levels.

Academic Significance and Societal Importance of the Research Achievements

肥満を伴う2型糖尿病発症過程において引き起こされるGLadaptationとGL-toxicity というインスリン分泌異常の一連の流れにtype I DGK 機能が関与しているという新たな発想に基づき計画された。本研究より、膵β細胞内ではtype I DGKの働きにより細胞内DAG量が適切に調節されていること、これらの調節機能の破綻によりインスリン分泌異常からの糖尿病増悪へと繋がる可能性が明らかとなった。本研究よりβ細胞内DAGの蓄積を調節し、β細胞機能障害からの回復を目的とした、全く新しい作用機序を有する糖尿病治療薬の開発につながることが期待される。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (34 results)

All 2020 2019 2018 2017

All Journal Article (3 results) (of which Peer Reviewed: 3 results) Presentation (31 results) (of which Int'l Joint Research: 7 results,  Invited: 5 results)

  • [Journal Article] Dual effect of reduced type I diacylglycerol kinase activity on insulin secretion from MIN6 β-cells2019

    • Author(s)
      Sawatani Toshiaki、Kaneko Yukiko K.、Ishikawa Tomohisa
    • Journal Title

      Journal of Pharmacological Sciences

      Volume: 140 Issue: 2 Pages: 178-186

    • DOI

      10.1016/j.jphs.2019.06.001

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] TRPV2 channels mediate insulin secretion induced by cell swelling in mouse pancreatic β-cells2019

    • Author(s)
      Toshiaki Sawatani, Yukiko K. Kaneko, Isao Doutsu, Ai Ogawa, Tomohisa Ishikawa
    • Journal Title

      Am J Physiol Cell Physiol

      Volume: 316 Issue: 3 Pages: C434-C443

    • DOI

      10.1152/ajpcell.00210.2017

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Concise synthesis of polymethoxyflavone sudachitin and its derivatives, and biological evaluations2018

    • Author(s)
      Sagara Hiroto、Kanakogi Masaki、Tara Yuki、Ouchi Hitoshi、Kimura Junko、Kaneko Yukiko、Inai Makoto、Asakawa Tomohiro、Ishikawa Tomohisa、Kan Toshiyuki
    • Journal Title

      Tetrahedron Letters

      Volume: 59 Issue: 19 Pages: 1816-1818

    • DOI

      10.1016/j.tetlet.2018.03.064

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Presentation] DGKδ機能抑制による膵β細胞増殖機序の解析2020

    • Author(s)
      青島 育美、金子 雪子、石川 揚子、木村 悠希、松田 有加里、石川 智久
    • Organizer
      日本薬学会 第140年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 創薬シンポジウム3 新たな視点からの治療を指向した糖尿病研究の新潮流 細胞内脂質シグナリングによる膵β細胞量の制御、2019

    • Author(s)
      金子雪子、石川智久
    • Organizer
      生体機能と創薬シンポジウム2019
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Diacylglycerol kinase によるβ細胞分泌調節と増殖制御研究2019

    • Author(s)
      金子雪子
    • Organizer
      Islet Biology’19
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] シンポジウム8 膵β細胞機能の新たなメッセンジャー:その生理と病態:Role of diacylglycerol kinase on the regulation of insulin secretion in pancreatic β-cells2019

    • Author(s)
      金子雪子、澤谷俊明、石川智久
    • Organizer
      第62回日本糖尿病学会年次学術集会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 膵β細胞I型DGKの糖尿病下での発現と血糖調節への影響の解析2019

    • Author(s)
      松浦 朋哉、金子雪子、芹澤 環、澤谷 俊明、白井 康仁、石川 智久
    • Organizer
      第21回応用薬理シンポジウム
    • Related Report
      2019 Annual Research Report
  • [Presentation] DGKγ欠損による膵α細胞機能への影響の検討2019

    • Author(s)
      芹澤 環、金子 雪子、戸倉 広貴、松浦 朋哉、澤谷 俊明、石川 智久
    • Organizer
      第140回日本薬理学会関東部会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Anti-diabetic effects of citrus flavonoids on pancreatic β-cell function.2019

