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Elucidation of mechanisms regulating pancreatic b-cell proliferation using single-cell epigenomic analysis

Research Project

Project/Area Number 17K19654
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Research Field General internal medicine and related fields
Research InstitutionKyoto University

Principal Investigator

Inagaki Nobuya  京都大学, 医学研究科, 教授 (30241954)

Research Collaborator YABE Daisuke  京都大学大学院医学研究科, 先端糖尿病学, 特定准教授
WATANABE Akira  京都大学iPS細胞研究所, 未来生命科学開拓部, 主任研究員
Project Period (FY) 2017-06-30 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2018: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2017: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Keywords膵β細胞 / 増殖 / インスリン / 老化
Outline of Final Research Achievements

Mechanisms regulating pancreatic β cell mass remain largely unknown; and need to be investigated critically to invent potential therapeutics for diabetes. The current study aims to understand such mechanisms through multi-omics approaches including single-cell RNA-sequence of β cells before and after partial pancreatectomy, which induces robust β cell proliferation in young but not old mice. Our study revealed that β cells falls into 4 distinct subpopulations, one for which is characterized by expression of genes involved in cell proliferation and found only in young mice. We also found novel transcriptional factors possibly involved in β cell proliferation. In addition, we succeeded in the establishment of mice expressing the cell cycle reporter in β cells. Combined with the tissue clearing technique, we succeeded in measuring β cell proliferation in situ.

Academic Significance and Societal Importance of the Research Achievements

膵β細胞量減少は糖尿病予防・治療の重要な課題であるが膵β細胞量の制御機構の全容は不明であり、膵β細胞量を標的とした糖尿病治療法は存在しない。特に加齢とともに膵β細胞が増殖能を失う分子機序については、十分な検討がなされていない。膵β細胞の増殖制御機構を解明しようとする本研究は、糖尿病の発症や重症化を阻止するための全く新しい治療戦略創出の糸口となることが期待できる。

Report

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

    (26 results)

All 2019 2018 2017 Other

All Int'l Joint Research (4 results) Journal Article (16 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 16 results,  Open Access: 10 results,  Acknowledgement Compliant: 1 results) Presentation (6 results) (of which Int'l Joint Research: 4 results,  Invited: 1 results)

  • [Int'l Joint Research] University of Geneva(スイス)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] University of British Columbia(カナダ)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] University of Geneva(Switzerland)

    • Related Report
      2017 Research-status Report
  • [Int'l Joint Research] University of British Columbina(Canada)

    • Related Report
      2017 Research-status Report
  • [Journal Article] Sphingosine kinase 1-interacting protein is a dual regulator of insulin and incretin secretion2019

    • Author(s)
      Liu Y, Harashima SI, Wang Y, Suzuki K, Tokumoto S, Usui R, Tatsuoka H, Tanaka D, Yabe D, Harada N, Hayashi Y, Inagaki N.
    • Journal Title

      FASEB J.

      Volume: 33 Issue: 5 Pages: 6239-6253

    • DOI

      10.1096/fj.201801783rr

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Medium-chain triglyceride diet stimulates less GIP secretion and suppresses body weight and fat mass gain compared with long-chain triglyceride diet2019

    • Author(s)
      Murata Yuki、Harada Norio、Yamane Shunsuke、Iwasaki Kanako、Ikeguchi Eri、Kanemaru Yoshinori、Harada Takanari、Sankoda Akiko、Shimazu-Kuwahara Satoko、Joo Erina、Poudyal Hemant、Inagaki Nobuya
    • Journal Title

      American Journal of Physiology-Endocrinology and Metabolism

      Volume: in press Issue: 1 Pages: E53-E64

    • DOI

      10.1152/ajpendo.00200.2018

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Solid-phase extraction treatment is required for measurement of active glucagon-like peptide-1 by enzyme-linked immunosorbent assay kit affected by heterophilic antibodies.2019

    • Author(s)
      Hasegawa T, Komagata M, Hamasaki A, Harada N, Seino Y, Inagaki N
    • Journal Title

      Journal of Clinical Investigation

      Volume: 10 Issue: 2 Pages: 302-308

    • DOI

      10.1111/jdi.12896

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Exogenous C-type natriuretic peptide restores normal growth and prevents early growth plate closure in its deficient rats2018

