Until now, the G-protein-coupled receptor GPR40 was classed as an orphan receptor, that is, its ligands were unidentified. In the 13th March issue of Nature, Hinuma and colleagues from Takeda Chemical Industries Ltd, Japan, show that GPR40, which is abundantly expressed in the pancreas, functions as a receptor for long-chain free fatty acids (FFAs).

Type 2 insulin-resistant diabetes accounts for 90–95% of all diabetes — the increasing incidence largely driven by the dramatic rise in obesity in Western societies. A complex network of signalling pathways are activated by stimulation of the insulin receptor, but in patients who suffer from type 2 diabetes, those receptors on cells in tissues such as muscle, fat and liver become less responsive, or resistant, to insulin. Various factors modify the way that insulin is secreted from pancreatic β cells in response to raised glucose levels in the blood plasma. FFAs provide an important energy source as nutrients, and act as signalling molecules in a variety of cellular processes, including insulin secretion. Although FFAs are thought to promote insulin secretion, this mechanism is not clearly understood.

By looking for changes in intracellular calcium ion flux, the authors identified GPR40 ligands as saturated FFAs of C12 to C16 length and unsaturated FFAs of C18 to C22. Then, they performed experiments to specifically inhibit the expression of GPR40 in pancreatic β-cells using small interfering RNA (siRNA) technology, monitoring glucose-stimulated insulin secretion from the cells in the presence of FFAs. The results showed that long-chain FFAs amplify the insulin secretion from pancreatic β-cells by activating GPR40.

These results shed light on the role of FFAs in glucose metabolism and indicate that they play a direct role in stimulating production of insulin. GPCRs are well characterized as drug targets, and development of agonists or antagonists of GPR40 could have potential as new anti-diabetic drugs.