People with type 2 diabetes (T2D) have elevated blood glucose levels due, at least in part, to a reduction in skeletal muscle glucose uptake in response to insulin (insulin resistance). The major site of whole body insulin-stimulated glucose uptake is skeletal muscle (80-90%). Importantly, although skeletal muscle insulin-stimulated glucose uptake is impaired in people with type 2 diabetes, glucose uptake during exercise is normal in these individuals. Contraction-stimulated glucose uptake during exercise is so effective in people with T2D that as little as 45 minutes of intense exercise can decrease blood glucose levels to within normal levels.The factors regulating skeletal muscle glucose uptake during contraction are not entirely clear; however, there is evidence that nitric oxide (NO) is involved (1). We have shown that NO regulates leg glucose uptake during exercise independently of leg blood flow. Importantly, we found that people with T2D are especially reliant on NO to achieve normal glucose uptake during exercise, since their glucose uptake was attenuated to a greater extent by NO synthase (NOS) inhibition than controls (2). We have also shown that NOS inhibition in rats (ex vivo and in situ) and mice (ex vivo) attenuates the normal increase in muscle glucose uptake during contractions/exercise (1). However, there are conflicting results from other laboratories concerning the role of NO in contraction-stimulated glucose uptake (3, 4). Although the cGMP/PKG (PKG: cGMP-dependent protein kinase) signalling pathway is generally considered to be the major downstream target of NO, we have preliminary evidence for cGMP/PKG-independent NO signalling of glucose uptake during contraction via S-nitrosylation, S-glutathionylation and tyrosine nitration (5). More work is required including in mice that do not express nNOSµ, the isoform of NOS in skeletal muscle which appears to be most involved in NO production during contraction/ exercise. Once there is a better understanding of the mechanisms though which NO signals glucose uptake during exercise, specific therapeutics can be designed for people with type 2 diabetes to mimic the contraction signalling pathway. Such an agent could assist with blood glucose control of people with type 2 diabetes who are either unable or unwilling to exercise regularly.