title: Fasiglifam (TAK-875) has dual potentiating mechanisms via Gαq-GPR40/FFAR1 signaling branches on glucose-dependent insulin secretion.
abstract: 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 IP3 or diacylglycerol (DAG), downstream second messengers of Gαq-FFAR1, augmented GSIS similar to fasiglifam, indicating their individual roles in the potentiation of GSIS pathway. Intriguingly, the IP3 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 Gαq signaling activated by fasiglifam enhances GSIS pathway via dual potentiating mechanisms in which IP3 amplifies glucose-induced Ca(2+) oscillations and DAG/protein kinase C (PKC) augments downstream secretory mechanisms independent of Ca(2+) oscillations.
authors.affiliation: Cardiovascular and Metabolic Drug Discovery Unit Pharmaceutical Research Division Takeda Pharmaceutical Company Limited Fujisawa Kanagawa Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Sakuma
authors.affiliation: Cardiovascular and Metabolic Drug Discovery Unit Pharmaceutical Research Division Takeda Pharmaceutical Company Limited Fujisawa Kanagawa Japan.
authors.forename: Chiori
authors.initials: C
authors.lastname: Yabuki
authors.affiliation: Cardiovascular and Metabolic Drug Discovery Unit Pharmaceutical Research Division Takeda Pharmaceutical Company Limited Fujisawa Kanagawa Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Maruyama
authors.affiliation: Cardiovascular and Metabolic Drug Discovery Unit Pharmaceutical Research Division Takeda Pharmaceutical Company Limited Fujisawa Kanagawa Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Abiru
authors.affiliation: Central Nervous System Drug Discovery Unit Pharmaceutical Research Division Takeda Pharmaceutical Company Limited Fujisawa Kanagawa Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Komatsu
authors.affiliation: Inflammation Drug Discovery Unit Pharmaceutical Research Division Takeda Pharmaceutical Company Limited Fujisawa Kanagawa Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Negoro
authors.affiliation: Cardiovascular and Metabolic Drug Discovery Unit Pharmaceutical Research Division Takeda Pharmaceutical Company Limited Fujisawa Kanagawa Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Tsujihata
authors.affiliation: Cardiovascular and Metabolic Drug Discovery Unit Pharmaceutical Research Division Takeda Pharmaceutical Company Limited Fujisawa Kanagawa Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Takeuchi
authors.affiliation: Cardiovascular and Metabolic Drug Discovery Unit Pharmaceutical Research Division Takeda Pharmaceutical Company Limited Fujisawa Kanagawa Japan.
authors.forename: Yugo
authors.initials: Y
authors.lastname: Habata
authors.affiliation: Cardiovascular and Metabolic Drug Discovery Unit Pharmaceutical Research Division Takeda Pharmaceutical Company Limited Fujisawa Kanagawa Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Mori
keywords: Ca2+ oscillation; FFAR1/GPR40; fasiglifam (TAK‐875); glucose‐stimulated insulin secretion (GSIS); type 2 diabetes mellitus (T2DM)