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

Am J Physiol Regul Integr Comp Physiol. 2019 May 1;316(5):R666-R677. doi: 10.1152/ajpregu.00285.2018. Epub 2019 Mar 20.

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.

Keywords: BRL37344; GLUT4; glucose uptake; isoprenaline; receptor desensitization; skeletal muscle; β-adrenoceptor; β-arrestin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-2 Receptor Agonists / pharmacology*
  • Animals
  • Cell Line
  • Cyclic AMP / metabolism
  • Ethanolamines / pharmacology*
  • Female
  • Glucose / metabolism*
  • Glucose Transporter Type 4 / genetics
  • Glucose Transporter Type 4 / metabolism*
  • Humans
  • Kinetics
  • Mechanistic Target of Rapamycin Complex 2 / metabolism
  • Mice, Knockout
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / metabolism
  • Myoblasts, Skeletal / drug effects*
  • Myoblasts, Skeletal / metabolism
  • Protein Transport
  • Rats
  • Receptors, Adrenergic, beta-2 / drug effects*
  • Receptors, Adrenergic, beta-2 / metabolism
  • Receptors, Adrenergic, beta-3 / genetics
  • Receptors, Adrenergic, beta-3 / metabolism
  • Signal Transduction

Substances

  • ADRB2 protein, human
  • ADRB2 protein, mouse
  • Adrb2 protein, rat
  • Adrb3 protein, mouse
  • Adrenergic beta-2 Receptor Agonists
  • Ethanolamines
  • Glucose Transporter Type 4
  • Receptors, Adrenergic, beta-2
  • Receptors, Adrenergic, beta-3
  • SLC2A4 protein, human
  • Slc2a4 protein, mouse
  • BRL 37344
  • Cyclic AMP
  • Mechanistic Target of Rapamycin Complex 2
  • Glucose