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Fasiglifam (TAK‐875) has dual potentiating mechanisms via G α q‐GPR40/FFAR1 signaling branches on glucose‐dependent insulin secretion
- Source :
- Pharmacology Research & Perspectives
- Publication Year :
- 2016
- Publisher :
- Wiley, 2016.
-
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.
- Subjects :
- 0301 basic medicine
Agonist
endocrine system
medicine.medical_specialty
medicine.drug_class
FFAR1/GPR40
03 medical and health sciences
Free fatty acid receptor 1
Internal medicine
medicine
General Pharmacology, Toxicology and Pharmaceutics
Receptor
Protein kinase C
Diacylglycerol kinase
glucose‐stimulated insulin secretion (GSIS)
fasiglifam (TAK‐875)
biology
Chemistry
type 2 diabetes mellitus (T2DM)
Depolarization
Original Articles
Ca2+ oscillation
030104 developmental biology
Endocrinology
Neurology
Gq alpha subunit
Second messenger system
biology.protein
Original Article
Subjects
Details
- ISSN :
- 20521707
- Volume :
- 4
- Database :
- OpenAIRE
- Journal :
- Pharmacology Research & Perspectives
- Accession number :
- edsair.doi.dedup.....82a37a31f44b1979940780049e0a4a90