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Role for two distinct lineages of beta cells in diabetes progression

Research Project

Project/Area Number 20H03463
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 49030:Experimental pathology-related
Research InstitutionGunma University

Principal Investigator

Fujitani Yoshio  群馬大学, 生体調節研究所, 教授 (30433783)

Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥14,560,000 (Direct Cost: ¥11,200,000、Indirect Cost: ¥3,360,000)
Fiscal Year 2022: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Keywords膵β細胞 / PP細胞 / 膵ラ氏島 / シングルセルRNA解析 / 膵島 / β細胞 / 糖尿病 / 細胞系譜追跡 / グルコース応答性 / Ppy
Outline of Research at the Start

これまでの研究で我々は糖尿病発症の鍵を握る膵β細胞に、起源の異なる2系統の細胞集団が存在することを突き止めた。また、この2系統のβ細胞は、遺伝子発現が異なることから、その働きにも違いがあることが強く示唆された。すなわち、より未分化な形質を示すβ細胞系列の方が高血糖などのストレス時に障害されにくい可能性がある。この2つのβ細胞系列の特徴を明らかにして、人為的に制御することにより、糖尿病の発症抑制を行なうことが可能かどうか、多面的に検討してゆきたい。

Outline of Final Research Achievements

By combining cell lineage tracing experiments using Ppy-Cre mice with single-cell RNA analysis, it was shown that β-cells can be categorized into two lineages: Ppy-lineage β-cells and non-Ppy-lineage β-cells. Ppy-lineage β-cells are located at the periphery of the islets, are less glucose- and Ca2+-responsive, have a gene expression profile similar to that of PP cells. Ppy-lineage β-cells are immature as multihormonal β-cells that express not only INS but also Ppy, Gcg, and Som. Furthermore, they were more resistant to β-cell injury in diabetic conditions than non-Ppy lineageβ-cells.

Academic Significance and Societal Importance of the Research Achievements

膵ラ氏島に存在するβ細胞はインスリン分泌を担う体内で唯一の細胞腫であり、その機能や数の低下は、現在日本の国民病のひとつとなっている糖尿病の原因となる。今回我々の研究により、他の膵内分泌細胞であるPP細胞が発現するPpy遺伝子をマーカーとして用いることにより、β細胞が大きく2種類に大別されることが明らかとなった。Ppyと関係のあるβ細胞は、関係のないβ細胞に比べて、機能的に未熟であり、血糖に応答してインスリンを分泌する能力は弱いが、傷害に強いβ細胞であることが明らかになった。このようなβ細胞の新しい多様性の発見は、糖尿病の病態の理解や新たな治療につながる可能性がある。

Report

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

    (40 results)

All 2023 2022 2021 2020 2019 Other

All Int'l Joint Research (3 results) Journal Article (14 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 14 results,  Open Access: 13 results) Presentation (19 results) (of which Int'l Joint Research: 2 results,  Invited: 10 results) Book (2 results) Remarks (2 results)

  • [Int'l Joint Research] ジュネーブ大学(スイス)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] ミネソタ大学(米国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] ジュネーブ大学(スイス)

    • Related Report
      2020 Annual Research Report
  • [Journal Article] Zinc and iron dynamics in human islet amyloid polypeptide-induced diabetes mouse model2023

    • Author(s)
      Fukunaka Ayako、Shimura Mari、Ichinose Takayuki、Pereye Ofejiro B.、Nakagawa Yuko、Tamura Yasuko、Mizutani Wakana、Inoue Ryota、Inoue Takato、Tanaka Yuto、Sato Takashi、Saitoh Tatsuya、Fukada Toshiyuki、Nishida Yuya、Miyatsuka Takeshi、Shirakawa Jun、Watada Hirotaka、Matsuyama Satoshi、Fujitani Yoshio
    • Journal Title

      Scientific Reports

      Volume: 13 Issue: 1 Pages: 3484-3484

    • DOI

      10.1038/s41598-023-30498-y

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Overexpression of Pdx1, reduction of p53, or deletion of CHOP attenuates pancreas hypoplasia in mice with pancreas-specific O-GlcNAc transferase deletion2023

    • Author(s)
      Wong A, Pritchard S, Moore M, Akhaphong B, Avula N, Beetch M, Fujitani Y, Alejandro EU.
    • Journal Title

