Previous studies have shown that Prostaglandin E-2 (PGE(2)) inhibits glucose-stimulated insulin secretion. However, the role of cyclooxygenase (COX)-1 vs. COX-2 derived PGE2 production in glucose-stimulated insulin secretion remains poorly understood. Here we investigated the expression of COX-I and COX-2 in pancreatic islets and the effect of selective inhibition of COX-1 and COX-2 on glucose-stimulated insulin secretion using C57BL/6 (136) mice. Although immunofluorescence histochemistry showed the constitutive expression of both COX-1 and COX-2 in 136 mouse pancreatic islets, insulin secretion and hyperglycemia after glucose loading were ameliorated in B6 mice treated with selective COX-2 inhibitor (SC58236) for 18 weeks. Interestingly, incubation with selective COX-2 inhibitor for 24 h led to a reduction in PGE(2) production in pancreatic islets isolated from B6 mice. In addition, selective COX-2 inhibition enhanced insulin secretion from the isolated islets. These results collectively suggest that selective inhibition of COX-2 enhances glucose-stimulated insulin secretion through a reduction in PGE(2) production in pancreatic islets. (C) 2007 Elsevier Inc. All rights reserved.