GPR40: Good Cop, Bad Cop?
- From the Montreal Diabetes Research Center, Research Center of the University of Montreal Hospital Center (CRCHUM), and Department of Medicine, University of Montreal, Montreal, Quebec, Canada.
- Corresponding author: Vincent Poitout, .
Since its deorphanization in 2003 (1,2), the fatty acid receptor GPR40 (FFAR1/FFA1) has drawn considerable attention as a potential therapeutic target 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 expressed in β-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 of glucose-induced insulin secretion. Although the role of GPR40 in the acute effects of fatty acid is relatively well established, its potential contribution to chronic deleterious effects of fatty acids on β-cell function has remained controversial. This question has important implications because a potential contribution of GPR40 to β-cell dysfunction would preclude the development of GPR40 agonists as therapeutic agents. Nagasumi et al. (3) generated a transgenic mouse overexpressing the human GPR40 gene under the mouse insulin II promoter (hGPR40 transgenic mice). GPR40 overexpression did not affect the metabolic status of the animals under fed conditions, but it was …