Free Fatty Acid Receptor 1: A New Drug Target for Type 2 Diabetes?

Ferdaoussi, Mourad; Bergeron, Valérie; Kebede, Melkam A.; Mancini, Arturo; Alquier, Thierry; Poitout, Vincent

doi:10.1016/j.jcjd.2012.08.002

Canadian Journal of Diabetes

2012

DOI: 10.1016/j.jcjd.2012.08.002

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Free Fatty Acid Receptor 1: A New Drug Target for Type 2 Diabetes?

Mourad Ferdaoussi

Valérie Bergeron

Melkam A. Kebede

et al.

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Cited by 8 publications

(2 citation statements)

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“…As FFAR1 activation stimulates insulin release only at high glucose concentration, it became an attractive therapeutic target , to enhance insulin secretion in T2D without the risk of hypoglycemia. Numerous synthetic FFAR1 agonists have been described in the last years and many of them are under development as T2D drugs .…”

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“…As this receptor is highly conserved between species (see Supporting Information for sequence homology), it should allow good translation of binding efficacy between different rodent and human cells. 25 As FFAR1 activation stimulates insulin release only at high glucose concentration, it became an attractive therapeutic target 26,27 to enhance insulin secretion in T2D without the risk of hypoglycemia. Numerous synthetic FFAR1 agonists have been described in the last years and many of them are under development as T2D drugs.…”

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confidence: 99%

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Synthesis and Characterization of a Promising Novel FFAR1/GPR40 Targeting Fluorescent Probe for β-Cell Imaging

et al. 2016

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Diabetes affects an increasing number of patients worldwide and is responsible for a significant rise in healthcare expenses. Imaging of β-cells bears the potential to contribute to an improved understanding, diagnosis, and development of new treatment options for diabetes. Here, we describe the first small molecule fluorescent probe targeting the free fatty acid receptor 1 (FFAR1/GPR40). This receptor is highly expressed on β-cells, and was up to now unexplored for imaging purposes. We designed a novel probe by facile modification of the selective and potent FFAR1 agonist TAK-875. Effective and specific binding of the probe was demonstrated using FFAR1 overexpressing cells. We also successfully labeled FFAR1 on MIN6 and INS1E cells, two widely used β-cell models, by applying an effective amplification protocol. Finally, we showed that the probe is capable of inducing insulin secretion in a glucose-dependent manner, thus demonstrating that functional activity of the probe was maintained. These results suggest that our probe represents a first important step to successful β-cell imaging by targeting FFAR1. The developed probe may prove to be particularly useful for in vitro and ex vivo studies of diabetic cellular and animal models to gain new insights into disease pathogenesis.

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Synthesis and Characterization of a Promising Novel FFAR1/GPR40 Targeting Fluorescent Probe for β-Cell Imaging

et al. 2016

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G protein-coupled receptors: signalling and regulation by lipid agonists for improved glucose homoeostasis

2016

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G protein-coupled receptors (GPCRs) play a pivotal role in cell signalling, controlling many processes such as immunity, growth, cellular differentiation, neurological pathways and hormone secretions. Fatty acid agonists are increasingly recognised as having a key role in the regulation of glucose homoeostasis via stimulation of islet and gastrointestinal GPCRs. Downstream cell signalling results in modulation of the biosynthesis, secretion, proliferation and anti-apoptotic pathways of islet and enteroendocrine cells. GPR40 and GPR120 are activated by long-chain fatty acids (>C12) with both receptors coupling to the Gαq subunit that activates the Ca(2+)-dependent pathway. GPR41 and GPR43 are stimulated by short-chain fatty acids (C2-C5), and activation results in binding to Gαi that inhibits the adenylyl cyclase pathway attenuating cAMP production. In addition, GPR43 also couples to the Gαq subunit augmenting intracellular Ca(2+) and activating phospholipase C. GPR55 is specific for cannabinoid endogenous agonists (endocannabinoids) and non-cannabinoid fatty acids, which couples to Gα12/13 and Gαq proteins, leading to enhancing intracellular Ca(2+), extracellular signal-regulated kinase 1/2 (ERK) phosphorylation and Rho kinase. GPR119 is activated by fatty acid ethanolamides and binds to Gαs utilising the adenylate cyclase pathway, which is dependent upon protein kinase A. Current research indicates that GPCR therapies may be approved for clinical use in the near future. This review focuses on the recent advances in preclinical diabetes research in the signalling and regulation of GPCRs on islet and enteroendocrine cells involved in glucose homoeostasis.

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Free fatty acid receptor 1: a ray of hope in the therapy of type 2 diabetes mellitus

et al. 2021

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Free Fatty Acid Receptor 1: A New Drug Target for Type 2 Diabetes?

Cited by 8 publications

References 49 publications

Synthesis and Characterization of a Promising Novel FFAR1/GPR40 Targeting Fluorescent Probe for β-Cell Imaging

Synthesis and Characterization of a Promising Novel FFAR1/GPR40 Targeting Fluorescent Probe for β-Cell Imaging

G protein-coupled receptors: signalling and regulation by lipid agonists for improved glucose homoeostasis

Free fatty acid receptor 1: a ray of hope in the therapy of type 2 diabetes mellitus

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