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Genetic basis of and biomarker for complete destruction of beta-cells in type 1 diabetes

Research Project

Project/Area Number 21K08589
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 InstitutionKindai University

Principal Investigator

Ikegami Hiroshi  近畿大学, 医学部, 名誉教授 (20221062)

Co-Investigator(Kenkyū-buntansha) 馬場谷 成  近畿大学, 医学部, 講師 (10449837)
武友 保憲  近畿大学, 医学部, 講師 (20580591)
廣峰 義久  近畿大学, 医学部, 講師 (30460851)
能宗 伸輔  近畿大学, 医学部, 准教授 (90460849)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Keywords1型糖尿病 / 遺伝因子 / ゲノムワイド関連解析 / メタボローム解析 / バイオマーカー / 膵β細胞 / 完全廃絶 / 1型糖尿病 / 膵β細胞完全廃絶 / メタボローム / 1型糖尿病 バイオマーカー / 遺伝子 / 膵β細胞機能 / 遺伝素因
Outline of Research at the Start

膵β細胞機能の完全廃絶を規定する遺伝子を同定し、その分子メカニズムを明らかにするとともに膵β細胞完全廃絶を予測するバイオマーカーを探索することにより、内因性インスリンの完全枯渇阻止に資する基盤情報を得ることを目的とし、我々が最近劇症1型糖尿病のGWASで同定した1型糖尿病を劇症化させる遺伝子とその機能情報に基づいて行う極めて独自性の高い研究である。膵β細胞機能廃絶を規定する遺伝子解析と並行して、廃絶を予測するバイオマーカーをメタボローム解析で同定し、得られた遺伝子・バイオマーカーに関する情報を進行中の縦断研究(TIDE-J)において検証することにより臨床応用・展開にもつながる重要研究である。

Outline of Final Research Achievements

Genetic basis of and biomarkers for complete destruction of pancreatic beta-cells was studied to obtain basic information of complete destruction of beta-cells to establish effective methods for prevention and intervention of type 1 diabetes. Several loci with genome-wide significance were identified by the genome-wide association study (GWAS). Metabolome analysis in peripheral blood identified several metabolites discriminating acute vs chronic phases and complete abolishment vs minimal residual function of beta cells. In particular, hypotaurine was found to be a biomarker of ongoing beta-cell destruction in acute phase of type 1 diabetes. Hypotaurine is an intermediate metabolite in taurine synthesis, whose key enzyme, CSAD, was identified as a gene for fulminant type 1 diabetes by GWAS, indicating that the same taurine synthesis pathway identified through different approach, GWAS and metabolome analysis, is a promissive target for prevention and intervention of type 1 diabetes.

Academic Significance and Societal Importance of the Research Achievements

膵β細胞の完全廃絶に関与する遺伝子座やバイオマーカーの同定は、完全廃絶の分子メカニズムの解明という極めて高い学術的意義を有するとともに、膵β細胞完全廃絶の予知・予防・阻止法の標的となる分子・パスウェイを提示することから、膵β細胞の保護・機能保持を通じて、1型糖尿病の根治につながる極めて高い社会的意義を有する。具体的には、同定した新規遺伝子CSADとヒト末梢血メタボローム解析で同定したβ細胞破壊の急性期バイオマーカーHypotaurineは同じタウリン合成系の鍵酵素と中間代謝産物であることから、タウリン合成系が膵β細胞破壊の阻止における重要な標的であることを示している。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (30 results)

All 2024 2023 2022 2021

All Journal Article (23 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 23 results,  Open Access: 22 results) Presentation (7 results) (of which Int'l Joint Research: 3 results,  Invited: 1 results)

  • [Journal Article] Glucose values from the same continuous glucose monitoring sensor significantly differ among readers with different generations of algorithm2024

    • Author(s)
      Babaya Naru、Noso Shinsuke、Hiromine Yoshihisa、Taketomo Yasunori、Niwano Fumimaru、Yoshida Sawa、Yasutake Sara、Kawabata Yumiko、Maeda Norikazu、Ikegami Hiroshi
    • Journal Title

