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

Abstract 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. Ca 2+ 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 Ca 2+ influx and phosphorylated Ca 2+ /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 (Ca 2+ 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 Ca 2+ signaling via GPR41, improving diabetes mellitus. image