Elexacaftor–tezacaftor–ivacaftor enhances first-phase insulin secretion and improves glucose control in cystic fibrosis

Objective: Cystic fibrosis (CF) is a congenital condition caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. CF-related diabetes (CFRD) is a common comorbidity among people with CF (pwCF) and is associated with increased morbidity. Previous in vitro studies have suggested that CFTR dysfunction is involved in the pathogenesis of CFRD. This prospective study aimed to evaluate the role of CFTR in glucose homeostasis by comparing glucose, insulin, C-peptide, glucagon and GLP-1 responses during an oral glucose tolerance test (OGTT) in pwCF and healthy controls and in pwCF before and after initiating elexacaftor-tezacaftor-ivacaftor (ETI) therapy. Methods: Twenty-four pwCF were enrolled, of which 18 underwent OGTT both before and after ETI initiation. Ten healthy controls were included for comparison. Plasma samples were collected at standard OGTT time points, including an additional 15 min sample. Hormonal and glucose responses during OGTT were compared across groups and in pwCF before and after starting ETI. Results: Compared with healthy controls, pwCF exhibited impaired glucose regulation, delayed insulin secretion, decreased insulin sensitivity index and reduced disposition index, indicating beta-cell dysfunction. In addition, p-glucagon levels were elevated in pwCF. Following ETI therapy, pwCF showed improved glucose control, increased first-phase insulin secretion and normalized glucagon secretion. Conclusions: These findings support a role for CFTR in islet hormone regulation, implicating direct effects on beta-cell function and a potential role in suppressing glucagon secretion.