      Scientific Reports

      Volume: 14 Issue: 1 Pages: 5099-5099

    • DOI

      10.1038/s41598-024-55124-3

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] New diagnostic criteria (2023) for slowly progressive type 1 diabetes (SPIDDM): Report from Committee on Type 1 Diabetes of the Japan Diabetes Society (English version)2024

    • Author(s)
      Shimada A, Kawasaki E, Abiru N, Awata T, Oikawa Y, Osawa H, Kajio H, Kozawa J, Takahashi K, Chujo D, Noso S, Fukui T, Miura J, Yasuda K, Yasuda H, Imagawa A, Ikegami H
    • Journal Title

      Journal of Diabetes Investigation

      Volume: 15 Issue: 2 Pages: 254-257

    • DOI

      10.1111/jdi.14121

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] New diagnostic criteria (2023) for slowly progressive type 1 diabetes (SPIDDM): Report from Committee on Type 1 Diabetes in Japan Diabetes Society (English version)2024

    • Author(s)
      Shimada Akira、Kawasaki Eiji、Abiru Norio、Awata Takuya、Oikawa Yoichi、Osawa Haruhiko、Kajio Hiroshi、Kozawa Junji、Takahashi Kazuma、Chujo Daisuke、Noso Shinsuke、Fukui Tomoyasu、Miura Junnosuke、Yasuda Kazuki、Yasuda Hisafumi、Imagawa Akihisa、Ikegami Hiroshi
    • Journal Title

      Diabetology International

      Volume: 15 Issue: 1 Pages: 1-4

    • DOI

      10.1007/s13340-023-00679-1

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Prediction of future insulin-deficiency in glutamic acid decarboxylase autoantibody enzyme-linked immunosorbent assay-positive patients with slowly-progressive type 1 diabetes2024

    • Author(s)
      Kawasaki E, Awata T, Ikegami H, Imagawa A, Oikawa Y, Osawa H, Katsuki T, Kanatsuna N, Kawamura R, Kozawa J, Kodani N, Kobayashi T, Shimada A, Shimoda M, Takahashi K, Chujo D, Tsujimoto T, Tsuchiya K, Terakawa A, Terasaki J, Nagasawa K, Noso S, Fukui T, Horie I, Yasuda K, Yasuda H, Yanai H, Hanafusa T, Kajio H
    • Journal Title

      J Diabetes Investig.

      Volume: 15 Issue: 7 Pages: 835-842

    • DOI

      10.1111/jdi.14178

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Glycemic Excursion and Insulin Action Revealed in a Rare Case of Type 1 Diabetes Complicated with Short Bowel Syndrome2023

    • Author(s)
      Hiromine Yoshihisa、Noso Shinsuke、Babaya Naru、Taketomo Yasunori、Niwano Fumimaru、Okuda Yuki、Yasutake Sara、Minohara Tatsuro、Tsuda Naonobu、Hama Yuichiro、Ikegami Hiroshi
    • Journal Title

      Internal Medicine

      Volume: 62 Issue: 7 Pages: 1023-1029

    • DOI

      10.2169/internalmedicine.0287-22

    • ISSN
      0918-2918, 1349-7235
    • Year and Date
      2023-04-01
    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Which comes first in type 1 diabetes: Autoimmunity or dysglycemia?2023

    • Author(s)
      Ikegami H
    • Journal Title

      J Diabetes Investig.

