Free fatty acid receptor 1 (GPR40) (GPR40)

Free fatty acid receptor 1 (GPR40) is a G protein-coupled receptor primarily expressed in pancreatic beta cells and enteroendocrine cells (UniProt: O14842). It serves as a sensor for medium- and long-chain fatty acids, playing a pivotal role in modulating insulin secretion in response to nutritional status. Upon activation, GPR40 initiates signaling through Gq/11 and Gs pathways, leading to increased intracellular calcium and cAMP levels, which subsequently activate downstream effectors like CaMKII to facilitate insulin vesicle exocytosis (PMID: 22407618). This mechanism enhances glucose-stimulated insulin secretion (GSIS) without increasing basal insulin levels, thereby offering a low risk of hypoglycemia. GPR40 also mediates the release of incretin hormones such as GLP-1 from the gut, further contributing to its anti-diabetic effects. Despite its promise, the clinical development of GPR40 agonists has been hampered by safety issues, most notably the idiosyncratic hepatotoxicity that led to the discontinuation of the Phase III candidate fasiglifam (PMID: 24035166). Research continues to focus on identifying safer agonists and understanding the receptor's complex signaling bias.

Other names

FFAR1G-protein coupled receptor 40FFA1RGPCR40

Agonist binding to GPR40 activates Gq/11 and Gs signaling pathways, leading to increased intracellular calcium and cAMP levels, which activates downstream effectors like CaMKII and Protein Kinase A to enhance glucose-stimulated insulin secretion (PMID: 22407618, 12750377).