title: Activation of GPR40 as a therapeutic target for the treatment of type 2 diabetes.
abstract: The stimulation of insulin secretion by glucose can be modulated by multiple nutritive, hormonal, and pharmacological inputs. Fatty acids potentiate insulin secretion through the generation of intracellular signaling molecules and through the activation of cell surface receptors. The G-protein-coupled receptor 40 (GPR40), also known as free fatty acid receptor 1 (we will use GPR40 in this review), has emerged as an important component in the fatty acid augmentation of insulin secretion. By signaling predominantly through Gαq/11, GPR40 increases intracellular calcium and activates phospholipases to generate diacylglycerols resulting in increased insulin secretion. Synthetic small-molecule agonists of GPR40 enhance insulin secretion in a glucose-dependent manner in vitro and in vivo with a mechanism similar to that found with fatty acids. GPR40 agonists have shown efficacy in increasing insulin secretion and lowering blood glucose in rodent models of type 2 diabetes. Recent phase I and phase II clinical trials in humans have shown that the GPR40 agonist TAK-875 reduces fasting and postprandial blood glucose and lowers HbA1c with efficacy equal to that of the sulfonylurea glimepiride without inducing hypoglycemia or evidence of tachyphylaxis. These data suggest that targeting the GPR40 receptor can be a viable therapeutic option for the treatment of type 2 diabetes.
authors.affiliation: Department of Internal Medicine and Michigan Metabolomics and Obesity Center, University of Michigan, Ann Arbor, Michigan, USA. burantc@umich.edu
authors.forename: Charles F
authors.initials: CF
authors.lastname: Burant
mesh_terms: D001572:Benzofurans / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D005227:Fatty Acids / Q000502:physiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D058990:Molecular Targeted Therapy / Q000379:methods*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D001572:Benzofurans; C473034:FFAR1 protein, human; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D013450:Sulfones; C557331:TAK-875