      Volume: 14 Issue: 5 Pages: 645-647

    • DOI

      10.1111/jdi.13984

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] High Incidence of Diabetes Mellitus After Distal Pancreatectomy and Its Predictors: A Long-term Follow-up Study2023

    • Author(s)
      Imamura Shuzo、Niwano Fumimaru、Babaya Naru、Hiromine Yoshihisa、Matsumoto Ippei、Kamei Keiko、Yoshida Yuta、Taketomo Yasunori、Yoshida Sawa、Takeyama Yoshifumi、Noso Shinsuke、Maeda Norikazu、Ikegami Hiroshi
    • Journal Title

      The Journal of Clinical Endocrinology & Metabolism

      Volume: 109 Issue: 3 Pages: 619-630

    • DOI

      10.1210/clinem/dgad634

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Association between glycemic control and patient-reported outcomes in adults with type 1 diabetes in Japan: the SAGE study subanalysis2023

    • Author(s)
      Nishimura Rimei、Shimada Akira、Abiru Norio、Matsuhisa Munehide、Takahashi Yoko、Ikegami Hiroshi
    • Journal Title

      Diabetology International

      Volume: 15 Issue: 2 Pages: 212-222

    • DOI

      10.1007/s13340-023-00668-4

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Metabolic signatures of β‐cell destruction in type 1 diabetes2023

    • Author(s)
      Noso Shinsuke、Babaya Naru、Hiromine Yoshihisa、Taketomo Yasunori、Niwano Fumimaru、Yoshida Sawa、Ikegami Hiroshi
    • Journal Title

      Journal of Diabetes Investigation

      Volume: 14 Issue: 1 Pages: 48-57

    • DOI

      10.1111/jdi.13926

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Novel loci for hyperglycemia identified by QTL mapping of longitudinal phenotypes and congenic analysis2023

    • Author(s)
      Babaya Naru、Itoi-Babaya Michiko、Ueda Hironori、Kobayashi Misato、Noso Shinsuke、Hiromine Yoshihisa、Ishikawa Akira、Fujisawa Tomomi、Ikegami Hiroshi
    • Journal Title

      Scientific Reports

      Volume: 13 Issue: 1 Pages: 1315-1315

    • DOI

      10.1038/s41598-023-28189-9

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Bivalent GAD autoantibody ELISA improves clinical utility and risk prediction for adult autoimmune diabetes2023

    • Author(s)
      Kawasaki E, Shimada A, Imagawa A, Abiru N, Awata T, Oikawa Y, Osawa H, Kawabata Y, Kozawa J, Kobayashi T, Takahashi K, Chujo D, Fukui T, Miura J, Yasuda K, Yasuda H, Kajio H, Hanafusa T, Ikegami H; Committee of type 1 diabetes, Japan Diabetes Society.
    • Journal Title

      J Diabetes Investig.

      Volume: 14 Issue: 4 Pages: 570-581

    • DOI

      10.1111/jdi.13980

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Comparing the clinical significance and antigen specificity of insulinoma-associated antigen-2 autoantibodies between radioimmunoassay and enzyme-linked immunosorbent assay in Japanese patients with type 1 diabetes2023

    • Author(s)
      Kawasaki E, Shimada A, Imagawa A, Abiru N, Awata T, Oikawa Y, Osawa H, Kawabata Y, Kozawa J, Kobayashi T, Takahashi K, Chujo D, Fukui T, Miura J, Yasuda K, Yasuda H, Kajio H, Hanafusa T, Ikegami H; Committee of type 1 diabetes, Japan Diabetes Society.
    • Journal Title

      J Diabetes Investig.

      Volume: 14 Issue: 1 Pages: 58-66

    • DOI

      10.1111/jdi.13910

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Three-Year Observation of Glucose Metabolism After Pancreaticoduodenectomy: A Single-Center Prospective Study in Japan2022

    • Author(s)
      Niwano Fumimaru、Babaya Naru、Hiromine Yoshihisa、Matsumoto Ippei、Kamei Keiko、Taketomo Yasunori、Yoshida Sawa、Takeyama Yoshifumi、Noso Shinsuke、Ikegami Hiroshi
    • Journal Title

      The Journal of Clinical Endocrinology and Metabolism

      Volume: 107 Issue: 12 Pages: 3362-3369

    • DOI

      10.1210/clinem/dgac529

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Poor glycemic control rather than types of diabetes is a risk factor for sarcopenia in diabetes mellitus: The MUSCLES-DM study.2022

    • Author(s)
      Hiromine Y, Noso S, Rakugi H, Sugimoto K, Takata Y, Katsuya T, Fukuda M, Akasaka H, Osawa H, Tabara Y, Ikegami H.
    • Journal Title

      J Diabetes Investig.

