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Analysis of islet remodeling in type 2 diabetes and exploratory regulation of endocrine cell transdifferentiation (metaplasia)

Research Project

Project/Area Number 16K09771
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Metabolomics
Research InstitutionThe Nukada Institute for Medical & Biological Research

Principal Investigator

Yagihashi Soroku  公益財団法人額田医学生物学研究所, その他部局等, その他 (40111231)

Research Collaborator Mizukami Hiroki  
Nukada Hitoshi  
Hotta Ryotarou  
Ogasawara Saori  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywords2型糖尿病 / 膵島 / アミロイド / 病理 / インスリン抵抗性 / 内分泌細胞分化 / β細胞 / ホルモン陰性内分泌細胞 / α細胞 / 膵ランゲルハンス島 / 分化転換 / 治療 / 細胞変換(化生) / 糖尿病治療 / インスリン / グルカゴンン / ソマトスタチン / 糖尿病 / 発生・分化 / トランスレーショナルリサーチ / 内科 / 細胞・組織
Outline of Final Research Achievements

Islet pathology in human type 2 diabetes is exemplified by beta-cell depletion and relative alpha-cell expansion as well as amyloid deposition. It is yet to be clear how these changes reflect clinical profile or predict the prognosis. In this study, we studied islet amyloid deposition and endocrine cell composition in 60 autopsy cases with type 2 diabetes and their correlation with clinical parameters. Islet pathology was morphometrically analyzed on pancreas sections stained with thioflavin to identify amyloid or with immunostains for endocrine cell discrimination. As results, amyloid deposition was associated with augmented reduction of both beta-cells and alpha-cells with impaired remodeling of islet endocrine cells. It was thus suggested that amyloid deposition destroyed islet microenvironment and compromised reserved capacity of the islet, worsening diabetes with resultant poor prognosis.

Academic Significance and Societal Importance of the Research Achievements

今回の研究により、日本人2型糖尿病の膵島でのアミロイド沈着が膵島リモデリングによる病態修復機構を干渉し、糖尿病病態を悪化、進展させている可能性が示された。脂質異常やインスリン抵抗性はアミロイド沈着と密接に関連しており、その抑制は糖尿病進展の抑制へとつながる。今回の研究成果は、2型糖尿病の新しい治療方向として、糖・脂質代謝と関連するインスリン抵抗性の改善、アミロイド沈着抑制による膵島微小環境の保護など有益である可能性を示すものである。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (35 results)

All 2019 2018 2017 2016

All Journal Article (16 results) (of which Int'l Joint Research: 9 results,  Peer Reviewed: 16 results,  Open Access: 14 results,  Acknowledgement Compliant: 4 results) Presentation (19 results) (of which Int'l Joint Research: 1 results,  Invited: 2 results)

  • [Journal Article] Cutaneous microangiopathy in patients with type2 diabetes: Impaired vascular endothelial growth factor expression and its correlation with neuropathy, retinopathy and nephropathy2019

    • Author(s)
      Sugimoto Kazuhiro、Murakami Hiroshi、Deguchi Takahisa、Arimura Aiko、Daimon Makoto、Suzuki Susumu、Shimbo Takuro、Yagihashi Soroku
    • Journal Title

      Journal of Diabetes Investigation

      Volume: 10 Issue: 5 Pages: 13020-13020

    • DOI

      10.1111/jdi.13020

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Diabetic Neuropathy: New Insights to Early Diagnosis and Treatments2018

    • Author(s)
      Yorek Mark、Malik Rayaz A.、Calcutt Nigel A.、Vinik Aaron、Yagihashi Soroku
    • Journal Title

      Journal of Diabetes Research

      Volume: 2018 Pages: 1-3

    • DOI

      10.1155/2018/5378439

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Distinct Inflammatory Changes of the Pancreas of Slowly Progressive Insulin-dependent (Type 1) Diabetes2018

