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

Peter J. Klover, Teresa Zimmers, Leonidas Koniaris, Robert A. Mooney

Research output: Contribution to journalArticle

337 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2784-2789
Number of pages6
JournalDiabetes
Volume52
Issue number11
DOIs
StatePublished - Nov 2003
Externally publishedYes

Fingerprint

Insulin Resistance
Interleukin-6
Liver
Insulin Receptor
Insulin Receptor Substrate Proteins
Obesity
Insulin
Signal Transduction
Phosphorylation
Glucokinase
Subcutaneous Infusions
Portal Vein
Type 2 Diabetes Mellitus
Tyrosine
Skeletal Muscle
Cytokines
Messenger RNA

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Chronic Exposure to Interleukin-6 Causes Hepatic Insulin Resistance in Mice. / Klover, Peter J.; Zimmers, Teresa; Koniaris, Leonidas; Mooney, Robert A.

In: Diabetes, Vol. 52, No. 11, 11.2003, p. 2784-2789.

Research output: Contribution to journalArticle

Klover, Peter J. ; Zimmers, Teresa ; Koniaris, Leonidas ; Mooney, Robert A. / Chronic Exposure to Interleukin-6 Causes Hepatic Insulin Resistance in Mice. In: Diabetes. 2003 ; Vol. 52, No. 11. pp. 2784-2789.
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