Dual role of interleukin-6 in regulating insulin sensitivity in murine skeletal muscle

Abstract

OBJECTIVE-Cytokines are elevated in various insulin-resistant states, including type 2 diabetes and obesity, although the contribution of interleukin-6(IL-6) in the induction of these diseases is controversial. RESEARCH DESIGN AND METHODS-We analyzed the impact of IL-6 on insulin action in murine primary myocytes, skeletal muscle cell lines, and mice(wild type and protein- tyrosine phosphatase 1B [PTP1B] deficient). RESULTS-IL-6 per se increased glucose uptake by activating serine/threonine protein kinase 11(LKB1)/AMP-activated protein kinase/protein kinase B substrate of 160 kDa(AS160) pathway. A dual effect on insulin action was observed when myotubes and mice were exposed to this cytokine: additive with short-term insulin(increased glucose uptake and systemic insulin sensitivity) but chronic exposure produced insulin resistance(impaired GLUT4 translocation to plasma membrane and defects in insulin signaling at the insulin receptor substrate 1 [IRS-1] level). Three mechanisms seem to operate in IL-6-induced insulin resistance: activation of c-Jun NH2-terminal kinase 1/2(JNK1/2), accumulation of suppressor of cytokine signaling 3(socs3) mRNA, and an increase in PTP1B activity. Accordingly, silencing JNK1/2 with either small interfering RNA or chemical inhibitors impaired phosphorylation of IRS-1(Ser307), restored insulin signaling, and normalized insulin-induced glucose uptake in myotubes. When using a pharmacological approach, liver X receptor agonists overcome IL-6-induced insulin resistance by producing down- regulation of socs3 and ptplb gene expression. Finally, the lack of PTP1B confers protection against IL-6-induced insulin resistance in skeletal muscle in vitro and in vivo, in agreement with the protection against the IL-6 hyperglycemic effect observed on glucose and insulin tolerance tests in adult male mice. CONCLUSIONS-These findings indicate the important role of IL-6 in the pathogenesis of insulin resistance and further implicate PTP1B as a potential therapeutic target in the treatment of type 2 diabetes. © 2008 by the American Diabetes Association.