2018 Fiscal Year Final Research Report
Selective insulin resistance with differential expressions of IRS-1 and IRS-2 in human NAFLD livers
| Project/Area Number |
16K09773
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | Tohoku University |
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Principal Investigator |
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| 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)
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| 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
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Keywords | 脂肪肝 / 選択的インスリン抵抗性 |
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| 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.
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| Free Research Field |
糖尿病学
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| 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。
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