Persistence of Residual Insulin Secretion in Long-Standing Cystic Fibrosis-Related Diabetes

OBJECTIVE: The pathophysiology of cystic fibrosis-related diabetes (CFRD) remains poorly understood, with uncertainty whether the insulin secretion defect progresses over time, characterized by a decline in C-peptide and an increase in proinsulin-to-C-peptide ratio. CFRD is often compared to type 1 diabetes (T1D), which is associated with complete beta-cell exhaustion. Similarly, insulin is the sole therapy recommended for CFRD. We aimed to examine beta-cell function over time in adults with CFRD and compare it with T1D. METHODS: This retrospective cross-sectional study compared fasting C-peptide measurements between 59 adults (≥18 years) with CFRD (PwCFRD) and 1185 people with T1D (PwT1D). The fasting and stimulated proinsulin-to-C-peptide ratio after a mixed meal tolerance test was quantified in a subset of 18 PwCFRD and 75 PwT1D. RESULTS: Fasting C-peptide was higher in PwCFRD (0.27 [0.34]) than in PwT1D (0.00 [0.04], P < .001). The duration of CFRD did not correlate with C-peptide secretion (P = .736), even after adjustment for glycated hemoglobin and insulin therapy (P = .714). Proinsulin-to-C-peptide ratio was lower in PwCFRD than in PwT1D at baseline (P < .001) and 2 h (P = .001) after a mixed meal tolerance test. PwCFRD who required intravenous antibiotics the previous year showed a significantly lower C-peptide secretion (P = .042), but there was no difference between patients receiving or not receiving cystic fibrosis transmembrane conductance regulator modulator therapy. CONCLUSION: C-peptide levels in our cohort of PwCFRD were independent of diabetes duration, in contrast to PwT1D. A lower proinsulin-to-C-peptide ratio in PwCFRD compared to PwT1D suggested lower beta-cell dysfunction at fasting and stimulated evaluation. This supports the use of non-insulin therapies for adults with CFRD.