1552-P: Mutations with Residual CFTR Function Are Associated to Better Glucose Tolerance and Insulin Secretion in Patients with Cystic Fibrosis

People with Cystic Fibrosis (pwCF) exhibit a defect of insulin secretion[1], potentially leading to Cystic Fibrosis Related Diabetes. Little information exists about the molecular mechanism that links the defect of insulin secretion to the CF-causing variants of the CFTR gene[2,3]. We sought to describe the relationship between the CFTR function and β-cell function in pwCF. We studied 341 patients (193 (57%) females, 271 (79%) pancreatic insufficient, median (IQR) age 19 (15, 24) years) with the oral glucose tolerance test (OGTT), sampling glucose, insulin, and C-peptide before and every 30 minutes over the 2 hour OGTT, modeling β-cell function expressed by the β-cell glucose sensitivity[4]. Each patient was characterized by either having at least one allele with a residual function mutation (group 1, 85 (25%)), or a minimal function mutation on both alleles (group 2, 255 (75%) ). After adjusting for sex, pancreatic insufficiency (PI), and age, patients in group 1 displayed better glucose tolerance at all OGTT timepoint (all p=<0.05), and better β-cell glucose sensitivity (22 pmol×min⁻¹×m⁻²×mM⁻¹; 95% CI 9.6, 34; p=<0.001).Within the whole sample, 162 patients (82 (51%) females, 136 (84%) of group 2, 139 (86%) pancreatic insufficient, median (IQR) age 20 (15, 25) years) carried variants on both alleles that had been tested for chloride conductance in the Fischer Rat Thyroid cell line (http://cftr2.org). The mean chloride conductance of the most functional allele was positively related to β-cell glucose sensitivity (0.96; 95% CI 0.13, 1.8; p=0.025), with no PI interaction (interaction term -0.63; 95% CI -3.7, 2.4; p=0.7), and adjusting for differences in sex and age.

In conclusion, we have shown that CFTR function is quantitatively related to β-cell function in pwCF. Even though exocrine PI is associated with worse β-cell function, the association of CFTR residual function and β-cell glucose sensitivity is not necessarily mediated by exocrine PI.