Interleukin-6 Induces Cellular Insulin Resistance in Hepatocytes

  1. Joseph J. Senn1,
  2. Peter J. Klover2,
  3. Irena A. Nowak2 and
  4. Robert A. Mooney3
  1. 1Graduate Program in Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, New York
  2. 2Graduate Program in Biochemistry, University of Rochester School of Medicine and Dentistry, Rochester, New York
  3. 3Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York

    Abstract

    Interleukin (IL)-6 is one of several proinflammatory cytokines that have been associated with insulin resistance and type 2 diabetes. A two- to threefold elevation of circulating IL-6 has been observed in these conditions. Nonetheless, little evidence supports a direct role for IL-6 in mediating insulin resistance. Here, we present data that IL-6 can inhibit insulin receptor (IR) signal transduction and insulin action in both primary mouse hepatocytes and the human hepatocarcinoma cell line, HepG2. This inhibition depends on duration of IL-6 exposure, with a maximum effect at 1–1.5 h of pretreatment with IL-6 in both HepG2 cells and primary hepatocytes. The IL-6 effect is characterized by a decreased tyrosine phosphorylation of IR substrate (IRS)-1 and decreased association of the p85 subunit of phosphatidylinositol 3-kinase with IRS-1 in response to physiologic insulin levels. In addition, insulin-dependent activation of Akt, important in mediating insulin’s downstream metabolic actions, is markedly inhibited by IL-6 treatment. Finally, a 1.5-h preincubation of primary hepatocytes with IL-6 inhibits insulin-induced glycogen synthesis by 75%. These data suggest that IL-6 plays a direct role in insulin resistance at the cellular level in both primary hepatocytes and HepG2 cell lines and may contribute to insulin resistance and type 2 diabetes.

    Footnotes

    • Address correspondence and reprint requests to Robert A. Mooney, Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave., Rochester, NY 14642. E-mail: robert_mooney{at}urmc.rochester.edu.

      Received for publication 28 March 2002 and accepted in revised form 9 September 2002.

      DMEM, Dulbecco’s modified Eagle’s medium; FBS, fetal bovine serum; IL, interleukin; IκB, NF-κB inhibitor; IR, insulin receptor; IRS, IR substrate; NF, nuclear factor; PI, phosphatidlyinositol; SOCS, suppressors of cytokine signaling; TNF, tumor necrosis factor.

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