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 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 PTP1B-deficient).

Results. IL-6 per se increased glucose uptake by activating LKB1/AMPK/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 IRS-1 level). Three mechanisms seem to operate in IL-6-induced insulin resistance: activation of JNK1/2, accumulation of socs3 mRNA, and an increase in PTP1B activity. Accordingly, silencing JNK1/2 with either siRNA 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, LXR agonists overcome IL-6-induced insulin resistance by producing down-regulation of socs3 and ptp1b 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.