Fasiglifam (TAK-875) has dual potentiating mechanisms via Gαq-GPR40/FFAR1 signaling branches on glucose-dependent insulin secretion.

摘要: Fasiglifam (TAK-875) is a free fatty acid receptor 1 (FFAR1)/G-protein-coupled 40 (GPR40) agonist that improves glycemic control in type 2 diabetes with minimum risk of hypoglycemia. potentiates glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells glucose dependently, although the precise mechanism underlying dependency still remains unknown. Here, we investigated key cross-talk between GSIS pathway and FFAR1 signaling, Ca(2+) dynamics using mouse insulinoma MIN6 cells. We demonstrated glucose-dependent insulinotropic effect fasiglifam required membrane depolarization induced increase intracellular level amplification oscillations. This differed sulfonylurea glimepiride changes independently. Stimulation cell-permeable analogs IP3 or diacylglycerol (DAG), downstream second messengers Gαq-FFAR1, augmented similar to fasiglifam, indicating their individual roles potentiation pathway. Intriguingly, analog triggered whereas DAG had no effect. Despite lack an on dynamics, elicited synergistic effects influx evoked by L-type voltage-dependent calcium channel opener mimics dynamics. These results indicate Gαq signaling activated enhances via dual potentiating mechanisms which amplifies glucose-induced oscillations DAG/protein kinase C (PKC) augments secretory independent