Physiology and therapeutics of the free fatty acid receptor GPR40.

The G protein-coupled receptor 40 (GPR40) was deorphanized in 2003 as a receptor of medium- and long-chain free fatty acids (FFAs), now also called FFA receptor 1 (FFAR1). Studies have shown that GPR40 not only directly mediates FFA amplification of glucose-stimulated insulin secretion but also indirectly enhances insulin secretion by stimulating incretin release. Therefore, GPR40 has attracted considerable attention as a therapeutic drug target of type 2 diabetes mellitus, and numerous GPR40 ligands have been developed and investigated for their antidiabetic actions. Recently, one of these ligands, TAK-875, has been successfully tested in phase II clinical trials with reduced risk of hypoglycemia. This chapter will summarize studies on GPR40, including its molecular cloning and tissue distribution, physiology, pharmacology, and pathophysiology.