Interleukin-6 Attenuates Insulin-Mediated Increases in Endothelial Cell Signaling but Augments Skeletal Muscle Insulin Action via Differential Effects on Tumor Necrosis Factor-α Expression

Abstract

OBJECTIVE The cytokine interleukin-6 (IL-6) stimulates AMP-activated protein kinase (AMPK) and insulin signaling in skeletal muscle, both of which result in the activation of endothelial nitric oxide synthase (eNOS). We hypothesized that IL-6 promotes endothelial cell signaling and capillary recruitment in vivo, contributing to increased glucose uptake. RESEARCH DESIGN AND METHODS The effect of IL-6 with and without insulin on AMPK, insulin, and eNOS signaling in and nitric oxide (NO) release from human aortic endothelial cells (HAECs) was examined. The physiological significance of these in vitro signaling events was assessed by measuring capillary recruitment in rats during control and euglycemic-hyperinsulinemic clamps with or without IL-6 infusion. RESULTS IL-6 blunted increases in insulin signaling, eNOS phosphorylation (Ser 1177 ), and NO production and reduced phosphorylation of AMPK in HAEC in vitro and capillary recruitment in vivo. In contrast, IL-6 increased Akt phosphorylation (Ser 473 ) in hindlimb skeletal muscle and enhanced whole-body glucose disappearance and glucose uptake during the clamp. The differences in endothelial cell and skeletal muscle signaling were mediated by the cell-specific, additive effects of IL-6 and insulin because this treatment markedly increased tumor necrosis factor (TNF)-α protein expression in HAECs without any effect on TNF-α in skeletal muscle. When HAECs were incubated with a TNF-α–neutralizing antibody, the negative effects of IL-6 on eNOS signaling were abolished. CONCLUSIONS In the presence of insulin, IL-6 contributes to aberrant endothelial cell signaling because of increased TNF-α expression.

Caveolin-1 is required for vascular endothelial insulin uptake

“…In addition, IL-6 has recently been reported to impair insulin signaling in vascular ECs (52). These findings suggest that these cytokines might inhibit insulin uptake not only through inhibition of caveolin-1 protein synthesis but also through inhibition of insulin signaling (20,49,52).…”

“…In other studies TNF␣ and IL-6 (20 ng/ml each for 24 h) have been found to inhibit IRS-1 expression and insulin-stimulated IRS-1 tyrosine phosphorylation, although insulin-stimulated IR tyrosine phosphorylation appeared unaffected (37). In addition, IL-6 has recently been reported to impair insulin signaling in vascular ECs (52). These findings suggest that these cytokines might inhibit insulin uptake not only through inhibition of caveolin-1 protein synthesis but also through inhibition of insulin signaling (20,49,52).…”

The global diabetes epidemic as a consequence of lifestyle-induced low-grade inflammation

“…The IL-6 serum concentrations increase up to 100-fold so that systemic effects are possible, e.g. the promotion of insulin resistance and lipolysis, whereas in skeletal muscle insulin action is augmented [70]. It seems difficult to reconcile this systemic pro-inflammatory effect of intense muscle work with the observed anti-inflammatory effect of regular exercise [46,71].…”

Metabolic and endocrine response to exercise: sympathoadrenal integration with skeletal muscle

“…The proposition that carbohydrate availability is linked with cytokine expression is further strengthened by the observation that the provision of exogenous carbohydrate has a suppressive effect on plasma IL6 concentration (Nieman et al 1998, Febbraio et al 2003. The activity of AMPK has been proposed as an intracellular signal that governs skeletal muscle cytokine expression (Weigert et al 2007), but another study suggests that AMPK activity is increased by IL6 (Yuen et al 2009). Furthermore, Lihn et al (2008) reported that cytokine expression is reduced by AMPK activity.…”