Islets of Langerhans control glucose homeostasis and metabolism by sensing blood glucose and nutrients. Factors secreted within the islet create a parallel tuning, defined autocrine-paracrine signaling, that modulates hormone release and cell viability (Barker et al., 2013). Studying the molecular actors of this signaling and their physiological significance may help in understanding diabetes pathogenesis thus providing novel therapeutic targets.G-protein coupled receptors (GPCRs) are expressed in islets of Langerhans, regulate hormone secretion and cell survival, and are emerging as new targets for type-2 diabetes therapies. In this work, we focused on the expression and role of the atypical orphan receptor GPR17, which is activated by uracil nucleotides and can be partially antagonized by ATP, a well known signal in islets (Ciana et al., 2006).We first verified the GPR17 expression in endocrine cell lines (αTC3, βTC3, RIN14B) and in human islets, then we investigated its possible role in islet physiology. By means of RT-PCR, we detected GPR17 mRNA in human islets, in α and δ cell lines, but not in β cell lines (n=5). We confirmed GPR17 protein expression in α and δ cell lines and in human islet by western blot (n=4). To investigate the specific endocrine cells where GPR17 is expressed in vivo, we carried out double immunofluorescence and confocal analysis on human pancreas slices, using hormones as markers of the different cell populations and we confirmed the expression of GPR17 in a sub-population of δ cells. No expression was detected in β-cells in physiological conditions. Furthermore, chronic incubation of human islets with 16 mM glucose, known to cause β-cell death, causes a two-fold increase in GPR17 expression (p<0.05 T-Test; n=4), thus indicating that the receptor may be sensitive to stress conditions. To understand the possible role of GPR17 in islet physiology we activated GPR17 with the agonist UDP-glucose, and we measured its effect on cell viability and hormone release in cell lines and human isolated islets. 3-day incubation of αTC3 with 100 µM UDP-G causes a significant increase in cell viability, measured by MTT test (108±2.56% UDP-G vs ctr, p<0.005 T-Test; n= 10). A similar behavior was observed in human islets, where we found a reduction of apoptosis in presence of 100 µM UDP-G (38±7% UDP-G vs ctr).Preliminary data on hormone release indicate that static acute incubation of human islets with 100 µM UDP-G, causes a decrease in glucagon and somatostatin release in normal glucose (5 mM) (ELISA, 2 diverse islets preparations, triplicate).In conclusion, we demonstrated for the first time that GPR17 is expressed and functional in human islets of Langerhans. Studies are in progress to better define its role in islet cell physiology and pathology.