    • Author(s)
      Hirota Keisho、Furuya Mayumi、… Yasoda Akihiro、Inagaki Nobuya
    • Journal Title

      PLOS ONE

      Volume: 13 Issue: 9 Pages: e0204172-e0204172

    • DOI

      10.1371/journal.pone.0204172

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Protein hypoacylation induced by Sirt5 overexpression has minimal metabolic effect in mice2018

    • Author(s)
      Bentley Nicholas L.、Fiveash Corrine E.、Osborne Brenna、Quek Lake-Ee、Ogura Masahito、Inagaki Nobuya、Cooney Gregory J.、Polly Patsie、Montgomery Magdalene K.、Turner Nigel
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 503 Issue: 3 Pages: 1349-1355

    • DOI

      10.1016/j.bbrc.2018.07.047

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Establishment of a method for in-vivo SPECT/CT imaging analysis of 111In-labeled exendin-4 pancreatic uptake in mice without the need for nephrectomy or a secondary probe.2018

    • Author(s)
      K. Hamamatsu, H. Fujimoto, N. Fujita, T. Murakami, H. Kimura, H. Saji, N. Inagaki
    • Journal Title

      Nucl Med Biol.

      Volume: 64-65 Pages: 22-27

    • DOI

      10.1016/j.nucmedbio.2018.06.002

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Live imaging analysis of the growth plate in a murine long bone explanted culture system2018

    • Author(s)
      Hirota Keisho、Yasoda Akihiro、Kanai Yugo、Ueda Yohei、Yamauchi Ichiro、Yamashita Takafumi、Sakane Yoriko、Fujii Toshihito、Inagaki Nobuya
    • Journal Title

      Scientific Reports

      Volume: 8 Issue: 1 Pages: 1-9

    • DOI

      10.1038/s41598-018-28742-x

    • NAID

      120006502590

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Transcriptional factor Pdx1 is involved in age-related GIP hypersecretion in mice.2018

    • Author(s)
      Ikeguchi E, Harada N, Kanemaru Y, Sankoda A, Yamane S, Iwasaki K, Imajo M, Murata Y, Suzuki K, Joo E, Inagaki N.
    • Journal Title

      Am J Physiol Gastrointest Liver Physiol.

      Volume: 315 Issue: 2 Pages: 272-272

    • DOI

      10.1152/ajpgi.00054.2018

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Glucose-dependent insulinotropic polypeptide is required for moderate high fat diet, but not high carbohydrate diet-induced weight gain.2018

    • Author(s)
      Maekawa R, Ogata H, Murase M, Harada N, Suzuki K, Joo E, Sankoda A, Iida A, Izumoto T, Tsunekawa S, Hamada Y, Oiso Y, Inagaki N, Arima H, Hayashi Y, Seino Y.
    • Journal Title

      Am J Physiol Endocrinol Metab.

      Volume: 6 Issue: 6 Pages: 111-112

    • DOI

      10.1152/ajpendo.00352.2017

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] β-cell-specific overexpression of adiponectin receptor 1 does not improve diabetes mellitus in Akita mice.2018

    • Author(s)
      Choi J, Kobayashi H, Okuda H, Harada KH, Takeda M, Fujimoto H, Yamane S, Tanaka D, Youssefian S, Inagaki N, Koizumi A.
    • Journal Title

      PLoS One

      Volume: 13 (1) Issue: 1 Pages: e0190863-e0190863

    • DOI

      10.1371/journal.pone.0190863

    • NAID

      120006459971

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] iPSC technology-based regenerative therapy for diabetes.2018

    • Author(s)
      Kondo Y, Toyoda T, Inagaki N, Osafune K.
    • Journal Title

      J Diabetes Investig

      Volume: 9 (2) Issue: 2 Pages: 234-243

    • DOI

      10.1111/jdi.12702

    • NAID

      120006454662

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance.2017

    • Author(s)
      Patel KA, Kettunen J, Laakso M, Stancakova; A, Laver TW, Colclough K, Johnson MB, Abramowicz M, Groop L, Miettinen PJ, Shepherd MH, Flanagan SE, Ellard S, Inagaki N, Hattersley AT, Tuomi T, Cnop M, Weedon MN.
    • Journal Title