    • Author(s)
      Aida Kaoru、Fukui Tomoyasu、Jimbo Erika、Yagihashi Soroku、Shimada Akira、Oikawa Yoichi、Mori Yasumichi、Fujii Takeshi、Nishida Yoriko、Koyama Rikako、Kobayashi Tetsuro
    • Journal Title

      Pancreas

      Volume: 47 Issue: 9 Pages: 1101-1109

    • DOI

      10.1097/mpa.0000000000001144

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Crucial role of Reg I from acinar-like cell cluster touching with islets (ATLANTIS) on mitogenesis of beta cells in EMC virus-induced diabetic mice2018

    • Author(s)
      Aida Kaoru、Kobayashi Tetsuro、Takeshita Akira、Jimbo Erika、Nishida Yoriko、Yagihashi Soroku、Hosoi Mitsuko、Fukui Tomoyasu、Sugawara Akira、Takasawa Shin
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 503 Issue: 2 Pages: 963-969

    • DOI

      10.1016/j.bbrc.2018.06.103

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A spontaneously immortalized Schwann cell line from aldose reductase-deficient mice as a useful tool for studying polyol pathway and aldehyde metabolism.2018

    • Author(s)
      Niimi N, Yako H, Takaku S, Kato H, Matsumoto T, Nishito Y, Watabe K, Ogasawara S, Mizukami H, Yagihashi S, Chung SK, Sango K.
    • Journal Title

      J Neurochem

      Volume: 144 Issue: 6 Pages: 710-722

    • DOI

      10.1111/jnc.14277

    • Related Report
      2018 Annual Research Report 2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Worsened outcome in patients with pancreatic ductal carcinoma on long-term diabetes: association with E-cadherin1 (CDH1) promoter methylation.2017

    • Author(s)
      Saito T, Mizukami H, Umetsu S, Uchida C, Inaba W, Abe M, Takahashi K, Kudo K, Itabashi C, Yagihashi S, Hakamada K.
    • Journal Title

      Sci Rep

      Volume: 7 Issue: 1 Pages: 18056-18067

    • DOI

      10.1038/s41598-017-18438-z

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Pancreas Atrophy and Islet Amyloid Deposition in patients with elderly-onset type 2 diabetes.2017

    • Author(s)
      Xin A, Mizukami H, Inaba W, Yoshida T, Takeuchi YK, Yagihashi S
    • Journal Title

      J Clin Endocrinol Metab.

      Volume: 102 Issue: 9 Pages: 3162-3171

    • DOI

      10.1210/jc.2016-3735

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Morphological dendritic spine changes of medium spiny neurons in the nucleus accumbens in 6-hydroxydopamine-lesioned rats treated with levodopa.2017

    • Author(s)
      Funamizu Y, Nishijima H, Ueno T, Ueno S, Mizukami H, Yagihashi S, Tomiyama M.
    • Journal Title

      Neurosci Res.

      Volume: 121 Pages: 49-53

    • DOI

      10.1016/j.neures.2017.03.010

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Impaired axonal regeneration in diabetes. Perspective on the underlying mechanism from in vivo and in vitro experimental studies.2017

    • Author(s)
      Sango K, Mizukami H, Horie H, Yagihashi S.
    • Journal Title

      Frontiers in Endocrinology

      Volume: 8 Pages: 12-12

    • DOI

      10.3389/fendo.2017.00012

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Four-year sequential nerve conduction changes since first visit in Japanese patients with early type 2 diabetes.2017

    • Author(s)
      Kobori M, Yagihashi S, Shiina N, Shiozawa N, Haginoya A, Ojima M, Douguchi S, Tamasawa A, Saitou M, Baba M, Osonoi T.
    • Journal Title

      J Diabetes Investig

      Volume: 8 Issue: 3 Pages: 369-376

    • DOI

      10.1111/jdi.12583

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Diabetes and pancreas size, does it matter?2017

