Interleukin-6 as a mediator of insulin resistance

Abstract

A potential role of interleukin (IL)-6 for the metabolic abnormalities seen in obesity and insulinresistance was postulated when it was discovered that circulating IL-6 levels were elevated in obeseand insulin-resistant as well as type 2 diabetic individuals. Later it was shown that the adipose tissuewas a major site of IL-6 production, accounting for 15-35% of the total circulating levels. Significantcorrelations have been shown between serum levels of IL-6 and body mass index (BMI), percent fatmass, blood pressure and fasting insulin levels. Moreover, IL-6 is an independent predictor of risk ofdeveloping type 2 diabetes, irrespective of amount of body fat.We have now found that the interstitial IL-6 concentration in adipose tissue was ~100 times higherthan that in plasma, suggesting a role for IL-6 as a paracrine regulator in this tissue. Furthermore, thegene expression of several adipocyte differerentiation markers, like adiponectin, aP2 and PPARgamma PPAR , wasdown-regulated in human adipose tissue treated with IL-6 in vitro, suggesting that IL-6 might favourthe development of enlarged adipocytes by reducing adipogenesis. Fat cell size is, independently ofBMI, a predictor of insulin resistance and type 2 diabetes. We found that gene expression as well asinterstitial levels and secretion of IL-6 from human adipose tissue is positively correlated with fatcell size. Moreover, non-obese, insulin-resistant subjects had markedly upregulated adipocyte IL-6gene expression.We also found that human adipose cells, like 3T3-L1 cells, express all components important forIL-6 signaling and that this signaling system is activated by IL-6. Long-term exposure to IL-6resulted in a significant decrease in insulin receptor substrate (IRS)-1 gene and protein expressionas well as tyrosine phosphorylation in response to insulin. Furthermore, a reduction in gene andprotein expression of GLUT-4 (glucose transporter-4) was also seen and this was accompanied bya significant decrease in insulin-stimulated glucose transport. IL-6 did not have any acute effectson the insulin receptor or downstream proteins in the insulin signaling pathway, e.g., IRS-1, IRS-2or Protein Kinase B (PKB). Th ese data show that IL-6 can induce insulin resistance in the adiposetissue.We investigated in vivo the short-term effect of IL-6 in rats during a two hour euglycemichyperinsulinemicclamp. The IL-6 signaling in fat, muscle and liver was activated by the IL-6infusion. However, we did not find any significant effect on glucose uptake or plasma levels ofadiponectin or free fatty acids, nor did we find changes in the upstream insulin signaling in fat,muscle or liver. There were only small or no changes in the expression of the genes analyzed (GLUT-4, PGC-1, IL-6 receptor, adiponectin, IL-6 and SOCS-3) after 120 min. These data clearly showthat IL-6 does not have important acute effects on insulin signaling in the adipose tissue or onglucose homeostasis in vivo, which supports our in vitro results that IL-6 is a cytokine that mainlyexerts chronic effects on insulin action.TNFalpha was found to be a potent activator of the expression of several cytokines in the adipose tissueof non-obese individuals, including IL-6, IL-8, IL-1beta as well as the IL-1 receptor antagonist. Thesecytokines are likely to be important for the chronic inflammatory condition seen in the adiposetissue of obese and insulin-resistant individuals. Furthermore, they can inhibit fat cell differentiationand recruitment, thus driving fat cell enlargement and ultimately lipid incorporation in to othertissues, which, in turn, is closely associated with insulin resistance.