      Nat Commun

      Volume: 8(1) Issue: 1 Pages: 888-888

    • DOI

      10.1038/s41467-017-00895-9

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Beta-cell replacement strategies for diabetes2017

    • Author(s)
      Kieffer Timothy J、Woltjen Knut、Osafune Kenji、Yabe Daisuke、Inagaki Nobuya
    • Journal Title

      Journal of Diabetes Investigation

      Volume: 9 Issue: 3 Pages: 457-463

    • DOI

      10.1111/jdi.12758

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Diverse metabolic effects of O-GlcNAcylation in the pancreas but limited effects in insulin-sensitive organs in mice.2017

    • Author(s)
      Ida S, Morino K, Sekine O, Ohashi N, Kume S, Chano T, Iwasaki K, Harada N, Inagaki N, Ugi S, Maegawa H.
    • Journal Title

      Diabetologia

      Volume: 60 (9) Issue: 6 Pages: 1761-1769

    • DOI

      10.1371/journal.pone.0179213

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of a small molecule that facilitates the differentiation of human iPSCs/ESCs and mouse embryonic pancreatic explants into pancreatic endocrine cells2017

    • Author(s)
      Kondo Yasushi、Toyoda Taro、Ito Ryo、Funato Michinori、Hosokawa Yoshiya、Matsui Satoshi、Sudo Tomomi、Nakamura Masahiro、Okada Chihiro、Zhuang Xiaotong、Watanabe Akira、Ohta Akira、Inagaki Nobuya、Osafune Kenji
    • Journal Title

      Diabetologia

      Volume: 60 Issue: 8 Pages: 1454-1466

    • DOI

      10.1007/s00125-017-4302-7

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Sphingosine kinase 1-interacting protein is a novel regulator of glucose-stimulated insulin secretion.2017

    • Author(s)
      Wang Y, Harashima SI, Liu Y, Usui R, Inagaki N.
    • Journal Title

      Sci Rep.

      Volume: 10 Issue: 1 Pages: 779-779

    • DOI

      10.1038/s41598-017-00900-7

    • NAID

      120006305887

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] 膵臓の再生を明らかにするシングルセル遺伝子発現及びマルチオミックス解析2018

    • Author(s)
      渡辺 亮、中村正裕、龍岡久登、矢部大介、稲垣暢也
    • Organizer
      第61回日本糖尿病年次学術集会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] ATP and Ca2+ dynamics in pancreatic b‐cells: ex vivo analysis using ATP biosensor GO‐ATeam12017

    • Author(s)
      R. Usui, D. Yabe, M. Fauzi, S. Tokumoto, H. Tatsuoka, Y. Tahara, M. Ogura, K. Nagashima and N. Inagaki.
    • Organizer
      9th Asian Association for the Study of Diabetes Scientific Meeting
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Sphingosine kinase 1‐interacting protein (SKIP) is a novel regulator of glucose‐stimulated insulin secretion2017

    • Author(s)
      Y. Wang, S.‐i. Harashima, Y. Liu, R. Usui and N. Inagaki
    • Organizer
      9th Asian Association for the Study of Diabetes Scientific Meeting
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Indium‐labeled Exendin probe enables to quantify beta cell mass non‐invasively with SPECT imaging2017

    • Author(s)
      N. Fujita, H. Fujimoto, K. Hamamatsu, T. Murakami, H. Kimura, K. Toyoda, H. Saji and N. Inagaki
    • Organizer
      9th Asian Association for the Study of Diabetes Scientific Meeting
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Depletion of sphingosine kinase 1‐interacting protein (SKIP) induces metabolically healthy obesity2017

    • Author(s)
      Y. Liu, S.‐i. Harashima, Y. Wang and N. Inagaki
    • Organizer
      9th Asian Association for the Study of Diabetes Scientific Meeting
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] 111InExendin4 SPECTを用いたカナグリフロジンの膵β細胞保護効果の検討2017

    • Author(s)
      浜松 圭太,藤本 裕之,藤田 直尚,塩谷 正治,木村 寛之, 豊田健太郎,佐治 英郎, 稲垣暢也
    • 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: 2017-07-21   Modified: 2020-03-30  

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