The role of Cox-2 and prostaglandin E2 receptor EP3 in pancreatic β-cell death.

Abstract

Elevated levels of lipids, in particular saturated fatty acids, are known to be associated with type 2 diabetes (T2D) and to have a negative effect on β-cell function and survival. We bring new evidence indicating that palmitate up-regulates cyclooxygenase-2 (COX-2) expression levels in human islets and in MIN6 β cells, and that it is elevated in islets isolated from T2D donors. Both small interfering specific cyclooxygenase-2 small interfering RNA (siRNA) or the COX-2 inhibitor celecoxib significantly inhibited apoptosis induced by palmitate. Prostaglandin E2 (PGE2), the predominant product of COX-2 enzymatic activity, activates membrane receptors, which are members of the GPCR-family (EP1-EP4). In the present study, elevated expression of the PGE2 receptor subtype 3 (EP3) receptor was observed in β cells exposed to palmitate and in islets from individuals with T2D. Down-regulation of the pathway using EP3 siRNA or the specific L-798,106 antagonist markedly decreased the levels of palmitate-induced apoptosis. Altogether, our data put forward the COX-2-PGE2-EP3 pathway as one of the mediators of palmitate-induced apoptosis in β-cells.-Amior, L., Srivastava, R., Nano, R., Bertuzzi, F., Melloul, D. The role of Cox-2 and prostaglandin E2 receptor EP3 in pancreatic β-cell death.