      Volume: 13 Issue: 11 Pages: 1881-1888

    • DOI

      10.1111/jdi.13882

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Insulin-dependent diabetes mellitus in older adults: Current status and future prospects.2022

    • Author(s)
      Ikegami H, Hiromine Y, Noso S.
    • Journal Title

      Geriatr Gerontol Int.

      Volume: 22 Issue: 8 Pages: 549-553

    • DOI

      10.1111/ggi.14414

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] β‐Cell failure in diabetes: Common susceptibility and mechanisms shared between type 1 and type 2 diabetes2021

    • Author(s)
      Ikegami Hiroshi、Babaya Naru、Noso Shinsuke
    • Journal Title

      Journal of Diabetes Investigation

      Volume: 12 Issue: 9 Pages: 1526-1539

    • DOI

      10.1111/jdi.13576

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Relationship of continuous glucose monitoring-related metrics with HbA1c and residual β-cell function in Japanese patients with type 1 diabetes2021

    • Author(s)
      Babaya Naru、Noso Shinsuke、Hiromine Yoshihisa、Taketomo Yasunori、Niwano Fumimaru、Yoshida Sawa、Yasutake Sara、Kawabata Yumiko、Ikegami Hiroshi
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 4006-4006

    • DOI

      10.1038/s41598-021-83599-x

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Glucose Metabolism After Pancreatectomy: Opposite Extremes Between Pancreaticoduodenectomy and Distal Pancreatectomy2021

    • Author(s)
      Niwano Fumimaru、Babaya Naru、Hiromine Yoshihisa、Matsumoto Ippei、Kamei Keiko、Noso Shinsuke、Taketomo Yasunori、Takeyama Yoshifumi、Kawabata Yumiko、Ikegami Hiroshi
    • Journal Title

      The Journal of Clinical Endocrinology & Metabolism

      Volume: - Issue: 5 Pages: e2203-e2214

    • DOI

      10.1210/clinem/dgab036

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The SAGE study: Global observational analysis of glycaemic control, hypoglycaemia and diabetes management in T1DM2021

    • Author(s)
      Renard Eric、Ikegami Hiroshi、Daher Vianna Andr? Gustavo、Pozzilli Paolo、Brette Sandrine、Bosnyak Zsolt、Lauand Felipe、Peters Anne、Pilorget Valerie、Juri?i?‐Er?en Dubravka、Kesavadev Jothydev、Seufert Jochen、Wilmot Emma G.
    • Journal Title

      Diabetes/Metabolism Research and Reviews

      Volume: - Issue: 7

    • DOI

      10.1002/dmrr.3430

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Associations between genetic loci related to lean mass and body composition in type2 diabetes2021

    • Author(s)
      Minohara Tatsuro、Noso Shinsuke、Babaya Naru、Hiromine Yoshihisa、Taketomo Yasunori、Niwano Fumimaru、Makutani Yukako、Yoshida Sawa、Yasutake Sara、Imamura Shuzo、Ikegami Hiroshi
    • Journal Title

      Geriatrics and Gerontology International

      Volume: 21 Issue: 10 Pages: 932-938

    • DOI

      10.1111/ggi.14259

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Glycemic Control and Insulin Improve Muscle Mass and Gait Speed in Type 2 Diabetes: The MUSCLES-DM Study2021

    • Author(s)
      Sugimoto Ken、Ikegami Hiroshi、Takata Yasunori、Katsuya Tomohiro、Fukuda Masahiro、Akasaka Hiroshi、Tabara Yasuharu、Osawa Haruhiko、Hiromine Yoshihisa、Rakugi Hiromi
    • Journal Title

