Interleukin-6 induces cellular insulin resistance in hepatocytes.
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
Joseph J
JJ
Graduate Program in Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Klover
Peter J
PJ
Nowak
Irena A
IA
Mooney
Robert A
RA
D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D007328:Insulin / Q000008:administration & dosage / Q000502:physiology; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000494:pharmacology*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism
D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D015850:Interleukin-6; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin; D014443:Tyrosine; C526292:IRS1 protein, human; C526295:Irs1 protein, mouse; C494918:AKT1 protein, human