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Elucidation of pancreatic beta-cell mass regulation mechanism by glucokinase

Research Project

Project/Area Number 19K08992
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54040:Metabolism and endocrinology-related
Research InstitutionHokkaido University

Principal Investigator

Nakamura Akinobu  北海道大学, 医学研究院, 講師 (70552420)

Project Period (FY) 2019-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Keywordsグルコキナーゼ / 膵β細胞 / 糖尿病
Outline of Research at the Start

2型糖尿病の病態の特徴の一つとして、進行性の膵β細胞量の低下があげられる。それゆえ、膵β細胞量の進行性低下を予防し、膵β細胞量を保持することが2型糖尿病の病態に即した治療として考えられる。グルコキナーゼは膵β細胞量調節機構に重要な役割を果たしているが、膵β細胞量の進行性低下に対するグルコキナーゼの影響は明らかでない。本研究において、グルコキナーゼの制御による膵β細胞量調節メカニズムの解明を目指す。

Outline of Final Research Achievements

One of the pathophysiological features of type 2 diabetes is the progressive decrease in pancreatic beta-cell mass. Therefore, prevention of the progressive decrease in beta-cell mass and maintenance of beta-cell mass are considered as therapeutics in type 2 diabetes. We aimed to elucidate the beta-cell mass regulation mechanism by glucokinase. As a result, administration of a glucokinase activator to a mouse model of obese diabetes did not increase insulin secretion and beta-cell mass. On the other hand, glucokinase inactivation improved glucose tolerance by maintaining beta-cell function and mass.

Academic Significance and Societal Importance of the Research Achievements

グルコキナーゼ活性の抑制は、糖尿病病態下で認められる過剰な糖代謝を適正化するという膵β細胞overworkの軽減、すなわち「Beta cell rest」という概念に一致しており、膵β細胞を刺激してインスリンを分泌させることで血糖を低下させるという従来の方法と逆の発想による2型糖尿病治療へのアプローチであり、極めて創造性、新規性は高い。さらに本研究は、トランスレーショナルリサーチとして、将来的な臨床試験を含めた2型糖尿病の臨床応用に展開できることが大いに期待される。

Report

(5 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (21 results)

All 2022 2021 2020 2019

All Journal Article (7 results) (of which Peer Reviewed: 6 results,  Open Access: 1 results) Presentation (14 results) (of which Int'l Joint Research: 4 results,  Invited: 3 results)

  • [Journal Article] Glucokinase as a therapeutic target based on findings from the analysis of mouse models2022

    • Author(s)
      Nakamura Akinobu
    • Journal Title

      Endocrine Journal

      Volume: 69 Issue: 5 Pages: 479-485

    • DOI

      10.1507/endocrj.EJ21-0742

    • ISSN
      0918-8959, 1348-4540
    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effects of Sodium-Glucose Co-Transporter-2 Inhibitors on Pancreatic β-Cell Mass and Function2022

    • Author(s)
      Nakamura Akinobu
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 23 Issue: 9 Pages: 5104-5104

    • DOI

      10.3390/ijms23095104

    • Related Report
      2022 Annual Research Report
  • [Journal Article] Glucokinase activation leads to an unsustained hypoglycaemic effect with hepatic triglyceride accumulation in db/db mice2021

    • Author(s)
      Kawata Shinichiro、Nakamura Akinobu、Miyoshi Hideaki、Yang Kelaier、Shigesawa Ikumi、Yamauchi Yuki、Tsuchida Kazuhisa、Omori Kazuno、Takahashi Kiyohiko、Nomoto Hiroshi、Kameda Hiraku、Cho Kyu Yong、Terauchi Yasuo、Atsumi Tatsuya
    • Journal Title

      Diabetes, Obesity and Metabolism

      Volume: 24 Issue: 3 Pages: 391-401

    • DOI

      10.1111/dom.14586

    • Related Report
      2022 Annual Research Report 2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Glucokinase activation or inactivation: Which will lead to the treatment of type 2 diabetes?2021

    • Author(s)
      Nakamura Akinobu、Omori Kazuno、Terauchi Yasuo
    • Journal Title

      Diabetes, Obesity and Metabolism

      Volume: 23 Issue: 10 Pages: 2199-2206

    • DOI

      10.1111/dom.14459

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Glucokinase is required for high‐starch diet‐induced β‐cell mass expansion in mice2021

    • Author(s)
      Tsuchida Kazuhisa、Nakamura Akinobu、Miyoshi Hideaki、Yang Kelaier、Yamauchi Yuki、Kawata Shinichiro、Omori Kazuno、Takahashi Kiyohiko、Kitao Naoyuki、Nomoto Hiroshi、Kameda Hiraku、Cho Kyu Yong、Seino Yusuke、Terauchi Yasuo、Atsumi Tatsuya
    • Journal Title

      Journal of Diabetes Investigation

      Volume: 12 Issue: 9 Pages: 1545-1554

    • DOI

      10.1111/jdi.13532

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Glucokinase Inactivation Paradoxically Ameliorates Glucose Intolerance by Increasing β-Cell Mass in db/db Mice2021

    • Author(s)
      Omori Kazuno、Nakamura Akinobu、Miyoshi Hideaki、Yamauchi Yuki、Kawata Shinichiro、Takahashi Kiyohiko、Kitao Naoyuki、Nomoto Hiroshi、Kameda Hiraku、Cho Kyu Yong、Terauchi Yasuo、Atsumi Tatsuya
    • Journal Title

