Background: Cystic fibrosis-related diabetes (CFRD) is the most common extra pulmonary complication in people with cystic fibrosis (pwCF), although other glucose abnormalities can also be observed in childhood. β-cell dysfunction has a pivotal role in the process leading to glucose alterations. Only few studies investigated the impact of CFTR on glucose metabolism in pwCF, and even less data are available on the impact of Elexacaftor/Tezacaftor/Ivacaftor (ETI) combination therapy. Aim: evaluate the effect of ETI on β-cell function and insulin sensitivity in pediatric and adult pwCF receiving ETI. Materials and methods: A cohort of pwCF and no history for CFRD was evaluated before and 6 months after the initiation of ETI with a frequently sampled oral glucose tolerance test (fsOGTT). Indication to, and treatments before and after the beginning of ETI were as per ongoing protocols in our Institution, and are strictly adherent to standards of care. β-cell function was assessed by state-of-art modelling of glucose/C-peptide curves during the fsOGTT. There are two key outputs of the model: derivative control (DC: amount of insulin secreted in response to the rate of plasma glucose increase; units: pmol*m-2 body surface area, BSA/mM*min-1) and proportional control of beta-cell function (PC: response to glucose concentration per se, presented as the stimulus-response curve linking glucose to insulin secretion rate, ISR, at the preselected glucose concentrations of 4.0, 5.5, 8.0 and 11.0 mM; units: pmol*min-1*m-2 BSA). The oral glucose insulin sensitivity (OGIS) index was also determined. Results: The study included 66 individuals. After fsOGTT, 7 patients had IFG, 14 showed IGT, and 23 had indeterminate glycemia. β-cell secretion was not affected by ETI initiation, both in the DC (+13.2, -435.3, 545.0, p=0.73) and the PC of β-cellular function (ISR 4: -9.6, -41.4, 26.8, p=0.40; ISR 5.5: -11.2, -61.1, 50.0, p=0.21; ISR 8: -22.7, -90.9, 71.2, p=0.33; ISR 11: -9.9, -127.5, 95.8, p=0.33). no significant changes were detected in the OGIS index (-9.6, -41.4, 26.8, p=0.21). Conclusions: In pwCF and no history of CFRD, ETI does not affect β-cell secretion and insulin sensitivity. However, further studies with an extended follow-up are necessary to determine whether a longer duration is required to observe any possible effects of ETI therapy on the mechanisms leading to the onset of CFRD and any potential protective effects against diabetes onset.