title: GPR40 agonists for the treatment of type 2 diabetes: life after 'TAKing' a hit.
abstract: The free fatty acid receptor GPR40 has been proposed as a potential target for type 2 diabetes (T2D) pharmacotherapy. This idea has been validated in both preclinical and clinical studies, in which activation of GPR40 was shown to improve glycaemic control by stimulating glucose-dependent insulin secretion; however, the recent termination of phase III clinical trials using the GPR40 agonist TAK-875 (fasiglifam) has raised important questions regarding the long-term safety and viability of targeting GPR40 and, more specifically, about our understanding of this receptor's basic biology. In the present review, we provide a summary of established and novel concepts related to GPR40's pharmacobiology and discuss the current status and future outlook for GPR40-based drug development for the treatment of T2D.
authors.affiliation: Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.|Department of Medicine, Université de Montréal, Montréal, QC, Canada.
authors.forename: A D
authors.initials: AD
authors.lastname: Mancini
authors.affiliation: Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.|Department of Medicine, Université de Montréal, Montréal, QC, Canada.
authors.forename: V
authors.initials: V
authors.lastname: Poitout
mesh_terms: D001572:Benzofurans / Q000627:therapeutic use*; D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D056737:Safety-Based Drug Withdrawals; D013450:Sulfones / Q000627:therapeutic use*
chemical_list: D001572:Benzofurans; D001786:Blood Glucose; C473034:FFAR1 protein, human; D007004:Hypoglycemic Agents; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D013450:Sulfones; C557331:TAK-875
keywords: antidiabetic drug; beta cell; insulin secretion; pharmacology; seven-transmembrane domain receptors