Enhanced glucose uptake in skeletal muscle is correlated with high sympathetic nervous system activity (e.g. exercise, fight or flight), resulting primarily from norepinephrine release from adrenergic nerve terminals in skeletal muscle. Sympathetically mediated glucose uptake in skeletal muscle occurs specifically by activation of beta2-adrenoceptors through canonical G protein-coupled receptor (GPCR) second messenger signaling as well as non-canonical signaling, but the distal pathways leading to glucose uptake are unclear. The mechanisms proposed include stimulation of transcription and translation of proteins (including glucose transporters), translocation or activation of glucose transporters or non-carrier mediated and unspecific effects. Previous studies have not provided a unifying concept and since the sympathetic nervous system has a central role in glucose homeostasis it is important to understand the intracellular signaling mechanisms involved. In addition, inhibition or activation of these processes specifically in skeletal muscle could provide a novel way to regulate blood glucose levels.

We show that activation of beta-adrenoceptors is potentially as important as insulin in stimulating glucose uptake in skeletal muscle, and have identified the novel intracellular signaling pathway involved. This pathway does not alter GLUT transcription or translation. Instead it depends on GLUT4 translocation but does not utilize a number of proteins normally considered necessary for GLUT4 translocation in response to insulin, muscle contraction or energy deficit. The pathway specifically activates mechanistic target of rapamycin complex 2 (mTORC2) utilizing cAMP, PKA and phosphorylation at S2481 to cause glucose uptake without the involvement of Akt, mTORC1 or AS160. We believe that beta-adrenoceptor-stimulated glucose uptake is of high physiological relevance since the signaling pathway was observed both in vitro, ex vivo and in vivo in rodents, and in vitro in humans. The signaling components identify novel targets that provide new opportunities for the treatment of metabolic diseases such as type 2 diabetes.