Aim: Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel and regulator of proteins1. Mutations in CFTR cause cystic fibrosis (CF) and a major complication of CF is diabetes2. It is largely unknown why these patients develop diabetes but there is increasing evidence that CFTR is involved in islet hormone release3. The aim of this project is to investigate presence of CFTR in mouse and human pancreatic islets and role of CFTR in mechanisms controlling β-cell insulin release. Method: Experiments where performed on islets and single β-cells from human donors and NMRI-mice. Detection of CFTR was investigated using PCR and confocal microscopy. Insulin secretion was measured with RIA. Patch-clamp measurements of currents and exocytosis were performed. Statistical significance was calculated using t-test. Results: Human- and mouse islets express CFTR mRNA and CFTR protein was detected in β-cells. The whole-cell configuration of the patch-clamp technique was used and a ramp from -100 mV to +100 mV was applied to single human and mouse β-cells to measure cAMP-activated currents. Forskolin (10 µM) evoked an increase in current that was inhibited by CFTR antagonists, CFTRinh-172 (10 µM) or GlyH-101 (25 µM, GlyH; P<0.001, nhuman=21, nmouse=17). A major part of the cAMP-activated current was also reduced by the chloride channel blocker DIDS (200 µM), where the remaining part was inhibited by GlyH-101 (P<0.05, nhuman=6, mouse=10). The calculated CFTR conductance was small and we propose that CFTR act as a regulator of the DIDS-sensitive chloride channel Outward Rectifier Chloride Channel (ORCC) as suggested in other cell-types4. This was further confirmed by insulin secretion measurements. Glucose- and cAMP-stimulated insulin secretion was reduced by 43±5% (p<0.001, n=11 donors) and 40±12% (p<0.05, n=5) in the presence of GlyH (50 µM) in human and mouse islets, respectively. When DIDS was added, GlyH had no further inhibitory effect on insulin secretion in mouse islets, confirming that CFTR controls ORCC. However, in human islets, addition of GlyH caused a further reduction (p<0.05, n=5 donors), suggesting that CFTR interact with additional proteins. Moreover, cAMP-amplified exocytosis elicited by a train of ten depolarizations from -70 mV to 0 mV and measured as an increase in membrane capacitance in single human and mouse β-cells was significantly reduced by >40% after pre-incubation with CFTR antagonists (P<0.05, nhuman=5; nmouse=7). The reduction was most prominent during the first two pulses representative of release of primed granules and first phase insulin secretion5. Conclusion: Based on our results we postulate that CFTR is an essential component in cAMP-dependent insulin secretion and exocytosis in human and mouse β-cells and hypothesize CFTR to be vital for granular priming and first phase insulin secretion.