ArticlePloS one2013
A novel antidiabetic drug, fasiglifam/TAK-875, acts as an ago-allosteric modulator of FFAR1.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 91 citations in OpenAlex.
- Efficacy and Safety of HD-6277, a Novel G Protein-Coupled Receptor 40 Agonist, in Individuals with Type 2 Diabetes Mellitus: A Double-Blind, Randomized, Placebo-Controlled, Parallel-Group, Multicenter Phase 2 Clinical Trial.Diabetes & metabolism journal · 2026Trial
- Activation of G protein-coupled receptor 40 alleviates STAT6 activation, airway inflammation and mucus hypersecretion in allergic asthma.Current research in pharmacology and drug discovery · 2026Article
- An update on current type 2 diabetes mellitus (T2DM) druggable targets and drugs targeting them.Molecular diversity · 2025Review
- The gut-liver axis: emerging mechanisms and therapeutic approaches for nonalcoholic fatty liver disease and type 2 diabetes mellitus.Naunyn-Schmiedeberg's archives of pharmacology · 2024Review
- GPCRs involved in metabolic diseases: pharmacotherapeutic development updates.Acta pharmacologica Sinica · 2024Review
- Structural basis for the ligand recognition and signaling of free fatty acid receptors.Science advances · 2024Article
- Molecular mechanism of fatty acid activation of FFAR1.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- How Arrestins and GRKs Regulate the Function of Long Chain Fatty Acid Receptors.International journal of molecular sciences · 2022Review
- Free fatty acid receptor 1: a ray of hope in the therapy of type 2 diabetes mellitus.Inflammopharmacology · 2021Review
- Selective Photoswitchable Allosteric Agonist of a G Protein-Coupled Receptor.Journal of the American Chemical Society · 2021Article
- Novel therapies with precision mechanisms for type 2 diabetes mellitus.Nature reviews. Endocrinology · 2021Review
- Targeting lipid GPCRs to treat type 2 diabetes mellitus - progress and challenges.Nature reviews. Endocrinology · 2021Review
- Pharmacology of Free Fatty Acid Receptors and Their Allosteric Modulators.International journal of molecular sciences · 2021Review
- Article
- Long Chain Fatty Acids as Modulators of Immune Cells Function: Contribution of FFA1 and FFA4 Receptors.Frontiers in physiology · 2021Review
- Covalent allosteric modulation: An emerging strategy for GPCRs drug discovery.European journal of medicinal chemistry · 2020Review
- Addressing free fatty acid receptor 1 (FFAR1) activation using supervised molecular dynamics.Journal of computer-aided molecular design · 2020Article
- Label-free cell phenotypic study of FFA4 and FFA1 and discovery of novel agonists of FFA4 from natural products.RSC advances · 2019Article
- Emerging structural biology of lipid G protein-coupled receptors.Protein science : a publication of the Protein Society · 2019Review
- Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts.Journal of medicinal chemistry · 2019Review
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Selective free fatty acid receptor 1 (FFAR1)/GPR40 agonist fasiglifam (TAK-875), an antidiabetic drug under phase 3 development, potentiates insulin secretion in a glucose-dependent manner by activating FFAR1 expressed in pancreatic β cells. Although fasiglifam significantly improved glycemic control in type 2 diabetes patients with a minimum risk of hypoglycemia in a phase 2 study, the precise mechanisms of its potent pharmacological effects are not fully understood. Here we demonstrate that fasiglifam acts as an ago-allosteric modulator with a partial agonistic activity for FFAR1. In both Ca(2+) influx and insulin secretion assays using cell lines and mouse islets, fasiglifam showed positive cooperativity with the FFAR1 ligand γ-linolenic acid (γ-LA). Augmentation of glucose-induced insulin secretion by fasiglifam, γ-LA, or their combination was completely abolished in pancreatic islets of FFAR1-knockout mice. In diabetic rats, the insulinotropic effect of fasiglifam was suppressed by pharmacological reduction of plasma free fatty acid (FFA) levels using a lipolysis inhibitor, suggesting that fasiglifam potentiates insulin release in conjunction with plasma FFAs in vivo. Point mutations of FFAR1 differentially affected Ca(2+) influx activities of fasiglifam and γ-LA, further indicating that these agonists may bind to distinct binding sites. Our results strongly suggest that fasiglifam is an ago-allosteric modulator of FFAR1 that exerts its effects by acting cooperatively with endogenous plasma FFAs in human patients as well as diabetic animals. These findings contribute to our understanding of fasiglifam as an attractive antidiabetic drug with a novel mechanism of action.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.