    • Author(s)
      Yagihashi S
    • Journal Title

      J Diabetes Investig

      Volume: 8 Issue: 4 Pages: 413-415

    • DOI

      10.1111/jdi.12590

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Pancreatic ductal hyperplasia/dysplasia with obstructive chronic pancreatitis: an association with reduced pancreatic weight in type 1 diabetes.2016

    • Author(s)
      Kobayashi T, Aida K, Fukui T, Jimbo E, Shimada A, Mori Y, Fujii T, Yagihashi S.
    • Journal Title

      Diabetologia

      Volume: 59 Issue: 4 Pages: 865-867

    • DOI

      10.1007/s00125-016-3867-x

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Neuropathy in the spontaneously hypertensive rat: An electrophysiological and histological study2016

    • Author(s)
      Nukada H, Baba M, Ogasawara S, McMorran D, Yagihashi S
    • Journal Title

      Muscle Nerve

      Volume: - Issue: 4 Pages: 756-762

    • DOI

      10.1002/mus.25098

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Dynamic pathology of islet endocrine cells in type 2 diabetes: β-Cell growth, death, regeneration and their clinical implications2016

    • Author(s)
      Yagihashi S, Inaba W, Mizukami H
    • Journal Title

      J Diabetes Investig

      Volume: 7 Issue: 2 Pages: 155-165

    • DOI

      10.1111/jdi.12424

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Glucotoxic Mechanisms and Related Therapeutic Approaches2016

    • Author(s)
      Yagihashi S
    • Journal Title

      Int Rev Neurobiolo

      Volume: 127 Pages: 121-149

    • DOI

      10.1016/bs.irn.2016.03.006

    • ISBN
      9780128039151
    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] mRNA expression of delta-HER2 and its clinicopathological correlation in HER2-overexpressing breast cancer.2016

    • Author(s)
      Wada R, Yagihashi S, Naito Z
    • Journal Title

      Mol Med Rep

      Volume: 14 Pages: 5104-5110

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 新しい2型糖尿病亜分類の膵島病理学的所見に基づく検証2019

    • Author(s)
      水上浩哉,高橋和久,遅野井祥,工藤和洋,板橋智映子,八木橋操六
    • Organizer
      第62回日本糖尿病学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] ヒト2型糖尿病におけるM1マクロファージ浸潤と末梢神経病理学的変化2019

    • Author(s)
      山田咲季子,遅野井祥,高橋和久,工藤和洋,板橋智映子,八木橋操六,水上浩哉
    • Organizer
      第62回日本糖尿病学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] キサンチンオキシダーゼ阻害は糖尿病性神経障害DRGを改善する2019

    • Author(s)
      高橋和久,遅野井祥,小笠原早織,八木橋操六,水上浩哉
    • Organizer
      第62回日本糖尿病学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 正常高値HbA1cは小径神経障害の危険因子である2019

    • Author(s)
      板橋智映子,小笠原早織,高橋和久,遅野井祥,工藤和洋,内田知顕,梅津誠子,井川明子,八木橋操六,水上浩哉
    • Organizer
      第62回日本糖尿病学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 糖尿病性神経障害におけるM1マクロファージ浸潤は逆行性軸索輸送を減弱させる2019

    • Author(s)
      遲野井祥,水上浩哉,進藤陸生,高橋和久,小笠原早織,三五一憲,山本靖彦,山本博,八木橋操六
    • Organizer
      第62回日本糖尿病学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 一戸寛,遅野井祥,大徳菜々子,高橋和久,稲葉渡,工藤和洋,水上浩哉,八木橋操六2019

    • Author(s)
      膵島α,β,δ細胞は異なる機序で成熟する
    • Organizer
      第62回日本糖尿病学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 劇症1型糖尿病における膵病理の特徴2019