      J Biol Chem

      Volume: 299 Issue: 2 Pages: 102878-102878

    • DOI

      10.1016/j.jbc.2023.102878

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Establishment of an enzyme-linked immunosorbent assay for mouse pancreatic polypeptide clarifies the regulatory mechanism of its secretion from pancreatic γ cells2022

    • Author(s)
      Saito Daisuke、Nakagawa Yuko、Sato Takashi、Fukunaka Ayako、Pereye Ofejiro Blessing、Maruyama Nobuhiro、Watada Hirotaka、Fujitani Yoshio
    • Journal Title

      PLOS ONE

      Volume: 17 Issue: 8 Pages: e0269958-e0269958

    • DOI

      10.1371/journal.pone.0269958

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cumulative autophagy insufficiency in mice leads to progression of β-cell failure2022

    • Author(s)
      Suzuki L, Miyatsuka T, Himuro M, Wakabayashi Y, Osonoi S, Miura M, Katahira T, Fujitani Y, Iida H, Mizukami H, Nishida Y, Watada H
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 611 Pages: 38-45

    • DOI

      10.1016/j.bbrc.2022.04.040

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] STAT3 suppression and β-cell ablation enhance α-to-β reprogramming mediated by Pdx12022

    • Author(s)
      Wakabayashi Y, Miyatsuka T, Miura M, Himuro M, Taguchi T, Iida H, Nishida Y, Fujitani Y, Watada H
    • Journal Title

      Sci Rep

      Volume: 12 Issue: 1 Pages: 21419-21419

    • DOI

      10.1038/s41598-022-25941-5

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Adult pancreatic islet endocrine cells emerge as fetal hormone-expressing cells.2022

    • Author(s)
      Merez-Frances M, Abate MV, Baronnier D, Scherer PE, Fujitani Y, Thorel F, Herrera PL
    • Journal Title

      Cell Reports

      Volume: 38 Issue: 7 Pages: 110377-110377

    • DOI

      10.1016/j.celrep.2022.110377

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Characterisation of Ppy-lineage cells clarifies the functional heterogeneity of pancreatic beta cells in mice2021

    • Author(s)
      Fukaishi Takahiro、Nakagawa Yuko、Fukunaka Ayako、Sato Takashi、Hara Akemi、Nakao Keiko、Saito Michiko、Kohno Kenji、Miyatsuka Takeshi、Tamaki Motoyuki、Matsuhisa Munehide、Matsuoka Taka-aki、Yamada Tetsuya、Watada Hirotaka、Fujitani Yoshio
    • Journal Title

      Diabetologia

      Volume: 64 Issue: 12 Pages: 2803-2816

    • DOI

      10.1007/s00125-021-05560-x

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Pancreatic islet Ppy-expressing gamma-cells display mixed phenotypic traits and have the adaptive plasticity to engage insulin production.2021

    • Author(s)
      Perez-Frances M, van Gurp L, Abate MV, Cigliola V, Furuyama K, Bru-Tari E, Oropeza D, Carreaux T, Fujitani Y, Thorel F, Herrera PL.
    • Journal Title

      Nature Communications

      Volume: 12 Issue: 1 Pages: 4458-4458

    • DOI

      10.1038/s41467-021-24788-0

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] ATF4-mediated transcriptional regulation protects against β-cell loss during endoplasmic reticulum stress in a mouse model2021

    • Author(s)
      Kitakaze Keisuke、Oyadomari Miho、Zhang Jun、Hamada Yoshimasa、Takenouchi Yasuhiro、Tsuboi Kazuhito、Inagaki Mai、Tachikawa Masanori、Fujitani Yoshio、Okamoto Yasuo、Oyadomari Seiichi
    • Journal Title

      Molecular Metabolism

      Volume: 54 Pages: 101338-101338

    • DOI

      10.1016/j.molmet.2021.101338

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] OGT regulates mitochondrial biogenesis and function via diabetes susceptibility gene Pdx1.2021

    • Author(s)
      Mohan R, Jo S, Lockridge A, Ferrington DA, Murray K, Eschenlauer A, Bernal-Mizrachi E, Fujitani Y, Alejandro EU.
    • Journal Title

