GPR40

GPR40, also known as free fatty acid receptor 1 (FFAR1), is a G protein-coupled receptor that is activated by long-chain free fatty acids. It belongs to the class A rhodopsin-like GPCR family and is predominantly expressed in pancreatic beta cells, with detectable expression in other tissues such as certain enteroendocrine cells.

In pancreatic beta cells, GPR40 couples mainly to Gq/11 proteins, triggering phospholipase C beta activation, inositol trisphosphate production, and diacylglycerol formation. This signaling increases intracellular calcium and enhances insulin secretion in response to elevated glucose levels, effectively amplifying glucose-stimulated insulin release in the presence of fatty acids. GPR40 is thought to influence insulin dynamics rather than initiating secretion on its own at low glucose concentrations.

Endogenous ligands for GPR40 are various long-chain fatty acids, including oleic and linoleic acids. The receptor has been the target of pharmacological efforts to treat type 2 diabetes through the development of selective GPR40 agonists. One of the most notable compounds was fasiglifam (TAK-875); it progressed to late-stage clinical trials but was ultimately discontinued due to concerns about hepatobiliary safety. Research continues to explore safer, more selective modulators and to better understand GPR40’s role in metabolism and extra-pancreatic tissues.

Overall, GPR40 is a nutritionally responsive receptor that modulates insulin secretion in a fatty acid- and glucose-dependent manner, representing a potential but challenging target for metabolic disease therapies.