GPR40: Good Cop, Bad Cop?

Since its deorphanization in 2003 (1,2), the fattyacid receptor GPR40 (FFAR1/FFA1) has drawnconsiderable attention as a potential therapeutictarget for type 2 diabetes. Because fatty acids acutely amplify insulin secretion only in the presence of glucose, the discovery of a “drugable ” cell surface receptor whose activation glucose-dependently enhances insulin release generated much interest in the pharmaceutical industry. The study by Nagasumi et al. (3) in this issue of Diabetes provides support for the notion that activation of GPR40 improves glucose tolerance and may thereby be beneficial for the treatment of type 2 diabetes. GPR40 is a G protein–coupled receptor highly ex-pressed in -cells and activated by long-chain fatty acids (1,2). Loss of function of GPR40 via small interfering RNA (2,4–6), antisense oligonucleotides (7), pharmacological inhibition (8), or gene deletion (9,10) has shown that GPR40 mediates, at least in part, fatty acid potentiation o