      Journal of the American Medical Directors Association

      Volume: 22 Issue: 4 Pages: 834-838.e1

    • DOI

      10.1016/j.jamda.2020.11.003

    • NAID

      120006952199

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Glycemic control status, diabetes management patterns, and clinical characteristics of adults with type 1 diabetes in Japan: Study of Adults’ Glycemia in T1DM subanalysis2021

    • Author(s)
      Abiru Norio、Shimada Akira、Nishimura Rimei、Matsuhisa Munehide、Ozaki Asuka、Ikegami Hiroshi
    • Journal Title

      Diabetology International

      Volume: 12 Issue: 4 Pages: 460-473

    • DOI

      10.1007/s13340-021-00504-7

    • NAID

      40022680897

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Japanese Type 1 Diabetes Database Study (TIDE-J): rationale and study design2021

    • Author(s)
      Daisuke Chujo, Akihisa Imagawa, Kazuki Yasuda, Hisafumi Yasuda, Toshiaki Hanafus, Hiroshi Kajio, et al.
    • Journal Title

      Diabetology International

      Volume: 13 Issue: 1 Pages: 288-294

    • DOI

      10.1007/s13340-021-00541-2

    • NAID

      40022803046

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Detectable proinsulin levels after the onset of fulminant type 1 diabetes: TIDE-J study2023

    • Author(s)
      Nagae R, Tachibana M, Imagawa A, Kodani N, Terasaki J, Kanatsuna N, Abiru N, Awata T, Ikegami H, Noso S, Oikawa Y, Shimada A, Osawa H, Kawamura R, Kawasaki E, Kozawa J, Kobayashi T, Shimoda M, Takahashi K, Chujo D, Tsujimoto T, Tsuchiya K, Nagasawa K, Fukui T, Yasuda K, Yasuda H, Hanafusa T, Kajio H
    • Organizer
      IDF-WPR Congress 2023 / 15th Scientific Meeting of AASD
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 受賞講演(ハーゲドーン賞)「1型糖尿病に関する分子遺伝学的研究」2023

    • Author(s)
      池上博司
    • Organizer
      第66回日本糖尿病学会年次学術集会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] 糖尿病患者におけるインスリン必要量に及ぼす膵β細胞量の影響:膵切除後前向き研究(KIP-MEPstudy)2023

    • Author(s)
      庭野史丸、馬場谷成、廣峰義久、松本逸平、亀井敬子、武友保憲、吉田左和、竹山宜典、能宗伸輔、池上博司
    • Organizer
      第96回日本内分泌学会学術総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] シンポジウム5:1型糖尿病の最前線 「我が国における1型糖尿病の遺伝素因」2023

    • Author(s)
      能宗伸輔、池上博司
    • Organizer
      第66回日本糖尿病学会年次学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] シンポジウム5:1型糖尿病の最前線 「日本糖尿病学会における1型糖尿病の臨床研究-レジストリ研究と免疫チェックポイント阻害薬による1型糖尿病研究について」2023

    • Author(s)
      今川彰久、島田朗、池上博司
    • Organizer
      第66回日本糖尿病学会年次学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Identification of rare variants in multiplex families of type 1 diabetes by whole-exome sequencing2021

    • Author(s)
      Noso S, Hosomichi K, Babaya N, Hiromine Y, Taketomo Y, Niwano F, Kawabata Y, Ikegami H
    • Organizer
      18th Immunology of Diabetes Society Congress
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] DIFFERENCES IN PATIENT-REPORTED OUTCOMES BY AGE AND REGION IN ADULTS WITH TYPE 1 DIABETES IN THE SAGE STUDY2021

    • Author(s)
      Berard L, Javier AF, Brette S, Kelly C, Ikegami H, Dubravka EJ, Bruttomesso D, Peters A, Pilorget V, Rammanthan B, Renard E, Wilmot E
    • Organizer
      14th International Conference on Advanced Technologies & Treatments for Diabetes
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research

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Published: 2021-04-28   Modified: 2025-01-30  

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