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BRL37344 stimulates GLUT4 translocation and glucose uptake in skeletal muscle via β2-adrenoceptors without causing classical receptor desensitization
- Source :
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 316:R666-R677
- Publication Year :
- 2019
- Publisher :
- American Physiological Society, 2019.
-
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.
- Subjects :
- 0301 basic medicine
Agonist
medicine.medical_specialty
Physiology
medicine.drug_class
Glucose uptake
030209 endocrinology & metabolism
Chromosomal translocation
Type 2 diabetes
03 medical and health sciences
0302 clinical medicine
Physiology (medical)
Internal medicine
Isoprenaline
medicine
Glucose homeostasis
biology
Chemistry
Skeletal muscle
medicine.disease
3. Good health
030104 developmental biology
medicine.anatomical_structure
Endocrinology
biology.protein
GLUT4
medicine.drug
Subjects
Details
- ISSN :
- 15221490 and 03636119
- Volume :
- 316
- Database :
- OpenAIRE
- Journal :
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
- Accession number :
- edsair.doi...........cce902b49b1e97999ef4d5f359cf2429