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

Type 2 diabetes (T2DM) is a complex disease characterized by β-cell failure in the setting of insulin resistance. In early stages of the disease, pancreatic β-cells adapt by increasing β-cell mass and function. As the need for insulin rises, the pancreas loses its ability to produce sufficient amounts of insulin to regulate blood glucose. Elevated levels of glucose and excess lipids are associated with the disease and have a negative effect on β-cell function and survival.

We bring new evidence suggesting that, the free fatty acid (FFA) palmitate preferentially upregulates Cox2 in human islets and more importantly COX2 elevated expression was confirmed in islets obtained from T2DM patients. The Cox2 inhibitor Celcoxib or COX2 siRNA, significantly inhibited palmitate-induced apoptosis, pointing towards a role for Cox2 enzymatic activity in the apoptotic process. PGE2 the main COX2 product, activates membrane receptors, members of the GPCR-family (EP1-EP4). EP3 receptor is differentially induced by palmitate in human and in murine beta-cells. Importantly, EP3 expression is also selectively elevated in islets from T2DM patients compared to normal individuals. Downregulation of the pathway using pharmacological tools (antagonists) and the RNA interference approach to EP3 significantly decreased the levels of palmitate-induced apoptosis. EP3 is therefore suggested to be one of the mediators of palmitate-induced cell death. Interfering with COX2-PGE2-EP3 pathway is presented as a strategy for preserving β-cell mass. Targeting the specific EP3 receptor is likely to be a more beneficial approach than the general inhibition of PGE2 biosynthesis using a Cox2 inhibitor.