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Background In non-cystic fibrosis (CF) subjects, the disposition index (DI) is a strong predictor of the development of type 2 diabetes. CF subjects are at high risk of diabetes. We hypothesized that DI would be reduced in CF patients with normal glucose tolerance (NGT), indicating β-cell dysfunction, and DI would worsen with progression from CF with NGT to CF-related diabetes (CFRD). Methods This was a cross-sectional study in 39 CF patients and 21 healthy controls (Con) who underwent oral glucose tolerance test (OGTT). Insulin sensitivity was estimated as (1/fasting insulin) and insulin secretion as (∆insulin 0–30 min/∆glucose 0–30 min). DI was calculated as (insulin sensitivity) × (insulin secretion). Results Among CF subjects, 14 had NGT, 20 had prediabetes and 5 had CFRD. Among the controls, 14 had NGT and 7 had prediabetes. DI was significantly lower in CF-NGT compared to Con-NGT ( p = 0.0035). DI was also lower in CFRD compared to CF-NGT ( p = 0.025). There were no significant relationships in the CF groups between DI and age, BMI, percent body fat or FEV1. Conclusion β-Cell function as measured by DI is reduced in CF patients compared to non-CF controls—even in CF-NGT—and is decreased further in CF patients with diabetes. If DI proves to be a predictor of the development of CFRD in larger studies, then it could be used to identify CF patients who are at particularly high risk, allowing early interventions aimed to delay or prevent CFRD. [ABSTRACT FROM AUTHOR]