    • Author(s)
      金子雪子、石川智久
    • Organizer
      第92回日本薬理学会年会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] DGKδ deficiency in mouse pancreatic β-cells alleviates STZ-induced diabetes.2019

    • Author(s)
      木村 悠希、金子 雪子、中山 貴寛、石川 揚子、松田 有加里、青島 育美、石川 智久
    • Organizer
      第92回日本薬理学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] ノビレチンはインスリン分泌促進および膵β細胞保護作用により糖尿病を改善させる2019

    • Author(s)
      多良勇輝、金子雪子、山本萌絵、青柳有紀、秋山季里子、菅敏幸、石川智久
    • Organizer
      日本薬学会第139年会
    • Related Report
      2018 Research-status Report
  • [Presentation] DAG accumulation due to type 1 DGK inhibition has a contradictory dual effect on Ca2+ signaling in pancreatic β-cells.2018

    • Author(s)
      Toshiaki Sawatani, Yukiko Kaneko, Tomohisa Ishikawa.
    • Organizer
      American Diabetes Association Scientific Sessions 2018
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] DGKδ deficiency in mouse pancreatic β-cells improves STZ-induced hyperglycemia.2018

    • Author(s)
      Yuki Kimura, Yukiko Kaneko, Taiji Sato, Chihiro Ishiwatari, Yoko Ishikawa, Yukari Matsuda, Tomohisa Ishikawa.
    • Organizer
      The 4th International Conference on Pharma and Food
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Contribution of TRPV2 channels in cell swelling-induced insulin secretion in mouse pancreatic β-cells.2018

    • Author(s)
      Toshiaki Sawatani, Yukiko K. Kaneko, Isao Dotsu, Ai Ogawa and Tomohisa Ishikawa
    • Organizer
      The 23rd Shizuoka Forum on Health and Longevity
    • Related Report
      2018 Research-status Report
  • [Presentation] Modulation of DDAH/ADMA/NOS pathway in pancreatic β-cells under diabetic condition.2018

    • Author(s)
      Yukiko K. Kaneko, Misaki Sano, Ami Morioka, Masato Nojiri, Nahoko Kasahara, Tomohisa Ishikawa
    • Organizer
      18th World Congress of Basic and Clinical Pharmacology
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] TRPV2 channels mediate cell swelling-induced insulin secretion in mouse pancreatic β-cells.2018

    • Author(s)
      Toshiaki Sawatani, Yukiko K. Kaneko, Tomohisa Ishikawa.
    • Organizer
      18th World Congress of Basic and Clinical Pharmacology
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Diacylglycerol accumulation due to type-1 diacylglycerol kinase dysfunction has a dual response on insulin secretion in pancreatic β-cells.2018

    • Author(s)
      Toshiaki Sawatani, Yukiko K. Kaneko and Tomohisa Ishikawa
    • Organizer
      The 4th International Conference on Pharma and Food
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 膵β細胞におけるDGKδ機能抑制による糖尿病病態改善効果とそのメカニズムの解析2018

    • Author(s)
      松田有加里、金子雪子、木村悠希、石川揚子、中山貴寛、石川智久
    • Organizer
      日本病院薬剤師会東海ブロック・日本薬学会東海支部合同学術大会2018
    • Related Report
      2018 Research-status Report
  • [Presentation] 膵β細胞においてI型ジアシルグリセロールキナーゼ機能低下はインスリン分泌を二面性に制御する2018

    • Author(s)
      澤谷俊明、金子雪子、石川智久
    • Organizer
      生体機能と創薬シンポジウム2018
    • Related Report
      2018 Research-status Report
  • [Presentation] 膵β細胞におけるDGKαおよびγ機能抑制によるDAG蓄積は細胞内Ca2+濃度に対して二面性を示す2018

    • Author(s)
      澤谷俊明、金子雪子、石川智久
    • Organizer
      第61回日本糖尿病学会年次学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] β細胞におけるDGKδ機能抑制による細胞増殖および糖尿病病態への効果の解析2018

