BRL37344 stimulates GLUT4 translocation and glucose uptake in skeletal muscle via β₂-adrenoceptors without causing...

Area of Science:

• Metabolic research
• Pharmacology
• Endocrinology

Background:

• The rising prevalence of type 2 diabetes necessitates novel therapeutic strategies targeting glucose homeostasis independent of insulin.
• Adrenoceptor agonists have shown potential in modulating glucose metabolism, but their precise mechanisms and long-term effects require further elucidation.

Purpose of the Study:

• To investigate the mechanisms by which the dual β2-/β3-adrenoceptor agonist BRL37344 enhances glucose uptake in skeletal muscle.
• To evaluate the in vivo effects of BRL37344 on glucose homeostasis and skeletal muscle glucose metabolism.

Main Methods:

• Utilized L6 skeletal muscle cells to assess glucose uptake, glucose transporter 4 (GLUT4) translocation, cAMP levels, receptor desensitization, β-arrestin recruitment, and key signaling pathway phosphorylation (Akt, AMPK, mTOR).
• Employed animal models for glucose tolerance tests and in vivo/ex vivo skeletal muscle glucose uptake measurements.

Main Results:

• BRL37344 significantly increased GLUT4 translocation and glucose uptake in L6 cells solely through β2-adrenoceptor activation, independent of Akt and AMPK but dependent on mTORC2.
• In contrast to isoprenaline, BRL37344 did not induce β2-adrenoceptor desensitization or β-arrestin recruitment.
• In vivo studies demonstrated that BRL37344 improved glucose tolerance and enhanced skeletal muscle glucose uptake.

Conclusions:

• BRL37344 effectively improves glucose tolerance and skeletal muscle glucose uptake via a β2-adrenoceptor-mediated pathway, independent of Akt signaling.
• The agonist acts as a full agonist for glucose uptake despite being a partial agonist for cAMP generation, crucially avoiding classical receptor desensitization and internalization.