We thank Xiang et al. (1) for their comments on our article published in Diabetes (2) that shows for the first time that activation of β2-adrenoceptors promotes GLUT4-translocation and glucose uptake in skeletal muscle via a specific pathway dependent on mammalian target of rapamycin (mTOR) complex 2 (mTORC2). Because this pathway bypasses several of the proteins used in the insulin pathway, which are downregulated and desensitized in type 2 diabetes, we hypothesize that this pathway may be used to regulate glucose uptake and blood glucose in diabetic patients.

However, Xiang et al. (1) raise important concerns regarding the use of β2-adrenoceptor agonists to treat type 2 diabetes. As they point out, systemic activation of β2-adrenoceptors can lead to an acute rise in blood glucose levels by increasing hepatic glucose output, and this could be detrimental for diabetic patients. Stimulation of β2-adrenoceptors can regulate both glucose output from the liver and its uptake into skeletal muscle. However, our novel finding makes it feasible to develop compounds that specifically enhance glucose uptake into skeletal muscle without activating glucose output from the liver.

There are several ways in which the β2-adrenergic pathway could be used to develop new medicines to treat type 2 diabetes. An emerging paradigm in pharmacology is the recognition of biased ligands that can stimulate a preferred subset of signaling pathways activated by the receptor (3). Another possibility would be to directly activate specific proteins in the novel β2-adrenergic pathway. Both approaches could promote glucose uptake in skeletal muscle without accompanying side effects in the liver and other tissues.

Furthermore, the rise in blood glucose after sympathetic stimulation is a short-term effect, as illustrated in another article by Xiang et al. (4) in which orthopedic trauma induced an increase in blood glucose that peaked after 2 h. In contrast, the long-term effect of β2-adrenoceptor agonist treatment is an improvement of glucose tolerance (2), suggesting that glucose uptake into skeletal muscle outweighs glucose release from the liver.

A final concern raised by Xiang et al. (1) is that our study does not directly show that the mTORC2 pathway is involved in the improvement of glucose tolerance in type 2 diabetes. Our study clearly shows that there is a novel β2-adrenoceptor signaling pathway that involves mTORC2 and promotes glucose uptake in skeletal muscle. This was shown in vitro, ex vivo, and in vivo. It is thus very likely that the novel pathway also mediates some or all of the beneficial effects and improvement of glucose tolerance induced by β2-adrenoceptor stimulation in type 2 diabetes, although further studies are required to fully understand this mechanism. These studies should dissect different parts of the physiological response, focusing particularly on glucose uptake in skeletal muscle, to better understand how this can best be used for the development of new medicines. Although β2-adrenoceptor stimulation of glucose uptake in skeletal muscle has been a neglected area of research, we believe that our study clearly identifies novel targets that can be exploited in the search for new treatments for type 2 diabetes.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

M.S., N.D., and A.I.Ö. contributed equally to the response.

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