Interleukin-6 Induces Cellular Insulin Resistance in Hepatocytes

Joseph J. Senn1, Peter J. Klover2, Irena A. Nowak2, and Robert A. Mooney3 

1 Graduate Program in Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, New York
2 Graduate Program in Biochemistry, University of Rochester School of Medicine and Dentistry, Rochester, New York
3 Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 

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.

Senn JJ, Klover PJ, Nowak IA, Mooney RA. Interleukin-6 Induces Cellular Insulin Resistance in Hepatocytes. Diabetes. 2002;51:3391-3399. 

Last Modified: 2/5/2013