vx-770 and Diabetes-Mellitus

To determine whether the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is involved in human insulin secretion by assessing the metabolic impact of the new CFTR corrector-ivacaftor.. This open-label pilot study was conducted in CF patients with the G551D mutation given new prescriptions for ivacaftor. At baseline and 4 wk after daily ivacaftor therapy, intravenous glucose tolerance tests (IVGTT) and oral glucose tolerance tests (OGTT) were performed.. Five patients aged 6-52 were studied. After 1 month on ivacaftor, the insulin response to oral glucose improved by 66-178% in all subjects except one with long-standing diabetes. OGTT glucose levels were not lower in the two individuals with diabetes or the two with normal glucose tolerance (NGT), but the glucose tolerance category in the subject with impaired glucose tolerance (IGT) improved to NGT after treatment. In response to intravenous glucose, the only patient whose acute insulin secretion did not improve had newly diagnosed, untreated CFRD. The others improved by 51-346%. Acute insulin secretion was partially restored in two subjects with no measurable acute insulin response at baseline, including the one with IGT and the one with long-standing diabetes.. This small pilot study suggests there is a direct role of CFTR in human insulin secretion. Larger, long-term longitudinal studies are necessary to determine whether early initiation of CFTR correction, particularly in young children with CF who have not yet lost considerable β-cell mass, will delay or prevent development of diabetes in this high-risk population.

Topics: Adolescent; Adult; Amino Acid Substitution; Aminophenols; Child; Cross-Sectional Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Diabetes Mellitus; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Mutation; Pilot Projects; Prediabetic State; Quinolones

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are a group of new drugs for the treatment of cystic fibrosis (CF) and elexacaftor + tezacaftor + ivacaftor (ETI) triple combination therapy has been approved as first choice therapy in the treatment of patients with at least 1 copy of F508del variation. Data on the effects of CFTR modulators on glucose metabolism are limited to small studies with conflicting results. We conducted a prospective observational study on 24 CF patients with CF-related diabetes requiring insulin therapy, with the aim to evaluate the effectiveness of ETI on glucose metabolism, glucose variability and body composition. After six months of treatment, HbA1c and coefficient of variation, measured through flash or continuous glucose monitoring, significantly decreased (median changes: -0.5, P = 0.029 and -6.3, P = 0.008, respectively), despite unchanged insulin requirements. Over the treatment period, percent of fat mass increased by a median value of 3% (p = 0.029).

Topics: Blood Glucose; Blood Glucose Self-Monitoring; Body Composition; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Diabetes Mellitus; Glycemic Control; Humans; Insulin; Mutation

Topics: Adolescent; Adult; Age Factors; Aminophenols; Chloride Channel Agonists; Cohort Studies; Cystic Fibrosis; Diabetes Mellitus; Female; Forced Expiratory Volume; Humans; Male; Quinolones; Young Adult

Half of adults with cystic fibrosis (CF) develop CF-related diabetes (CFRD). CFRD contributes to worsened pulmonary function and malnutrition. We undertook this study to determine the effect of cystic fibrosis transmembrane regulator (CFTR) modulators on CRFD.. We reviewed the medical records of adults with CF who followed in the CF clinic at Oklahoma University Medical Center. We collected data for age at diagnosis of CF and CFRD, CF mutations present, first date of ivacaftor therapy either alone or in combination, insulin use, pulmonary function, body mass index data, and home glucose monitoring results. Clinical resolution of CFRD was taken as discontinuation of routine insulin and resolution of high interstitial home glucose values.. We identified 69 adult CF patients, of whom 31 had CFRD. Among these 14 CFRD patients taking ivacaftor alone or in combination, four patients completely stopped using insulin. Another patient went from three times a day pre-prandial insulin to using insulin once a week. Home blood glucose and hemoglobin A1c values supported resolution of CFRD. Three patients continued to have hypoglycemia despite stopping insulin. No CFRD patient not taking CFTR modulators markedly changed the insulin regimen. Pulmonary function was preserved in those patients with resolved CFRD (FEV. About one-third of patients on CFTR modulator therapy had resolution or near resolution of CFRD.

Topics: Adult; Aminophenols; Blood Glucose; Blood Glucose Self-Monitoring; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Diabetes Mellitus; Humans; Insulin; Quinolones

Topics: Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Diabetes Mellitus; Humans; Incretins; Insulin Secretion; Quinolones

Topics: Adult; Aminophenols; Cystic Fibrosis; Diabetes Mellitus; Humans; Hypoglycemic Agents; Male; Quinolones