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Fasiglifam (TAK‐875) has dual potentiating mechanisms via Gαq‐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 dependent...

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Autores principales: Sakuma, Kensuke, Yabuki, Chiori, Maruyama, Minoru, Abiru, Akiko, Komatsu, Hidetoshi, Negoro, Nobuyuki, Tsujihata, Yoshiyuki, Takeuchi, Koji, Habata, Yugo, Mori, Masaaki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876146/
https://www.ncbi.nlm.nih.gov/pubmed/27433346
http://dx.doi.org/10.1002/prp2.237
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author Sakuma, Kensuke
Yabuki, Chiori
Maruyama, Minoru
Abiru, Akiko
Komatsu, Hidetoshi
Negoro, Nobuyuki
Tsujihata, Yoshiyuki
Takeuchi, Koji
Habata, Yugo
Mori, Masaaki
author_facet Sakuma, Kensuke
Yabuki, Chiori
Maruyama, Minoru
Abiru, Akiko
Komatsu, Hidetoshi
Negoro, Nobuyuki
Tsujihata, Yoshiyuki
Takeuchi, Koji
Habata, Yugo
Mori, Masaaki
author_sort Sakuma, Kensuke
collection PubMed
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 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 Gαq‐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 Gαq 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.
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spelling pubmed-48761462016-07-18 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 Pharmacol Res Perspect Original Articles 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 Gαq‐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 Gαq 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. John Wiley and Sons Inc. 2016-04-27 /pmc/articles/PMC4876146/ /pubmed/27433346 http://dx.doi.org/10.1002/prp2.237 Text en © 2016 Takeda Pharmaceutical Company Limited. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs (http://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Sakuma, Kensuke
Yabuki, Chiori
Maruyama, Minoru
Abiru, Akiko
Komatsu, Hidetoshi
Negoro, Nobuyuki
Tsujihata, Yoshiyuki
Takeuchi, Koji
Habata, Yugo
Mori, Masaaki
Fasiglifam (TAK‐875) has dual potentiating mechanisms via Gαq‐GPR40/FFAR1 signaling branches on glucose‐dependent insulin secretion
title Fasiglifam (TAK‐875) has dual potentiating mechanisms via Gαq‐GPR40/FFAR1 signaling branches on glucose‐dependent insulin secretion
title_full Fasiglifam (TAK‐875) has dual potentiating mechanisms via Gαq‐GPR40/FFAR1 signaling branches on glucose‐dependent insulin secretion
title_fullStr Fasiglifam (TAK‐875) has dual potentiating mechanisms via Gαq‐GPR40/FFAR1 signaling branches on glucose‐dependent insulin secretion
title_full_unstemmed Fasiglifam (TAK‐875) has dual potentiating mechanisms via Gαq‐GPR40/FFAR1 signaling branches on glucose‐dependent insulin secretion
title_short Fasiglifam (TAK‐875) has dual potentiating mechanisms via Gαq‐GPR40/FFAR1 signaling branches on glucose‐dependent insulin secretion
title_sort fasiglifam (tak‐875) has dual potentiating mechanisms via gαq‐gpr40/ffar1 signaling branches on glucose‐dependent insulin secretion
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876146/
https://www.ncbi.nlm.nih.gov/pubmed/27433346
http://dx.doi.org/10.1002/prp2.237
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