Fasiglifam (TAK‐875) has dual potentiating mechanisms via G α q‐GPR40/FFAR1 signaling branches on glucose‐dependent insulin secretion

Fasiglifam (TAK‐875) is a free fatty acid receptor 1 (FFAR1)/G‐protein–coupled receptor 40 (GPR40) agonist that improves glycemic control in type 2 diabetes with minimum risk of hypoglycemia. Fasiglifam potentiates glucose‐stimulated insulin secretion (GSIS) from pancreatic β ‐cells glucose dependently, although the precise mechanism underlying the glucose dependency still remains unknown. Here, we investigated key cross‐talk between the GSIS pathway and FFAR1 signaling, and Ca 2+ dynamics using mouse insulinoma MIN6 cells. We demonstrated that the glucose‐dependent insulinotropic effect of fasiglifam required membrane depolarization and that fasiglifam induced a glucose‐dependent increase in intracellular Ca 2+ level and amplification of Ca 2+ oscillations. This differed from the sulfonylurea glimepiride that induced changes in Ca 2+ dynamics glucose independently. Stimulation with cell‐permeable analogs of IP 3 or diacylglycerol ( DAG), downstream second messengers of G α q‐FFAR1, augmented GSIS similar to fasiglifam, indicating their individual roles in the potentiation of GSIS pathway. Intriguingly, the IP 3 analog triggered similar Ca 2+ dynamics to fasiglifam, whereas the DAG analog had no effect. Despite the lack of an effect on Ca 2+ dynamics, the DAG analog elicited synergistic effects on insulin secretion with Ca 2+ influx evoked by an L‐type voltage‐dependent calcium channel opener that mimics glucose‐dependent Ca 2+ dynamics. These results indicate that the G α q signaling activated by fasiglifam enhances GSIS pathway via dual potentiating mechanisms in which IP 3 amplifies glucose‐induced Ca 2+ oscillations and DAG/protein kinase C (PKC) augments downstream secretory mechanisms independent of Ca 2+ oscillations.