    • Author(s)
      木村悠希、金子雪子、石川揚子、中山貴寛、石川智久
    • Organizer
      第61回日本糖尿病学会年次学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] Effects of citrus flavonoids on pancreatic β-cell function.2018

    • Author(s)
      Yuki Tara, Yukiko K. Kaneko, Moe Yamamoto, Yuki Aoyagi, Megumi Kaji, Kiriko Akiyama, Toshiyuki Kan, and Tomohisa Ishikawa
    • Organizer
      The 4th International Conference on Pharma and Food
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 膵β細胞量増加を目指した新規糖尿病治療創薬標的としての膵β細胞脂質代謝制御、一般シンポジウムS70 若手が取り組む新規糖尿病治療・予防法の開発を目指した研究戦略2018

    • Author(s)
      金子雪子、石川智久
    • Organizer
      日本薬学会第138年会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] 糖尿病下における細胞内ADMAの蓄積はNOによる膵β細胞保護作用を減弱させる2018

    • Author(s)
      佐野実咲、金子雪子、森岡亜望、石川智久
    • Organizer
      日本薬学会第138年会
    • Related Report
      2017 Research-status Report
  • [Presentation] 膵β細胞概日リズム形成に関わる分子の発現および機能解析2018

    • Author(s)
      鴨志田ありさ、金子雪子、八木雄也、中村哲、石川智久
    • Organizer
      第138回日本薬理学会関東部会
    • Related Report
      2017 Research-status Report
  • [Presentation] 膵β細胞における柑橘類果皮抽出成分ノビレチンの抗糖尿病効果の解析2018

    • Author(s)
      青柳有紀、金子雪子、秋山季里子、多良勇輝、山本萌絵、石川智久
    • Organizer
      第138回日本薬理学会関東部会
    • Related Report
      2017 Research-status Report
  • [Presentation] Inhibition of Type I DGK Leads to a Dual Response on Ca2+ Signaling in Pancreatic β-Cells.2017

    • Author(s)
      Toshiaki Sawatani, Yukiko Kaneko, Tomohisa Ishikawa
    • Organizer
      20th International Sympoium on Calcium Binding Proteins and Calsium Function in Health and Disease (CaBP20)
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] マウス膵β細胞におけるDGKδ発現抑制によりSTZ誘発糖尿病は改善する2017

    • Author(s)
      石川揚子、金子雪子、中山貴寛、木村悠希、石川智久
    • Organizer
      次世代を担う創薬・医療薬理シンポジウム2017
    • Related Report
      2017 Research-status Report
  • [Presentation] 膵β細胞におけるDGKαおよびγ機能抑制は細胞内Ca2+濃度に対して二面的作用を示す2017

    • Author(s)
      澤谷俊明、金子雪子、石川智久
    • Organizer
      次世代を担う創薬・医療薬理シンポジウム2017
    • Related Report
      2017 Research-status Report
  • [Presentation] 膵β細胞において細胞膨張によるTRPV2活性化はインスリン分泌反応を惹起する.2017

    • Author(s)
      澤谷俊明、金子雪子、石川智久
    • Organizer
      生体機能と創薬シンポジウム2017
    • Related Report
      2017 Research-status Report
  • [Presentation] 糖尿病下における内因性NOS阻害物質の蓄積は膵β細胞障害を亢進させる2017

    • Author(s)
      佐野実咲、金子雪子、森岡亜望、石川智久
    • Organizer
      第136回日本薬理学会関東部会
    • Related Report
      2017 Research-status Report
  • [Presentation] 膵β細胞TRPV2活性化は細胞膨張誘発インスリン分泌反応に関与する2017

    • Author(s)
      澤谷俊明、金子雪子、石川智久
    • Organizer
      第136回日本薬理学会関東部会
    • Related Report
      2017 Research-status Report
  • [Presentation] 膵β細胞における細胞膨張誘発インスリン分泌反応にはTRPV2活性化が関与する2017

    • Author(s)
      澤谷俊明、金子雪子、石川智久
    • Organizer
      第60回日本糖尿病学会年次学術集会
    • Related Report
      2017 Research-status Report

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Published: 2017-04-28   Modified: 2021-02-19  

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