The significance of GPR119 agonists as a future treatment for type 2 diabetes.

GPR119 is a G protein-coupled receptor that is expressed on only a limited number of tissues, including pancreatic β-cells and enteroendocrine cells in the small intestine, and that appears to be involved in the regulation of metabolic homeostasis. The protein was originally defined as an orphan receptor, but it has subsequently been shown to bind a variety of lipid-derived ligands, as well as a range of small synthetic molecules. There is still debate as to the identity of its principal endogenous ligand, but certain lysophospholipids species, various fatty acyl-ethanolamides and N-oleoyldopamine have all been proposed as potential agonists. GPR119 is coupled to the signal transducer Gαs and activation of the receptor leads to increased adenylate cyclase activity via Gαs and a rise in intracellular cAMP. This then potentiates glucose-induced insulin secretion or promotes the release of intestinal incretin hormones, according to cell type. Both mechanisms ultimately lead to a rise in insulin secretion (either directly or indirectly) and improved glucose control. Thus, GPR119 may represent an important new therapeutic target for the design of insulin secretagogues able to promote improvements in blood glucose control in patients with type 2 diabetes. Accordingly, a range of lead compounds are in development as potential therapeutic agents.