      Diabetes

      Volume: 70 Issue: 11 Pages: 2608-2625

    • DOI

      10.2337/db21-0468

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Leukotriene A4 hydrolase deficiency protects mice from diet-induced obesity by increasing energy expenditure through neuroendocrine axis.2020

    • Author(s)
      Uzawa H, Kohno D, Koga T, Sasaki T, Fukunaka A, Okuno T, Jo-Watanabe A, Kazuno S, Miyatsuka T, Kitamura T, Fujitani Y, Watada H, Saeki K*, Yokomizo T
    • Journal Title

      FASEB J

      Volume: 34(10) Issue: 10 Pages: 13949-13958

    • DOI

      10.1096/fj.202001148r

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Rubicon is dispensable for maintaining homeostasis in pancreatic beta cells following increased insulin resistance.2020

    • Author(s)
      Aoyama S, Nishida Y, Fujitani Y, Fukunaka A, Miyatsuka T, Suzuki L, Himuro M, Yoshimori T, Watada H.
    • Journal Title

      Endocr J.

      Volume: 67(11) Issue: 11 Pages: 1119-1126

    • DOI

      10.1507/endocrj.ej20-0326

    • NAID

      130007945802

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Transcriptome Analysis Dissects the Replicating Process of Pancreatic Beta Cells in Partial Pancreatectomy Model2020

    • Author(s)
      Tatsuoka H, Sakamoto S, Yabe D, Kabai R, Kato U, Okumura T, Botagarova A, Tokumoto S, Usui R, Ogura M, Nagashima K, Mukai E, Fujtani Y, Watanabe A, Inagaki N
    • Journal Title

      iScience

      Volume: 23 Issue: 12 Pages: 101774-101774

    • DOI

      10.1016/j.isci.2020.101774

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] How do you make new β-cells in humans? An attempt to create human β-cells from α-cells of brain-dead donors.2019

    • Author(s)
      Fujitani Y
    • Journal Title

      J Diabetes Investig

      Volume: 未定 Issue: 3 Pages: 513-515

    • DOI

      10.1111/jdi.13197

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 膵β細胞の機能的多様性2023

    • Author(s)
      藤谷与士夫
    • Organizer
      第57回糖尿病学の進歩 (オンデマンド配信)
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Genetically induced immortalization of Ppy-expressing cells results in pancreatic ductal adenocarcinoma2023

    • Author(s)
      Ofejiro B. Pereye, Takashi Sato, Yuko Nakagawa, Ayako Fukunaka, Akihisa Fukuda, Hiroki Mizukami and Yoshio Fujitani
    • Organizer
      第36回日本糖尿病肥満動物学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Genetically induced immortalization of Ppy-expressing cells results in pancreatic ductal adenocarcinoma2023

    • Author(s)
      Ofejiro B. Pereye, 佐藤隆史, 中川祐子,福中彩子, 青山周平, 西田友哉, 綿田裕孝, 福田晃久, 水上浩哉, 藤谷与士夫
    • Organizer
      日本生理学会 第100回記念大会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Ppy遺伝子の活性化が膵β細胞の機能的多様性を規定する2022

    • Author(s)
      藤谷与士夫
    • Organizer
      第65回日本糖尿病学会年次学術集会 シンポジウム
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] PP細胞研究から解き明かす膵β細胞の多様性2022

    • Author(s)
      藤谷与士夫
    • Organizer
      第95回日本内分泌学会学術総会 シンポジウム
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] A novel Islet-derived mouse pancreatic ductal adenocarcinoma model2022

    • Author(s)
      Ofejiro B. Pereye, 佐藤隆史, 中川祐子, 福中彩子, 藤谷与士夫
    • Organizer
      第35回日本糖尿病肥満動物学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Genetically induced immortalization of Ppy-expressing cells results in malignant transformation2022

    • Author(s)
      Ofejiro B. Pereye, 佐藤隆史, 中川祐子, 福中彩子, 藤谷与士夫
    • Organizer
      第95回日本内分泌学会学術総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Genetically induced immortalization of Ppy-expressing cells results in Pancreatic Ductal Adenocarcinoma2022

