G-protein coupled receptors (GPCRs) are targets of approximately 30 % of currently marketed drugs. Over the last decade, a number of GPCRs expressed in pancreatic beta cells and activated by lipids have been discovered, and a number of them are being actively pursued as potential drug targets to enhance insulin secretion in type 2 diabetes.

GPR40 is specifically expressed in pancreatic beta-cells and has been identified as a long-chain fatty acid receptor. Since fatty acids do not initiate insulin secretion in the absence of glucose but strongly potentiate glucose-stimulated insulin secretion (GSIS), GPR40 has received considerable interest as a potential therapeutic target.  Work performed in our laboratory over the past few years has demonstrated that GPR40 mediates approximately 50% of the effect of fatty acids in potentiating glucose-induced insulin secretion. Deletion of GPR40 renders mice more susceptible to high-fat-diet induced diabetes, indicating that the receptor is important for beta-cell compensation for insulin resistance and supporting the concept that GPR40 agonists have therapeutic potential in type 2 diabetes.

GPR119 is expressed in pancreatic beta cells and enteroendocrine L-cells, and augments circulating insulin levels both via its direct insulinotropic action on beta cells and via stimulation of glucagon-like peptide 1 (GLP-1) secretion. GPR120 is expressed in L-cells and was also shown to stimulate GLP-1 release. Finally, GPR41 and GPR43 are receptors for short-chain fatty acids but their physiological role remains unclear.

In summary, the discovery of lipid receptors expressed at the beta-cell surface opens new and exciting avenues of research for drug development, as exemplified by the encouraging outcome of recent phase 2 trials of a GPR40 agonist. Nevertheless, a number of questions regarding the mechanisms of action and physiological roles of these receptors remain to be answered before their therapeutic potential can be fully exploited.