skip to main content
Language:
Search Limited to: Search Limited to: Resource type Show Results with: Show Results with: Index

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

Sakuma, Kensuke ; Yabuki, Chiori ; Maruyama, Minoru ; Abiru, Akiko ; Komatsu, Hidetoshi ; Negoro, Nobuyuki ; Tsujihata, Yoshiyuki ; Takeuchi, Koji ; Habata, Yugo ; Mori, Masaaki

Pharmacology Research & Perspectives, June 2016, Vol.4(3), pp.n/a-n/a [Peer Reviewed Journal]

Full text available

View all versions
Citations Cited by
  • Title:
    Fasiglifam (TAK‐875) has dual potentiating mechanisms via Gαq‐GPR40/FFAR1 signaling branches on glucose‐dependent insulin secretion
  • Author: Sakuma, Kensuke ; Yabuki, Chiori ; Maruyama, Minoru ; Abiru, Akiko ; Komatsu, Hidetoshi ; Negoro, Nobuyuki ; Tsujihata, Yoshiyuki ; Takeuchi, Koji ; Habata, Yugo ; Mori, Masaaki
  • Description: 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 ‐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 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 level and amplification of Ca oscillations. This differed from the sulfonylurea glimepiride that induced changes in Ca dynamics glucose independently. Stimulation with cell‐permeable analogs of IP or diacylglycerol DAG), downstream second messengers of Gq‐FFAR1, augmented GSIS similar to fasiglifam, indicating their individual roles in the potentiation of GSIS pathway. Intriguingly, the IP analog triggered similar Ca dynamics to fasiglifam, whereas the DAG analog had no effect. Despite the lack of an effect on Ca dynamics, the DAG analog elicited synergistic effects on insulin secretion with Ca influx evoked by an L‐type voltage‐dependent calcium channel opener that mimics glucose‐dependent Ca dynamics. These results indicate that the Gq signaling activated by fasiglifam enhances GSIS pathway via dual potentiating mechanisms in which IP amplifies glucose‐induced Ca oscillations and DAG/protein kinase C (PKC) augments downstream secretory mechanisms independent of Ca oscillations.
  • Is Part Of: Pharmacology Research & Perspectives, June 2016, Vol.4(3), pp.n/a-n/a
  • Identifier: ISSN: 2052-1707 ; E-ISSN: 2052-1707 ; DOI: 10.1002/prp2.237
  • Subjects: Ca 2+ Oscillation ; Fasiglifam Tak ‐875 ; Ffar 1/ Gpr 40 ; Glucose‐Stimulated Insulin Secretion Gsis ; Type 2 Diabetes Mellitus T2 Dm

Searching Remote Databases, Please Wait