It is well-known that exercise training is a very effective treatment in people with Type 2 diabetes (1). Furthermore, a single bout of exercise increases skeletal muscle insulin sensitivity. However, the factors regulating the increase in skeletal muscle insulin sensitivity after contraction are not well characterized. Nitric oxide (NO) plays an important role in the increase in skeletal muscle glucose uptake during contraction/exercise in rodents and humans (2). However, whether NO production during acute contractions is critical for the consequential increase in insulin-stimulated glucose uptake after contraction is unknown.
To address this question, isolated extensor digitorum longus (EDL) muscles from C57BL/6J mice were stimulated ex vivo to contract for 10 min (in the presence or absence of the NO synthase (NOS) inhibitor NG-monomethyl-L-arginine (L-NMMA)). Paired EDL muscles were incubated with [3H]-2-deoxyglucose and [14C]-mannitol with or without insulin (120µU/ml) to measure glucose uptake 3.5hr post contraction. Glucose uptake without insulin in the EDL muscles was not different 3.5h post contraction group compared with non-contraction group, and NOS inhibition had no effect on basal glucose uptake. However, contraction significantly increased the sensitivity of muscle to insulin, increasing glucose uptake in response to insulin 3.5 hr post contraction (143% increase from basal, p< 0.01) compared with non-contraction (57% increase, p< 0.01). NOS inhibition during the insulin exposure significantly prevented this increase in insulin-stimulated glucose uptake 3.5 hr post contraction, which was not observed with NOS inhibition during contraction. These results demonstrate that NO is essential for the increase in insulin sensitivity (glucose uptake) after acute contractions of mouse skeletal muscle ex vivo. To examine whether NO effects were through the cGMP/PKG pathway, we used the sGC inhibitor ODQ and the PDE 5 inhibitor T1032, with both having no effect. We conclude that NO is required for increases in insulin sensitivity following ex vivo contraction of mouse skeletal muscle via a cGMP/PKG independent pathway.