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 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

Myokines in insulin resistance and type 2 diabetes

“…Acute IL-6 treatment increased glucose uptake, while chronic exposure resulted in insulin resistance owing to activation of JNK and impairment of insulin signalling on the level of IRS-1 [15]. Interestingly, in vivo animal studies revealed that chronically elevated serum levels of IL-6 serum induced by either treatment with recombinant protein [16] or using a transgenic approach [17] improved whole body glucose tolerance and insulin sensitivity, which might be linked to augmentation of central leptin action.…”

“…As summarised in Table 1, in vitro studies have shown that IL-6 increases myotube fatty acid oxidation and lipolysis via AMPK activation [32,33]. [46] No data available regarding endocrine metabolic effects of muscle-derived BDNF IL-6 ↑ GLUT4 translocation [19,20] ↑ Glucose uptake [15,19] ↑ Glycogen synthesis [18,20] ↑ Fatty acid oxidation [18][19][20] ↑ Lipolysis [32][33][34] Liver: ↑ Glucose production [23] Intestine: ↑ GLP-1 secretion of L cells [52] Pancreas: ↑ Beta cell proliferation [52] ↑ GLP-1 secretion of alpha cells [52] ↑ Proliferation and ↓ apoptosis of alpha cells [51] IL-13 ↑ Glucose uptake [28] ↑ Glucose oxidation [28] ↑ Glycogen synthesis [28] Liver: ↓ Glucose production [29] IL-15 ↑ Fatty acid oxidation [43] Adipose tissue: ↓ Lipid accumulation [44,45] ↑ Adiponectin secretion [44] Irisin No data available Adipose tissue: ↑ White to brown shift [98,111] No effect on browning [100] FGF21 ↑ Glucose uptake [99,136] Adipose tissue: ↑ White to brown shift [99] ↑ Glucose uptake [99] ↑ Adiponectin secretion [127,128] Liver: ↑ Fatty acid oxidation [137] ↑ Gluconeogenesis [137] Recently, a study using isolated mouse muscle reported that IL-6...…”

“…A study on C2C12 myotubes has reported that the effect of IL-6 on muscle insulin sensitivity depends on the duration of exposure [15]. Acute IL-6 treatment increased glucose uptake, while chronic exposure resulted in insulin resistance owing to activation of JNK and impairment of insulin signalling on the level of IRS-1 [15].…”

NOD1 expression is increased in the adipose tissue of women with gestational diabetes

“…In mice, the absence of NOD1 and NOD2 attenuates diet-induced insulin intolerance, and NOD1 ligands induce wholebody insulin resistance (Schertzer et al 2011). IL6 is one of several pro-inflammatory cytokines that have been associated with insulin resistance and type 2 diabetes (Kern et al 2001, Pradhan et al 2001, Senn et al 2002, Nieto-Vazquez et al 2008. High levels of IL6 are also associated with GDM (Yu et al 2007, Kuzmicki et al 2009, Morisset et al 2011.…”

ER Stress in Adipocytes Inhibits Insulin Signaling, Represses Lipolysis, and Alters the Secretion of Adipokines Without Inhibiting Glucose Transport

“…Chronically elevated levels of IL-6 are associated with the development of type 2 diabetes [14][15][16] and it has been found to inhibit insulin secretion from pancreatic islets [17] as well as insulin action in the liver [18][19][20]. Two other important products secreted into circulation by adipocytes are adiponectin and leptin [21,22] that either negatively or positively correlate with body fat mass, respectively.…”