Growth Hormone Induces Cellular Insulin Resistance by Uncoupling Phosphatidylinositol 3-Kinase and Its Downstream Signals in 3T3-L1 Adipocytes

  1. Atsuko Takano,
  2. Tetsuro Haruta,
  3. Minoru Iwata,
  4. Isao Usui,
  5. Tatsuhito Uno,
  6. Junko Kawahara,
  7. Eiichi Ueno,
  8. Toshiyasu Sasaoka and
  9. Masashi Kobayashi
  1. First Department of Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan

    Abstract

    Growth hormone (GH) is well known to induce in vivo insulin resistance. However, the molecular mechanism of GH-induced cellular insulin resistance is largely unknown. In this study, we demonstrated that chronic GH treatment of differentiated 3T3-L1 adipocytes reduces insulin-stimulated 2-deoxyglucose (DOG) uptake and activation of Akt (also known as protein kinase B), both of which are downstream effects of phosphatidylinositol (PI) 3-kinase, despite enhanced tyrosine phosphorylation of insulin receptor substrate (IRS)-1, association of IRS-1 with the p85 subunit of PI 3-kinase, and IRS-1–associated PI 3-kinase activity. In contrast, chronic GH treatment did not affect 2-DOG uptake and Akt activation induced by overexpression of a membrane-targeted form of the p110 subunit of PI 3-kinase (p110CAAX) or Akt activation stimulated by platelet-derived growth factor. Fractionation studies indicated that chronic GH treatment reduces insulin-stimulated translocation of Akt from the cytosol to the plasma membrane. Interestingly, chronic GH treatment increased insulin-stimulated association of IRS-1 with p85 and IRS-1–associated PI 3-kinase activity preferentially in the cytosol. These results indicate that cellular insulin resistance induced by chronic GH treatment in 3T3-L1 adipocytes is caused by uncoupling between activation of PI 3-kinase and its downstream signals, which is specific to the insulin-stimulated PI 3-kinase pathway. This effect of GH might result from the altered subcellular distribution of IRS-1–associated PI 3-kinase.

    Footnotes

    • Address correspondence and reprint requests to Tetsuro Haruta, MD, PhD, First Dept. of Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan. E-mail: tharuta-tym{at}umin.ac.jp.

      Received for publication 19 September 2000 and accepted in revised form 8 May 2001.

      BSA, bovine serum albumin; DMEM, Dulbecco’s modified Eagle’s medium; DOG, deoxyglucose; FBS, fetal bovine serum; GH, growth hormone; HDM, high-density microsome; IR, insulin receptor; IRS, IR substrate; JAK2, Janus kinase 2; KRP, Krebs-Ringer phosphate; LDM, low-density microsome; MOI, multiplicity of infection; PDGF, platelet-derived growth factor; PDK-1; phosphoinositide-dependent protein kinase 1; PH, pleckstrin homology; PI, phosphatidylinositol; PM, plasma membrane; PMSF, phenylmethylsulfonyl fluoride; SH2, Src homology 2; STAT, signal transducers and activators of transcription.

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