Gαi -coupled GPR41 activation increases Ca2+ influx in C2C12 cells and shows a therapeutic effect in diabetic animals

Objective: This study aimed to investigate the possible mechanisms by which orphan G protein-coupled receptor GPR41 activation enhances glucose uptake into C2C12 myotubes using a GPR41-selective agonist, AR420626, and to examine the ability of this agent to improve Insulin sensitivity and glucose homeostasis in vivo.

Methods: Basal and insulin-stimulated glucose uptake and glucose transporter 4 translocations were measured in C2C12 myotubes. CA²⁺ influx into cells was measured and GPR41-mediated signaling by AR420626 was examined. An oral glucose tolerance test was performed, and plasma Insulin levels were measured in streptozotocin-treated or high-fat diet-fed diabetic mice. The glycogen content was measured in skeletal muscle tissue.

Results: AR420626 increased basal and insulin-stimulated glucose uptake, which was reduced by pertussis toxin, an inhibitor of Gα_i -mediated signaling, and treatment with small interfering RNA for GPR41 (siGPR41). AR420626 increased intracellular CA²⁺ influx and phosphorylated CA²⁺ /calmodulin-dependent protein kinase type II, cyclic AMP-responsive element-binding protein, and mitogen-activated protein kinase (p38) in C2C12 myotubes, which were inhibited by treating with pertussis toxin, amlodipine (CA²⁺ channel blocker), and siGPR41. AR420626 increased plasma Insulin levels and skeletal muscle glycogen content and improved glucose tolerance in streptozotocin- and high-fat diet-induced diabetic mouse models.

Conclusions: GPR41 activation with AR420626 increased glucose uptake mediated by CA²⁺ signaling via GPR41, improving diabetes mellitus.