BRL37344 stimulates GLUT4 translocation and glucose uptake in skeletal muscle via β 2 -adrenoceptors without causing classical receptor desensitization.

The type 2 diabetes epidemic makes it important to find insulin independent ways to improve glucose homeostasis. This study examines the mechanisms activated by a dual β2 -/β3 -adrenoceptor agonist BRL37344 to increase glucose uptake in skeletal muscle, and its effects on glucose homeostasis in vivo. We measured the effect of BRL37344 on glucose uptake, GLUT4 translocation, cAMP levels, β2 -adrenoceptor desensitization, β-arrestin recruitment, Akt, AMPK and mTOR phosphorylation using L6 skeletal muscle cells as a model. We further tested the ability of BRL37344 to modulate skeletal muscle glucose metabolism in animal models (glucose tolerance tests, in vivo and ex vivo skeletal muscle glucose uptake). In L6 cells, BRL37344 increased GLUT4 translocation and glucose uptake only by activation of β2 -adrenoceptors, with a similar potency and efficacy to that of the non-selective β-adrenoceptor agonist isoprenaline, despite being a partial agonist with respect to cAMP generation. GLUT4 translocation occurred independently of Akt and AMPK phosphorylation but was dependent upon mTORC2. Furthermore, in contrast to isoprenaline, BRL37344 did not promote agonist-mediated desensitization, and failed to recruit β-arrestin1/2 to the β2 -adrenoceptor. In conclusion, BRL37344 improved glucose tolerance and increased glucose uptake into skeletal muscle in vivo and ex vivo through a β2 -adrenoceptor mediated mechanism independently of Akt. BRL37344 was a partial agonist with respect to cAMP, but a full agonist for glucose uptake, and importantly did not cause classical receptor desensitization or internalization of the receptor.