Mutations with residual CFTR function are associated with better glucose tolerance and insulin secretion in people with Cystic fibrosis

Background People with Cystic Fibrosis (pwCF) often exhibit impaired insulin secretion, which may lead to Cystic Fibrosis-Related Diabetes (CFRD). The impact of CF variants in the complex relationship between CFTR channel function, pancreatic function, and glucose metabolism remains only partially understood. Methods In this multicenter study, 341 pwCF (57 % females, 79 % with pancreatic insufficiency; median age 19 yrs.) underwent an oral glucose tolerance test (OGTT) sampling glucose, insulin, and C-peptide every 30 min for 2 h to assess β-cell function, expressed by β-cell glucose sensitivity. Participants were grouped by having either a minimal function (MF) mutation on both alleles (256 pts, 75 %) or at least one residual function (RF) mutation (85 pts, 25 %). Each variant was then associated to the CFTR-chloride conductance (CC) values from the CFTR2 database. The highest CC value (from each allele) was selected as the patient’ representative CC, and used to assess its relationship with β-cell glucose sensitivity. Results 162 pwCF (84 % of MF group) carried variants on both alleles with CC data available in the CFTR2 database. PwCF in the RF group exhibited better glucose tolerance and β-cell glucose sensitivity ( p ≤ 0.001). After adjustment for sex and age, a strong positive linear association was found between CFTR-CC values and β-cell glucose sensitivity ( p < 0.001), without a significant interaction with pancreatic status. Conclusions Clinical data, OGTT results, and in vitro CC analysis demonstrate an independent relationship between the extent of CFTR channel dysfunction and β-cell function.