Chronic Exposure to Interleukin-6 Causes Hepatic Insulin Resistance in Mice

  1. Peter J. Klover12,
  2. Teresa A. Zimmers3,
  3. Leonidas G. Koniaris3 and
  4. Robert A. Mooney1
  1. 1Department of Pathology and Laboratory Medicine, 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 Surgery, University of Rochester School of Medicine and Dentistry, Rochester, New York
  1. 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

Abstract

Interleukin (IL)-6 is one of several proinflammatory cytokines associated with the insulin resistance of obesity and type 2 diabetes. There is, however, little direct evidence in vivo for a causative role of IL-6 in insulin resistance. Here, a 5-day constant subcutaneous infusion of hIL-6 before portal vein insulin challenge resulted in impairment of early insulin receptor signaling in the liver of mice. Importantly, the sixfold elevation of IL-6 attained with constant infusion was similar to levels reached in obesity. Consistent with an hepatic response to IL-6, STAT3 phosphorylation was increased in livers of IL-6-treated mice at 5 days. Chronic infusion of IL-6 also reduced hepatic insulin receptor autophosphorylation by 60% and tyrosine phosphorylation of insulin receptor substrates-1 and -2 by 60 and 40%, respectively. IL-6 had no effect on the mass of these proteins. IL-6 also decreased refeeding-dependent glucokinase mRNA induction by ∼40%. Insulin tolerance tests revealed reduced insulin sensitivity. In contrast to hepatic insulin receptor signal transduction, 5-day IL-6 exposure failed to suppress skeletal muscle insulin receptor signal transduction. These data suggest that chronic IL-6 treatment selectively impairs hepatic insulin signaling in vivo, further supporting a role for IL-6 in hepatic insulin resistance of obesity.

Footnotes

    • Accepted August 15, 2003.
    • Received June 25, 2003.
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