    • Author(s)
      滝田美夏子,神保江莉加,福井智康,会田薫,及川洋一,島田朗,八木橋操六,小林哲郎
    • Organizer
      第62回日本糖尿病学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 緩徐進行1型糖尿病(SPIDDM)における膵内外分泌腺異常2019

    • Author(s)
      神保江莉加,滝田美夏子,福井智康,会田薫,島田朗,及川洋一,八木橋操六,小林哲郎
    • Organizer
      第62回日本糖尿病学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 膵島アミロイド沈着と低酸素関連分子の発現について2019

    • Author(s)
      新井仁,遅野井祥,高橋和久,工藤和洋,板橋智映子,八木橋操六,水上浩哉
    • Organizer
      第62回日本糖尿病学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 緩徐進行1 型糖尿病と急性発症1 型糖尿病膵の同異点2018

    • Author(s)
      福井智康,八木橋操六,小林哲郎
    • Organizer
      第61回日本糖尿病学会学術集会総会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] 2型糖尿病と膵導管癌CDKN2A/P16プロモーターメチル化の関連2018

    • Author(s)
      阿部信,斎藤傑,内田知顕,梅津誠子,板橋智映子, 工藤和洋,八木橋操六,水上浩哉
    • Organizer
      第61回日本糖尿病学会学術集会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] 緩徐進行1型糖尿病(SPIDDM)における膵内外分泌腺異常2018

    • Author(s)
      神保江莉加,増田治美,福井智康,会田薫,八木橋操六, 島田朗,小林哲郎
    • Organizer
      第61回日本糖尿病学会学術集会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] 2型糖尿病モデルdb/dbマウスにおけるキサンチン酸化還元酵素阻害薬による膵島病理学的変化への影響2018

    • Author(s)
      吉田健一郎,高橋和久,遅野井祥,小笠原早織,八木橋操六,水上浩哉
    • Organizer
      第61回日本糖尿病学会学術集会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] 小児膵島は成人と異なる機序で維持される2018

    • Author(s)
      一戸寛,遅野井祥,成瀬亜純,木村ひより,高橋和久,阿部信,稲葉渉,水上浩哉,八木橋操六
    • Organizer
      第61回日本糖尿病学会学術集会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] 糖尿病性神経障害Update(教育講演)2016

    • Author(s)
      八木橋操六
    • Organizer
      第27回日本末梢神経学会
    • Place of Presentation
      大阪国際会議場
    • Year and Date
      2016-08-26
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] Islet alterations in patients with type 2 diabetes complicated with macroangiopathic diseases2016

    • Author(s)
      Takahashi K, Hiroki Mizukami, Tetsuyuki Tateda, Soroku Yagihashi
    • Organizer
      American Diabetes Association 76th meeting
    • Place of Presentation
      New Orleans, USA
    • Year and Date
      2016-06-08
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] 中高齢期の自然発症2型糖尿病GKラットの膵島変化に対するDPP-IV阻害薬効果2016

    • Author(s)
      稲葉渉、水上浩哉、小笠原早織、八木橋操六
    • Organizer
      第59回日本糖尿病学会
    • Place of Presentation
      京都国際会議場
    • Year and Date
      2016-05-16
    • Related Report
      2016 Research-status Report
  • [Presentation] 大血管障害を有する2型糖尿病者膵島の病理学的検討2016

    • Author(s)
      高橋和久、水上浩哉、八木橋操六
    • Organizer
      第59回日本糖尿病学会
    • Place of Presentation
      京都国際会議場
    • Year and Date
      2016-05-16
    • Related Report
      2016 Research-status Report
  • [Presentation] 緩徐進行1型糖尿病(SPIDDM)の病理学的検討2016

    • Author(s)
      神保絵梨佳、小林哲郎、福井智朗、八木橋操六
    • Organizer
      第59回日本糖尿病学会
    • Place of Presentation
      京都国際会議場
    • Year and Date
      2016-05-16
    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2020-03-30  

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