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Selective insulin resistance with differential expressions of IRS-1 and IRS-2 in human NAFLD livers

Research Project

Project/Area Number 16K09773
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Metabolomics
Research InstitutionTohoku University

Principal Investigator

Sawada Shojiro  東北大学, 大学病院, 講師 (60509420)

Co-Investigator(Kenkyū-buntansha) 宇野 健司  帝京大学, 医学部, 准教授 (50596632)
高 俊弘  東北大学, 学際科学フロンティア研究所, 助教 (70455781)
Research Collaborator HONMA Midori  
UENO Yoshiyuki  
MURAKAMI Keigo  
YAMADA Tetsuya  
KODAMA Shinjiro  
IZUMI Tomohito  
TAKAHASHI Kei  
TSUKITA Sohei  
IMAI Junta  
KAKAZU Eiji  
KONDO Yasuteru  
MIZUNO Kei  
KAWAGISHI Naoki  
SHIMOSEGAWA Toru  
KATAGIRI Hideki  
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: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords脂肪肝 / 選択的インスリン抵抗性 / 非アルコール性脂肪性肝疾患 / NAFLD / NASH
Outline of Final Research Achievements

In NAFLD patients, insulin receptor substrate (IRS)-2 expression was decreased, while those of key enzymes for gluconeogenesis were increased. The alterations in the expressions of IRS-2 and gluconeogenesis enzymes showed strong negative correlations. In contrast, fatty acid synthase (FAS) expression was not decreased in NAFLD, despite IRS-2 downregulation, but correlated strongly with IRS-1 expression. Thus, IRS-1 signaling, which is not impaired in NAFLD, appears to modulate FAS expression. These analyses revealed that selective insulin resistance is present in human NAFLD livers. The effect of insulin, during the IRS step, on gene expressions for lipogenesis and gluconeogenesis are apparently distinct and preferential downregulation of IRS-2 may contribute to selective resistance to the suppressive effects of insulin on gluconeogenesis.

Academic Significance and Societal Importance of the Research Achievements

NAFLDは2型糖尿病ともに世界的に増加している疾患であり、両疾患は疫学的にも密接な関連性を認める。一方、脂肪肝モデル動物による病態解析では肝脂肪化とインスリン作用を主とした糖代謝異常との間に共通の病態基盤が存在することが知られていたが、ヒトにおいても同様の病態が存在するかどうかは不明であった。。今回の研究でNAFLDの病態形成に「肝選択的インスリン抵抗性」の存在をヒトで明らかにしたことは、今後の脂肪肝診療に重要な学術的および社会的意義があると考える。

Report

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

    (2 results)

All 2018 2017

All Journal Article (1 results) (of which Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (1 results)

  • [Journal Article] Selective insulin resistance with differential expressions of IRS-1 and IRS-2 in human NAFLD livers2018

    • Author(s)
      Honma M, Sawada S, Ueno Y, Murakami K, Yamada T, Gao J, Kodama S, Izumi T, Takahashi K, Tsukita S, Uno K, Imai J, Kakazu E, Kondo Y, Mizuno K, Kawagishi N, Shimosegawa T, Katagiri H.
    • Journal Title

      Int J Obes (Lond).

      Volume: 42 Issue: 9 Pages: 1544

    • DOI

      10.1038/s41366-018-0062-9

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 非アルコール性脂肪性肝疾患(NAFLD)における2017

    • Author(s)
      澤田正二郎, 本間緑, 上野義之, 村上圭吾, 山田哲也, 児玉慎二郎, 井泉知仁, 高橋圭, 突田壮平, 宇野健司, 今井淳太, 嘉数英二, 近藤泰輝, 水野恵, 川岸直樹, 下瀬川徹, 片桐秀樹
    • 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: 2016-04-21   Modified: 2020-03-30  

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