The fatty acid receptor FFA1/GPR40 a decade later: how much do we know?

• Activation of GPR40 by fatty acids potentiates glucose-induced insulin secretion.
• GPR40 is not implicated in the toxic effects of chronic fatty acids on β-cells.
• GPR40 couples to Gαq/11, activation of protein kinase D1, and actin depolymerization.
• The GPR40 agonist TAK-875 is a promising drug candidate for type 2 diabetes.
• Our understanding of the biology and pharmacology of GPR40 remains incomplete.

Glucose homeostasis requires the highly coordinated regulation of insulin secretion by pancreatic β cells. This is primarily mediated by glucose itself, but other nutrients, including free fatty acids (FFAs), potentiate the insulinotropic capacity of glucose. A decade ago, the seven-transmembrane domain receptor (7TMR) GPR40 was demonstrated to be predominantly expressed in β cells and activated by long-chain FFAs. This discovery added a new dimension to our understanding of FFA-mediated control of glucose homeostasis. Furthermore, GPR40 has drawn considerable interest as a novel therapeutic target to enhance insulin secretion in type 2 diabetes. However, our understanding of the biology of GPR40 remains incomplete and its physiological role controversial. Here we summarize the current state of knowledge and emerging concepts regarding the role of GPR40 in regulating glucose homeostasis.