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

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 b-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 b 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 b 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 b-cells.