We examined the transcriptional expression and functional effects of receptors for the extracellular pyrimidines uridine triphosphate (UTP) and uridine diphosphate (UDP), on insulin and glucagon secretion in isolated mouse pancreatic islets and purified beta-cells. Using real-time PCR, the UDP receptor P2Y(6) was found to be highly expressed in both whole islets and beta-cells purified by repeated counter-flow elutriation, whereas no mRNA expression for UTP receptors P2Y(4) and P2Y(2) could be detected. Functional in vitro experiments revealed that the P2Y(6) agonist UDP beta S dose-dependently enhanced insulin and glucagon release during short-term incubation (1 h), while P2Y6 activation during a longer period (24 h), selectively increased insulin release, especially at high glucose levels. The corresponding EC50 value for UDP beta S ranged from 3.2 x 10(-8) M to 1.6 x 10(-8) M for both glucose concentrations. The P2Y(6) antagonist MRS2578 inhibited the effects of UDP beta s, supporting a P2Y(6) specific effect. In addition to negative RT-PCR results, the lack of response to UTP gamma S a selective P2Y(2/4) agonist further rule out the involvement of P2Y(2/4) receptors in the islet hormone release. Our results suggest a modulatory role for UDP via a functional active P2Y(6) receptor in the regulation of islet hormone release. (c) 2008 Elsevier Inc. All rights reserved.