Islet Hormone and Incretin Secretion in Cystic Fibrosis after Four Months of Ivacaftor Therapy

Abstract

Diabetes is associated with worse cystic fibrosis (CF) outcomes. The CFTR potentiator ivacaftor is suggested to improve glucose homeostasis in individuals with CF. To test the hypothesis that clinically indicated ivacaftor would be associated with improvements in glucose tolerance and insulin and incretin secretion. Oral glucose tolerance tests, mixed-meal tolerance tests, and glucose-potentiated arginine tests were compared preivacaftor initiation and 16 weeks postivacaftor initiation in CF participants with at least one CFTR gating or conductance mutation. Meal-related 30-minute (early phase) and 180-minute incremental area under the curves were calculated as responses for glucose, insulin, C-peptide, and incretin hormones; glucagon-like peptide-1; and glucose-dependent insulinotropic polypeptide. First-phase insulin secretion, glucose potentiation of arginine-induced insulin secretion, and disposition index were characterized by glucose-potentiated arginine stimulation tests. Twelve subjects completed the study: six male/six female; seven normal/five abnormal glucose tolerance (oral glucose tolerance test 1-h glucose ≥155 and 2-h glucose <200 mg/dl); of median (minimum-maximum) age (13.8 yr [6.0-42.0]), body mass index-Z of 0.66 (-2.4 to 1.9), and FEV1% predicted of 102 (39-122). Glucose tolerance normalized in one abnormal glucose tolerance subject. Ivacaftor treatment did not alter meal responses except for an increase in early phase C-peptide (P = 0.04). First-phase (P = 0.001) and glucose potentiation of arginine-induced (P = 0.027) insulin secretion assessed by acute C-peptide responses improved after ivacaftor treatment. Consistent with an effect on β-cell function, the disposition index relating the amount of insulin secreted for insulin sensitivity also improved (P = 0.04). Insulin secretion improved following 4 months of clinically indicated ivacaftor therapy in this relatively young group of patients with CF with normal to mildly impaired glucose tolerance, whereas incretin secretion remained unchanged.