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

Saori Mukaida, Masaaki Sato, Anette I. Öberg, Nodi Dehvari, Jessica M. Olsen, Martina Kocan, Michelle Louise Halls, Jon Merlin, Anna L. Sandström, Robert I. Csikasz, Bronwyn Anne Evans, Roger James Summers, Dana Sabine Hutchinson, Tore Bengtsson

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2 Citations (Scopus)

Abstract

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, glucose transporter 4 (GLUT4) translocation, cAMP levels, β2-adrenoceptor desensitization, β-arrestin recruitment, Akt, AMPK, and mammalian target of rapamycin (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 and 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 nonselective 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 on 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.

Original languageEnglish
Pages (from-to)R666-R677
Number of pages12
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume316
Issue number5
DOIs
Publication statusPublished - 1 May 2019

Keywords

  • BRL37344
  • glucose uptake
  • GLUT4
  • isoprenaline
  • receptor desensitization
  • skeletal muscle
  • β-adrenoceptor
  • β-arrestin

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