Chronic Exposure to SCO-267, an Allosteric GPR40 Full Agonist, Is Effective in Improving Glycemic Control in Rats

Full agonist-mediated activation of free fatty acid receptor 1 (FFAR1/GPR40) alleviates diabetes in rodents. Considering that is a chronic disease, assessment treatment durability exposure to GPR40 full agonist pivotal for treating patients with diabetes. However, the physiologic significance vitro and vivo agonists largely unclear. Here, we evaluated effects SCO-267, agonist, on signal transduction glucose control. In experiments showed SCO-267 an allosteric GPR40, which activates G?q, G?s, G?12/13 pathways ?-arrestin recruitment. The calcium response was sustained GPR40-overexpressing CHO cells even after prolonged incubation SCO-267. To evaluate relevance agonists, (1 10 mg/kg) administered once daily neonatally streptozotocin-induced diabetic rats 15–33 days, control evaluated. After 15 days dosing followed by drug washout period, improved tolerance, most likely increasing insulin sensitivity rats. 33 repeated highly effective improving tolerance Furthermore, increased pancreatic content. These results demonstrated exposure, effectively rats, suggesting clinical application diseases including SIGNIFICANCE STATEMENT validated therapeutic target This study rats; these suggest durable efficacy patients.