    • Author(s)
      Ofejiro B. Pereye, 佐藤隆史, 中川祐子,福中彩子, 青山周平, 西田友哉, 綿田裕孝, 福田晃久, 水上浩哉, 藤谷与士夫
    • Organizer
      25th Diabetes Research Forum in Tokyo
    • Related Report
      2022 Annual Research Report
  • [Presentation] Genetically induced immortalization of Ppy-expressing cells results in Pancreatic Ductal Adenocarcinoma2022

    • Author(s)
      Ofejiro B. Pereye, Takashi Sato, Yuko Nakagawa, Ayako Fukunaka, Shuhei Aoyama, Yuya Nishida, Hirotaka Watada, Akihisa Fukuda, Hiroki Mizukami and Yoshio Fujitani
    • Organizer
      The 8th IMCR Symposium on Endocrine and Metabolism
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 膵ラ氏島の残されたフロンティア―PP細胞の生物学2021

    • Author(s)
      藤谷与士夫
    • Organizer
      第94回日本内分泌学会年次学術集会 シンポジウム
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Ppy遺伝子の活性化が規定する膵β細胞の機能的多様性2021

    • Author(s)
      藤谷与士夫
    • Organizer
      The14th Diabetes Leading-edge Conference
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] PP細胞から切り拓く膵島研究の新展開2021

    • Author(s)
      藤谷与士夫
    • Organizer
      Islet E-quality Meeting 9th
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] PP細胞から切り拓く膵島研究の新展開2021

    • Author(s)
      藤谷与士夫
    • Organizer
      徳島大学先端酵素学研究所 2021年度 共同利用・共同研究拠点 成果報告会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 内分泌前駆細胞としてのPpy lineage cellの解析2020

    • Author(s)
      深石貴大, 佐藤隆史, 中川祐子, 福中彩子, 松岡孝昭, 原朱美, 宮塚健, 綿田裕孝, 藤谷与士夫
    • Organizer
      第63回日本糖尿病学会年次学術総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Ppy-lineage beta cells as a minor subpopulation from different origin2020

    • Author(s)
      Fukaishi T, Fukunaka A , Nakagawa Y, Sato T, Matsuoka TA, Hara A, Miyatsuka T, Watada H, and Fujitani Y
    • Organizer
      The 15th International Symposium of the Institute Network for Biomedical Sciences The 6th IMCR Symposium on Endocrine and Metabolism
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] A trial for the establishment of pancreatic endocrine cell lines using a new transgenic-mouse model2020

    • Author(s)
      Ofejiro P, Sato T, Nakagawa Y, Ayako Fukunaka A, Fujitani Y
    • Organizer
      第67回北関東医学会総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] グルカゴンシグナルによる膵PP細胞の過形成のメカニズムの解明2020

    • Author(s)
      中川祐子、林 良敬、北村忠弘、堀居拓郎、畑田出穂、藤谷与士夫
    • Organizer
      第63回日本糖尿病学会年次学術総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 糖尿病発症予防にかかわる 膵β細胞恒常性維持機構の基礎知識2020

    • Author(s)
      藤谷与士夫
    • Organizer
      第54回糖尿病学の進歩
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] PP細胞の可塑性2020

    • Author(s)
      藤谷与士夫
    • Organizer
      第63回日本糖尿病学会年次学術集会 シンポジウム
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Book] 朝倉内科学 第12版 代謝栄養系の異常 1)生体のホメオスターシスと代謝調節2021

    • Author(s)
      藤谷与士夫
    • Total Pages
      5
    • Publisher
      朝倉書店
    • Related Report
      2021 Annual Research Report
  • [Book] 糖尿病・内分泌代謝科 [モデル動物を用いた糖尿病・肥満症研究による病態解明と治療法開発]ベージュ脂肪細胞の発生起源(解説/特集)2020

    • Author(s)
      福中彩子、藤谷与士夫
    • Total Pages
      6
    • Publisher
      科学評論社
    • Related Report
      2020 Annual Research Report
  • [Remarks] 生体調節研究所 分子糖代謝制御分野 藤谷研究室

    • URL

      https://tou-taisha.imcr.gunma-u.ac.jp/

    • Related Report
      2022 Annual Research Report
  • [Remarks] 群馬大学生体調節研究所 分子糖代謝制御分野

    • URL

      https://tou-taisha.imcr.gunma-u.ac.jp/

    • Related Report
      2021 Annual Research Report

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

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