-Cystic fibrosisrelated diabetes (CFRD) is the most common comorbidity associated with cystic fibrosis (CF), impacting more than half of patients over age 30. CFRD is clinically significant, portending accelerated decline in lung function, more frequent pulmonary exacerbations, and increased mortality. Despite the profound morbidity associated with CFRD, little is known about the underlying CFRD-related pulmonary pathology. Our aim was to develop a murine model of CFRD to explore the hypothesis that elevated glucose in CFRD is associated with reduced lung bacterial clearance. A diabetic phenotype was induced in gut-corrected CF transmembrane conductance regulator (CFTR) knockout mice (CFKO) and their CFTR-expressing wild-type littermates (WT) utilizing streptozotocin. Mice were subsequently challenged with an intratracheal inoculation of Pseudomonas aeruginosa (PAO1) (75 l of 1-5 ϫ 10 6 cfu/ml) for 18 h. Bronchoalveolar lavage fluid was collected for glucose concentration and cell counts. A portion of the lung was homogenized and cultured as a measure of the remaining viable PAO1 inoculum. Diabetic mice had increased airway glucose compared with nondiabetic mice. The ability to clear bacteria from the lung was significantly reduced in diabetic WT mice and control CFKO mice. Critically, bacterial clearance by diabetic CFKO mice was significantly more diminished compared with nondiabetic CFKO mice, despite an even more robust recruitment of neutrophils to the airways. This finding that CFRD mice boast an exaggerated, but less effective, inflammatory cell response to intratracheal PAO1 challenge presents a novel and useful murine model to help identify therapeutic strategies that promote bacterial clearance in CFRD.cystic fibrosis-related diabetes; murine model; Pseudomonas; pneumonia; cystic fibrosis CYSTIC FIBROSIS (CF) is the most common inheritable lethal disorder among Caucasians (25). Although often primarily characterized by a progressive pulmonary decline due to frequent pulmonary exacerbations, the disease carries risk for numerous other comorbidities (27). More than 75% of adults with CF demonstrate some aberrancy in glucose regulation, for many of which constitutes a comorbidity termed cystic fibrosis-related diabetes (CFRD) (4,12,25). CFRD is now recognized as the most common comorbidity associated with CF, affecting more than 50% of patients over the age of 30 with increasing prevalence rates rising with increasing age (4,5,25). CFRD is punctuated by delayed insulin secretion, glucose dysregulation, and hyperglycemia (22-24, 34). Consequences of prolonged hyperglycemia can include significant microvascular complications similar to what is observed in other types of diabetes (36,40, 44). However, by far the most egregious insult to a patient with CFRD is the rapid decline in pulmonary function and increase in pulmonary exacerbations associated with onset of the disease (19). The inception of CFRD at any age accelerates pulmonary decline, as noted in multiple epidemiological studies documenting both dete...