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

Midori Honma, Shojiro Sawada, Yoshiyuki Ueno, Keigo Murakami, Tetsuya Yamada, Junhong Gao, Shinjiro Kodama, Tomohito Izumi, Kei Takahashi, Sohei Tsukita, Kenji Uno, Junta Imai, Eiji Kakazu, Yasuteru Kondo, Kei Mizuno, Naoki Kawagishi, Tooru Shimosegawa, Hideki Katagiri

研究成果: Article査読

51 被引用数 (Scopus)


Background/objective:: Insulin signals, via the regulation of key enzyme expression, both suppress gluconeogenesis and enhance lipid synthesis in the liver. Animal studies have revealed insulin signaling favoring gluconeogenesis suppression to be selectively impaired in steatotic livers. However, whether, and if so how, such selective insulin resistance occurs in human steatotic livers remains unknown. Our aim was to investigate selective insulin resistance in human livers with non-alcoholic fatty liver disease (NAFLD). Subjects/methods:: We examined mRNA expressions of key molecules for insulin signaling, gluconeogenesis and lipogenesis in human liver biopsy samples obtained from 51 non-diabetic subjects: 9 healthy controls and 42 NAFLD patients, and analyzed associations of these molecules with each other and with detailed pathological and clinical biochemistry data. Results:: In NAFLD patients, insulin receptor substrate (IRS)-2 expression was decreased, while those of key enzymes for gluconeogenesis were increased. These alterations of IRS-2 and gluconeogenesis enzymes were induced both in simple steatosis (SS) and non-alcoholic steatohepatitis (NASH), while these expression levels did not differ between SS and NASH. Furthermore, alterations in the expressions of IRS-2 and gluconeogenesis enzymes showed strong negative correlations and were concurrently induced in the early histological stage of NAFLD. In contrast, fatty acid synthase (FAS) expression was not decreased in NAFLD, despite IRS-2 downregulation, but correlated strongly with IRS-1 expression. Furthermore, no histological scores were associated with these molecules. Thus, IRS-1 signaling, which is not impaired in NAFLD, appears to modulate FAS expression. Conclusion:: These analyses revealed that selective insulin resistance is present in human NAFLD livers and occurs in its early phases. 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.

ジャーナルInternational Journal of Obesity
出版ステータスPublished - 2018 9月 1

ASJC Scopus subject areas

  • 医学(その他)
  • 内分泌学、糖尿病および代謝内科学
  • 栄養および糖尿病


「Selective insulin resistance with differential expressions of IRS-1 and IRS-2 in human NAFLD livers」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。