G protein–coupled receptor 40 (GPR40)

G protein–coupled receptor 40 (GPR40), also known as free fatty acid receptor 1 (FFAR1), is a class A GPCR predominantly expressed in pancreatic β-cells, enteroendocrine cells of the gut, and the brain[2][4]. It is activated primarily by medium and long-chain fatty acids, which, upon dietary intake, stimulate GPR40 and induce secretion of key incretin hormones (e.g., GLP-1, GIP, PYY) and potentiate glucose-dependent insulin release[2][4]. GPR40’s physiological roles are centered on the regulation of glucose and metabolic homeostasis as well as appetite regulation, making it a critical therapeutic target for type 2 diabetes and metabolic syndrome[2][4]. Several synthetic agonists have been developed, but clinical development has been hindered by safety concerns, especially drug-induced liver injury and potential pancreatic toxicity[2]. The target remains of high interest due to its robust incretin- and insulinotropic effects, and research is ongoing to develop safer, gut-restricted GPR40 modulators[2].

Other names

Free fatty acid receptor 1 (FFAR1)GPR40

Agonists (orthosteric/partial, full, agoPAM) activate GPR40, leading to increased intracellular Ca²⁺ in β-cells and glucose-dependent insulin secretion[2][4] Induction of incretin secretion (GLP-1, GIP, PYY) from enteroendocrine cells, contributing to glycemic control and appetite regulation[2][4] Positive allosteric modulators (AgoPAMs) may amplify endogenous fatty acid responses