Obesity is a major inducer of type II diabetes and it is estimated by the World Health Organisation that 300 and 150 million people worldwide respectively suffer from these diseases, with the incidence increasing dramatically over the last 5 years. At present there is no definite treatment for either disease and complications of diabetes include severe cardiovascular problems, kidney failure, blindness and even loss of limbs and death in the later stages of the disorder. Insulin is an important mediator for the regulation of glucose homeostasis and insulin signaling is severely impaired in these disorders.

There is thus great interest in identifying insulin-independent mechanisms that stimulate glucose transport in skeletal muscle, since muscle accounts for ~85 % of total body glucose metabolism.

We have reason to believe that activation of sympathetic nerves and the release of norepinephrine and activation of adrenergic receptors lead to an insulin-independent mechanism that increases glucose uptake in skeletal muscle and fat.

Insulin and adrenergic signaling has been viewed as two opposing anabolic and catabolic pathways and according to “general” knowledge, adrenergic stimulation decreases glucose uptake in insulin-sensitive tissues. The textbook example is that circulating epinephrine from the adrenal gland not only acutely raises the hepatic glucose output but also inhibits insulin-stimulated glucose uptake in skeletal muscle. It has thus been perceived that insulin increase glucose uptake and adrenergic signaling would decrease glucose uptake in skeletal muscle.

We have, however, good reason to believe that focally released norepinephrine from sympathetic nerve endings (in contrast to circulating epinephrine) can have the opposite effect and stimulate glucose uptake in brown adipocytes and skeletal muscle through adrenergic receptors (AR) by a mechanism independent of insulin.
We have found that stimulation of beta-adrenergic receptors, in addition to increasing cAMP levels, also activates PI3K an important kinase normally associated with the insulin signaling pathway. The beta2-activation of PI3K in skeletal muscle cells leads to an increase in glucose uptake of the same magnitude as that mediated by insulin. Interestingly, and in contrast to insulin, the beta2-adrenergic receptor activation of PI3K does not lead to Akt/PKB activation and translocation of GLUT4 (or other GLUTs examined) which is a requirement for insulin-stimulated glucose uptake.

The anabolic and catabolic pathways of insulin and adrenergic receptors are thus connected at the level of PI3K. It is of high importance to understand the connection between these two pathways due to the impact this could have in our understanding of how several diseases such as obesity and type II diabetes develops.

The specific questions asked are 1) Through which mechanism do adrenergic receptors activate glucose uptake 2) Is sympathetic-norepinephrine-adrenergic activation an important non-insulin pathway for stimulating glucose uptake in-vivo.