Palmitate-induced beta-cell dysfunction is associated with excessive NO production and is reversed by thiazolidinedione-mediated inhibition of GPR40 transduction mechanisms.

Background: Type 2 diabetes often displays hyperlipidemia. We examined palmitate effects on pancreatic islet function in relation to FFA receptor GPR40, NO generation, insulin release, and the PPARgamma agonistic thiazolidinedione, rosiglitazone.

Principal Findings: Rosiglitazone suppressed acute palmitate-stimulated GPR40-transduced PI hydrolysis in HEK293 cells and insulin release from MIN6c cells and mouse islets.

GPR40 is expressed in glucagon producing cells and affects glucagon secretion.

The free fatty acid receptor, GPR40, has been coupled with insulin secretion via its expression in pancreatic beta-cells. However, the role of GPR40 in the release of glucagon has not been studied and previous attempts to identify the receptor in alpha-cells have been unfruitful. Using double-staining for glucagon and GPR40 expression, we demonstrate that the two are expressed in the same cells in the periphery of mouse islets.

A human cell surface receptor activated by free fatty acids and thiazolidinedione drugs.

Fatty acids, which are essential nutritional components, are also involved in cardiovascular and metabolic diseases. Here we report a human cell surface receptor that we name free fatty acid receptor (FFAR), because it is specifically activated by medium to long-chain free fatty acids. The receptor belongs to the class of seven-transmembrane, G-protein coupled receptors (GPCRs) and also mediates responses to antidiabetic drugs of the thiazolidinedione type.