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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 proteintyrosine 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 NH 2 -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 downregulation 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. Diabetes 57:3211-3221, 2008

OBJECTIVEInsulin resistance is associated with the pathogenesis of metabolic disorders as type 2 diabetes and obesity. Given the emerging role of signal transduction in these syndromes, we set out to explore the possible role that G protein–coupled receptor kinase 2 (GRK2), first identified as a G protein–coupled receptor regulator, could have as a modulator of insulin responses.RESEARCH DESIGN AND METHODSWe analyzed the influence of GRK2 levels in insulin signaling in myoblasts and adipocytes with experimentally increased or silenced levels of GRK2, as well as in GRK2 hemizygous animals expressing 50% lower levels of this kinase in three different models of insulin resistance: tumor necrosis factor-α (TNF-α) infusion, aging, and high-fat diet (HFD). Glucose transport, whole-body glucose and insulin tolerance, the activation status of insulin pathway components, and the circulating levels of important mediators were measured. The development of obesity and adipocyte size with age and HFD was analyzed.RESULTSAltering GRK2 levels markedly modifies insulin-mediated signaling in cultured adipocytes and myocytes. GRK2 levels are increased by ∼2-fold in muscle and adipose tissue in the animal models tested, as well as in lymphocytes from metabolic syndrome patients. In contrast, hemizygous GRK2 mice show enhanced insulin sensitivity and do not develop insulin resistance by TNF-α, aging, or HFD. Furthermore, reduced GRK2 levels induce a lean phenotype and decrease age-related adiposity.CONCLUSIONSOverall, our data identify GRK2 as an important negative regulator of insulin effects, key to the etiopathogenesis of insulin resistance and obesity, which uncovers this protein as a potential therapeutic target in the treatment of these disorders.