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The elucidation of Txnip-dependent mechanisms in pancreatic beta cell dedifferentiation leading diabetes

Research Project

Project/Area Number 20K08887
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 InstitutionYamaguchi University

Principal Investigator

TANABE KATSUYA  山口大学, 医学部附属病院, 講師 (00397994)

Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2020: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywords糖尿病 / 膵β細胞 / インスリン / 小胞体ストレス / 脱分化 / GLP-1 / WFS1 / β細胞不全 / 膵島 / 細胞可塑性 / 可塑性
Outline of Research at the Start

小胞体ストレスモデルWfs1欠損マウスはβ細胞脱分化を来し糖尿病を発症する。Wfs1欠損膵島ではTxnipの発現亢進を来し、Txnip欠損により脱分化が抑制され糖尿病が予防される。本課題では、脱分化の成因についてエピゲノムに着目し、膵島で行った網羅的遺伝子解析より1)脱分化に特異的なクロマチン構造変化を解明し、2)Txnipを介したエピゲノム調節を解明する。さらに、3)GLP-1受容体作動薬によるTxnip発現抑制と脱分化阻止を明らかにする。これらの成果よりTxnipを標的とする脱分化抑制とその先にある膵β細胞不全進展阻止の分子基盤と新規治療戦略の創出を行う。

Outline of Final Research Achievements

Pancreatic beta-cells become dedifferentiated in Wolfram syndrome caused by the WFS1 mutations. We investigated molecular mechanisms underlying beta-cell dedifferentiation in Wfs1KO mice. We found that Txnip highly expressed in mutant islets implicated to attenuated oxidative glycolysis and negative regulation of numerous genes involved in beta-cell function, oxidative metabolism, and development. The role of Txnip in beta-cell dedifferentiation was examined by crossing Wfs1KO mice with TxnipKO mice. A loss of Txnip maintained beta-cell identity and insulin secretion, and none of the double KO mice developed hyperglycemia over a 50-week observation period. Furthermore, the chronic administration with GLP-1 alleviated beta-cell dedifferentiation and restored the function in Wfs1KO mice with decreasing Txnip expression in islets. Taken together, Txnip could be a therapeutic target for prevention of beta-cell dedifferentiation and insulin insufficiency in Wolfram syndrome.

Academic Significance and Societal Importance of the Research Achievements

糖尿病は血糖値を下げるインスリンが十分に分泌されないことで発症する。この原因は現在でも十分解明されていないが、私たちはインスリンを産生分泌する細胞でこれまでに知られていない脱分化という細胞現象よりこの難問の解明に取り組んでいる。この研究で取り上げているウォルフラム症候群は希少な疾患であるが、病気の発症メカニズムはわが国に1000万人以上とされる2型糖尿病と多くの共通点があり、脱分化現象は2型糖尿病でも観察される。そのため、研究成果はウォルフラム症候群だけではなく一般の糖尿病の発症や病気が進行するメカニズムの解明とともに新しい治療法の開発にも貢献できることが期待される。

Report

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

    (18 results)

All 2023 2022 2021 2020

All Journal Article (7 results) (of which Peer Reviewed: 6 results,  Open Access: 5 results) Presentation (10 results) (of which Int'l Joint Research: 6 results,  Invited: 5 results) Book (1 results)

  • [Journal Article] A case of multiple glucagonomas with no clinical manifestations of excess glucagon despite hyperglucagonemia2023

    • Author(s)
      Amano S, Suenaga S, Hamamoto K, Yada S, Tsuyama T, Shinoda S, Tanaka Y, Takemoto Y, Harada E, Tanabe K, Asahara S, Hoshii K, Takami T.
    • Journal Title

      DEN Open

      Volume: 3 Issue: 1

    • DOI

      10.1002/deo2.230

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Gsk-3-Mediated Proteasomal Degradation of ATF4 Is a Proapoptotic Mechanism in Mouse Pancreatic β-Cells2022

    • Author(s)
      Nagao Y, Amo-Shiinoki K, Nakabayashi H, Hatanaka M, Kondo M, Matsunaga K, Emoto M, Okuya S, Tanizawa Y, Tanabe K
    • Journal Title

      Int J Mol Sci.

      Volume: 23 Issue: 21 Pages: 13586-13586

    • DOI

      10.3390/ijms232113586

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] ウォルフラム症候群の原因遺伝子WFS1の欠損が加齢性脳病理に及ぼす影響の解析2022

    • Author(s)
      榊原 泰史, 廣田 湧, 茨木 京子, 竹井 喜美, 西島 里咲, 田部 勝也, 谷澤 幸生, 関谷 倫子, 飯島 浩一
    • Journal Title

      Dementia Japan

      Volume: 36 Pages: 757-757

    • Related Report
      2022 Annual Research Report
  • [Journal Article] Importance of Intestinal Environment and Cellular Plasticity of Islets in the Development of Postpancreatectomy Diabetes.2021

    • Author(s)
      Fukuda T, Bouchi R, Takeuchi T, Amo-Shiinoki K, Kudo A, Tanaka S, Tanabe M, Akashi T, Hirayama K, Odamaki T, Igarashi M, Kimura I, Tanabe K, Tanizawa Y, Yamada T, Ogawa Y
    • Journal Title

