Interleukin-6 in combination with the interleukin-6 receptor stimulates glucose uptake in resting human skeletal muscle independently of insulin action

Aim: To examine if the physiological concentrations of both interleukin-6 (IL-6), in combination with IL-6 receptor (IL-6R), are able to stimulate glucose uptake in human skeletal muscle and to identify the associated signalling pathways. Methods: Skeletal muscle tissue (̃60mg) obtained from healthy female volunteers via muscle biopsy was subjected to incubation in the absence or presence of insulin (60μU/ml), recombinant human IL-6 (rhIL-6) (4ng/ml) or a combination of rhIL-6 (4ng/ml) and rhIL-6R (100ng/ml) for 30min, with glucose transport measured for each incubation. Western blot analysis was conducted on key signalling proteins, protein kinase B (PKB/Akt), adenosine monophosphate kinase (AMPK) and mammalian target of rapamycin (mTOR) to gain an early insight into any differing transport mechanisms. Results: Human skeletal muscle exhibited increased glucose uptake with insulin (1.85-fold; p<0.05) and stimulated phosphorylation of PKB/Akt and AMPK (0.98±0.23 and 1.49±0.13, respectively, phosphorylated: total; p<0.05). IL-6/IL-6R increased phosphorylation of mTOR (fourfold, p<0.05) compared to insulin, IL-6 alone and basal control. IL-6 did not stimulate glucose uptake but combined with IL-6R, induced 1.5-fold increase in glucose uptake (p<0.05) and phosphorylation of AMPK (0.95±0.19; phosphorylated: total, p<0.05). Conclusions: IL-6 in combination with IL-6R and not IL-6 alone increased glucose uptake in human skeletal muscle. IL-6/IL-6R-mediated glucose uptake occurred independently of PKB/Akt phosphorylation, showing that IL-6/IL-6R-induced glucose uptake is dependent on a divergent pathway. © 2014 John Wiley & Sons Ltd.