RESIDUAL CFTR function in cystic fibrosis, associated to improved glucose tolerance and insulin secretion in 341 OGTT participants.
Residual CFTR Function and Beta Cell Performance
People with cystic fibrosis (CF) frequently develop impaired insulin secretion that can progress to cystic fibrosis-related diabetes (CFRD). In a multicenter study, investigators examined whether differences in CFTR channel activity, defined by mutation type and in vitro chloride conductance, were associated with measures of glucose tolerance and insulin secretion.
The cohort included 341 people with cystic fibrosis, 57% of whom were female, with a median age of 19 years. Most participants had pancreatic insufficiency. All participants completed an oral glucose tolerance test with sampling of glucose, insulin, and C peptide every 30 minutes over two hours. Beta cell function was summarized using beta cell glucose sensitivity.
OGTT Results by Mutation Group
Participants were grouped by genotype as either minimal function mutations on both alleles or at least one residual function mutation. Those with at least one residual function mutation demonstrated better glucose tolerance and higher beta cell glucose sensitivity than the minimal function group, with statistical significance reported at p ≤ 0.001.
To connect genotype with functional CFTR activity, each variant was mapped to CFTR chloride conductance values from the CFTR2 database. For each individual, the highest conductance value across the two alleles was used as their representative CFTR chloride conductance. Among those with available conductance data, the analysis found a strong positive linear association between CFTR chloride conductance and beta cell glucose sensitivity after adjustment for age and sex, with p < 0.001.
CFTR Chloride Conductance Independently Correlates with Beta Cell Function
Importantly, the relationship between CFTR chloride conductance and beta cell glucose sensitivity did not show a significant interaction with pancreatic status. The authors concluded that clinical data, OGTT results, and in vitro conductance measures together support an independent relationship between the extent of CFTR channel dysfunction and beta cell function in people with cystic fibrosis.
Reference: Ciciriello F et al. Mutations with residual CFTR function are associated with better glucose tolerance and insulin secretion in people with Cystic fibrosis. Journal of Cystic Fibrosis. 2025;doi:10.1016/j.jcf.2025.11.001.