      Diabetes Care

      Volume: 44(4) Issue: 4 Pages: 1002-1011

    • DOI

      10.2337/dc20-0864

    • Related Report
      2021 Research-status Report 2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Deficiency of WFS1 leads to the impairment of AVP secretion under dehydration in male mice.2021

    • Author(s)
      Kurimoto J, Takagi H, Miyata T, Hodai Y, Kawaguchi Y, Hagiwara D, Suga H, Kobayashi T, Sugiyama M, Onoue T, Ito Y, Iwama S, Banno R, Tanabe K, Tanizawa Y, Arima H.
    • Journal Title

      Pituitary

      Volume: in press Issue: 4 Pages: 582-588

    • DOI

      10.1007/s11102-021-01135-6

    • Related Report
      2021 Research-status Report 2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Islet cell dedifferentiation is a pathologic mechanism of long-standing progression of type 2 diabetes.2021

    • Author(s)
      Amo-Shiinoki K, Tanabe K, Hoshii Y, Matsui H, Harano R, Fukuda T, Takeuchi T, Bouchi R, Takagi T, Hatanaka M, Takeda K, Okuya S, Nishimura W, Kudo A, Tanaka S, Tanabe M, Akashi T, Yamada T, Ogawa Y, Ikeda E, Nagano H, Tanizawa Y.
    • Journal Title

      JCI Insight

      Volume: 6 Issue: 1 Pages: 143791-143791

    • DOI

      10.1172/jci.insight.143791

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] A patient with sudden hearing loss induced by propylthiouracil2021

    • Author(s)
      Tanabe Katsuya、Nishimura Shogo、Sugahara Kazuma、Yamashita Hiroshi、Tanizawa Yukio
    • Journal Title

      Heliyon

      Volume: 7 Issue: 2 Pages: e06196-e06196

    • DOI

      10.1016/j.heliyon.2021.e06196

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] グルカゴン需要増大に対するα細胞の挙動と細胞量調節機構.2022

    • Author(s)
      田部 勝也, 椎木 幾久子, 谷澤 幸生, 奥屋 茂
    • Organizer
      第65回日本糖尿病学会年次学術集会
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 糖尿病における膵島細胞の可塑性と脱分化.2022

    • Author(s)
      椎木 幾久子, 田部 勝也, 幡中 雅行, 奥屋 茂, 谷澤 幸生
    • Organizer
      第65回日本糖尿病学会年次学術集会
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Txnip preserves brown fat innate thermogenic activity2022

    • Author(s)
      Zou Meng, 田部 勝也, 椎木 幾久子, 田口 昭彦, 河野 大輔, 北村 忠弘, 奥屋 茂, 増谷 弘, 谷澤 幸生
    • Organizer
      第65回日本糖尿病学会年次学術集会
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] p:Gly44Ser変異によるMODY2患者6例の検討2022

    • Author(s)
      松隈 雅史, 豊重 充広, 山本 薫, 田部 勝也, 谷澤 幸生
    • Organizer
      第65回日本糖尿病学会年次学術集会
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 糖尿病における膵島細胞の可塑性と脱分化2021

    • Author(s)
      田部勝也
    • Organizer
      第64回日本糖尿病学会年次学術集会
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] 膵β細胞脱分化は2型糖尿病の病態進展に関連する2020

    • Author(s)
      椎木幾久子, 田部勝也, 幡中雅行, 奥屋茂, 福田達也, 竹内崇人, 坊内良太郎, 山田哲也, 小川佳宏, 谷澤幸生
    • Organizer
      第63回日本糖尿病学会年次学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] 膵β細胞脱分化は2型糖尿病の病態進展に関連する2020

    • Author(s)
      田部 勝也, 椎木 幾久子, 幡中 雅行, 谷澤 幸生
    • Organizer
      第93回日本内分泌学会学術総会
    • Related Report
      2020 Research-status Report
  • [Presentation] 膵β細胞脱分化は糖尿病患者の膵β細胞不全に関連する2020

    • Author(s)
      椎木 幾久子, 田部 勝也, 佐藤 吉彦, 駒津 光久, 谷澤 幸生
    • Organizer
      第70回日本体質医学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] 壮年期に診断されたMEN2Aの一例2020

    • Author(s)
      秋山優, 藤本留理子, 淀川拓馬, 竹田孔明, 田部勝也, 内野眞也, 横山繁生, 谷澤幸生
    • Organizer
      第93回日本内分泌学会学術総会
    • Related Report
      2020 Research-status Report
  • [Presentation] Islet beta-Cell Dedifferentiation Is Involved in Progression of Type 2 Diabetes.2020

    • Author(s)
      Kikuko Amo-Shiinoki, Katsuya Tanabe, Ryotaro Bouchi, Wataru Nishimura, Yoshihiro Ogawa, Yukio Tanizawa
    • Organizer
      80th Annual Meeting and Scientific Sessions of the American Diabetes Association
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Book] 月刊糖尿病2020

    • Author(s)
      椎木幾久子, 田部勝也, 谷澤幸生
    • Total Pages
      96
    • Publisher
      医学出版社
    • ISBN
      9784287821237
    • Related Report
      2020 Research-status Report

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Published: 2020-04-28   Modified: 2024-01-30  

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