      Diabetes

      Volume: 70 Issue: 4 Pages: 917-931

    • DOI

      10.2337/db20-0881

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Effects of dapagliflozin and/or insulin glargine on beta cell mass and hepatic steatosis in db/db mice2019

    • Author(s)
      Omori Kazuno、Nakamura Akinobu、Miyoshi Hideaki、Takahashi Kiyohiko、Kitao Naoyuki、Nomoto Hiroshi、Kameda Hiraku、Cho Kyu Yong、Takagi Ryo、Hatanaka Kanako C.、Terauchi Yasuo、Atsumi Tatsuya
    • Journal Title

      Metabolism

      Volume: 98 Pages: 27-36

    • DOI

      10.1016/j.metabol.2019.06.006

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Presentation] 膵β細胞量保持を目指した2型糖尿病の治療戦略2022

    • Author(s)
      大森一乃、中村昭伸
    • Organizer
      第65回日本糖尿病学会年次学術集会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] グルコキナーゼの抑制が2型糖尿病病態下の膵β細胞量を保持する2022

    • Author(s)
      大森一乃、中村昭伸、三好秀明、山内裕貴、川田晋一朗、野本博司、亀田啓、曺圭龍、寺内康夫、渥美達也
    • Organizer
      第35回日本糖尿病・肥満動物学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] グルコキナーゼ活性化薬の長期投与に伴う血糖降下作用の消失機序の解明2022

    • Author(s)
      川田晋一朗、中村昭伸、三好秀明、山内裕貴、土田和久、大森一乃、高橋清彦、野本博司、亀田啓、曺圭龍、寺内康夫、渥美達也
    • Organizer
      第95回日本内分泌学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Improved mitochondrial function by luseogliflozin prevents pancreatic beta-cell damage.2021

    • Author(s)
      Yamauchi Y, Nakamura A, Yokota T, Takahashi K, Kawata S, Tsuchida K, Omori K, Nomoto H, Kameda H, Cho KY, Anzai T, Tanaka S, Terauchi Y, Miyoshi H, Atsumi T.
    • Organizer
      81st Scientific Sessions for American Diabetes Association.
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] グルコキナーゼの制御が膵β細胞量に与える影響2021

    • Author(s)
      中村昭伸、寺内康夫
    • Organizer
      第64回日本糖尿病学会年次学術集会シンポジウム
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] モデル動物を用いた2型糖尿病治療法の確立に向けた研究2021

    • Author(s)
      中村昭伸
    • Organizer
      第94回日本内分泌学会学術総会研究奨励賞受賞講演
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] db/dbマウスを用いたグルコキナーゼ活性化薬の血糖降下作用消失機序の解明2021

    • Author(s)
      川田晋一朗、中村昭伸、三好秀明、重沢郁美、山内裕貴、関崎知紀、土田和久、大森一乃、高橋清彦、北尾直之、野本博司、亀田啓、曺圭龍、寺内康夫、渥美達也
    • Organizer
      第64回日本糖尿病学会年次学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] 膵β細胞グルコキナーゼの抑制が肥満2型糖尿病モデルマウスの膵β細胞機能・量を保持する2021

    • Author(s)
      中村昭伸、大森一乃、三好秀明、野本博司、亀田啓、曺圭龍、寺内康夫、渥美達也
    • Organizer
      第41回日本肥満学会
    • Related Report
      2020 Research-status Report
  • [Presentation] Glucokinase haploinsufficiency ameliorates glucose intolerance by increasing beta-cell mass in db/db mice2020

    • Author(s)
      Kazuno Omori, Akinobu Nakamura, Hideaki Miyoshi, Shinichiro Kawata, Kiyohiko Takahashi, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, Yasuo Terauchi, Tatsuya Atsumi
    • Organizer
      56th Annual Meeting of the European Association for the Study of Diabetes
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] グルコキナーゼ活性化薬の長期投与に伴う血糖降下作用の消失機序の解明2020

    • Author(s)
      川田晋一朗、中村昭伸、土田和久、大森一乃、高橋清彦、野本博司、亀田啓、曺圭龍、寺内 康夫、三好秀明、渥美達也
    • 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] Effects of dapagliflozin and/or insulin glargine on beta cell mass and hepatic steatosis in db/db mice.2019

    • Author(s)
      Omori K, Nakamura A, Miyoshi H, Takahashi K, Kitao N, Nomoto H, Kameda H, Cho KY, Terauchi Y, Atsumi T.
    • Organizer
      American Diabetic Association’s 79th Scientific Sessions.
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Reduced hypoglycemic property of glucokinase activator by longitudinal administration in db/db mice.2019

    • Author(s)
      Kawata S, Nakamura A, Miyoshi H, Tsuchida K, Omori K, Takahashi K, Kameda H, Cho KY, Terauchi Y, Atsumi T.
    • Organizer
      55th Annual Meeting of the European Association for the Study of Diabetes.
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] SGLT2阻害薬またはインスリンによる血糖降下作用が膵β細胞量および肝脂肪化に与える影響2019

    • Author(s)
      大森一乃、中村昭伸、三好秀明、川田晋一朗、土田和久、高橋清彦、寺内 康夫、渥美達也
    • Organizer
      第56回臨床分子学会年次学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] SGLT2阻害薬またはインスリンによる血糖降下作用が肝脂肪化に与える影響2019

    • Author(s)
      大森一乃、中村昭伸、三好秀明、川田晋一朗、土田和久、高橋清彦、寺内 康夫、渥美達也
    • Organizer
      第62回日本糖尿病学会年次学術集会
    • Related Report
      2019 Research-status Report

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Published: 2019-04-18   Modified: 2024-01-30  

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