In patients with cystic fibrosis, CF-related diabetes mellitus (CFRD) has been associated in several studies with increased morbidity and mortality. These studies have raised the question of whether the presence of glucose metabolism abnormalities contributes to clinical decline, or whether the sickest patients are simply the most likely to develop diabetes. Currently we perform oral glucose tolerance testing (OGTT) in our patients without fasting hyperglycemia (FH) on a yearly basis. According to the results they are classified into normal (NGT), impaired (IGT) or CFRD without FH. We have previously reported a direct association between this classification of the OGTT and trends in pulmonary function in CF patients. In order to evaluate the potential role of insulin deficiency per se in this process, we determined insulin production during glucose tolerance testing at baseline and then prospectively followed the pulmonary function and nutritional parameters of 152 patients without FH at baseline. Glucose tolerance was determined by a standard OGTT, and insulin levels were measured every 30 minutes during the OGTT. With the insulin results, insulin production during the 2 hour period was assessed by the Area-Under-the-Curve, determined by the trapezoid method, and expressed as pmol/L/Hr. All subjects performed spirometry at baseline, and for the following four years on a quarterly basis. The median insulin AUC observed at baseline was 17,370 pmol/L/Hr (Range 270 to 78,390 pmol/L/Hr). There was no significant association between insulin AUC and classification of the OGTT. (Medians NGT: 15,570; IGT: 19,710;650 pmol/L/Hr, p>0.1). At baseline the level of pulmonary function was comparable between subjects in the different quartiles for insulin AUC. During the study period a mild but significant decline in FEV 1 occurred in the group as a whole, at a rate of -0.8 %-predicted/year (p=0.001). By insulin AUC quartile, and after adjustment for gender and baseline age, BMI, microbiology and FEV 1 , those subjects in the lower quartile had the highest rates of decline as opposed to subjects in the higher quartiles. Very similar rates of decline were seen for subjects in the higher two quartiles, suggesting a threshold effect. These data strongly support the concept that the insulin deficient state per se leads to detrimental pulmonary outcomes and complements previous observations by ourselves and others of increased morbidity and mortality in CF patients with diabetes. Further studies are necessary to determine whether intervention with insulin or other diabetes treatments might prevent these derangements.