Growth hormone inhibition of glucose uptake in adipocytes occurs without affecting GLUT4 translocation through an insulin receptor substrate-2-phosphatidylinositol 3-kinase-dependent pathway

Naoko Sasaki-Suzuki, Kiyoshi Arai, Tomomi Ogata, Kouhei Kasahara, Hideyuki Sakoda, Kazuhiro Chida, Tomoichiro Asano, Jeffrey E. Pessin, Fumihiko Hakuno, Shin Ichiro Takahashi

Research output: Contribution to journalArticle

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Abstract

Growth hormone (GH) pretreatment of 3T3-L1 adipocytes resulted in a concentration- and time-dependent inhibition of insulin-stimulated glucose uptake. Surprisingly, this occurred without significant effect on insulin-stimulated glucose transporter (GLUT) 4 translocation or fusion with the plasma membrane. In parallel, the inhibitory actions of chronic GH pretreatment also impaired insulin-dependent activation of phosphatidylinositol (PI) 3-kinase bound to insulin receptor substrate (IRS)-2 but not to IRS-1. In addition, insulin-stimulated Akt phosphorylation was inhibited by GH pretreatment. In contrast, overexpression of IRS-2 or expression of a constitutively active Akt mutant prevented the GH-induced insulin resistance of glucose uptake. Moreover, small interfering RNA-mediated IRS-2 knockdown also inhibited insulin-stimulated Akt activation and glucose uptake without affecting GLUT4 translocation and plasma membrane fusion. Together, these data support a model in which chronic GH stimulation inhibits insulin-dependent activation of phosphatidylinositol 3-kinase through a specific interaction of phosphatidylinositol 3-kinase bound to IRS-2. This inhibition leads to suppression of Akt activation coupled to glucose transport activity bur not translocation or plasma membrane fusion of GLUT4.

Original languageEnglish (US)
Pages (from-to)6061-6070
Number of pages10
JournalJournal of Biological Chemistry
Volume284
Issue number10
DOIs
StatePublished - Mar 6 2009

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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