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 (˜60 mg) obtained from healthy female volunteers via muscle biopsy was subjected to incubation in the absence or presence of insulin (60 µU /ml), recombinant human IL‐6 (rhIL‐6) (4 ng/ml) or a combination of rhIL ‐6 (4 ng/ml) and rhIL‐6R (100 ng/ml) for 30 min, 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.