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

ABSTRACT: RATIONALE:Diabetes is associated with worse cystic fibrosis (CF) outcomes. The CFTR potentiator ivacaftor is suggested to improve glucose homeostasis in individuals with CF. OBJECTIVES:To test the hypothesis that clinically indicated ivacaftor would be associated with improvements in glucose tolerance and insulin and incretin secretion. METHODS: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. MEASUREMENTS AND MAIN RESULTS: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). CONCLUSIONS: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.

SUBMITTER: Kelly A

PROVIDER: S-EPMC6835076 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:People with cystic fibrosis (pwCF) experience a range of persistent gastrointestinal symptoms throughout life. There is evidence indicating interaction between the microbiota and gut pathophysiology in CF. However, there is a paucity of knowledge on the potential effects of CF transmembrane conductance regulator (CFTR) modulator therapies on the gut microbiome. In a pilot study, we investigated the impact of Tezacaftor/Ivacaftor dual combination CFTR modulator therapy on the gut microbiota and metabolomic functioning in pwCF. Fecal samples from 12 pwCF taken at baseline and following placebo or Tezacaftor/Ivacaftor administration were subjected to microbiota sequencing and to targeted metabolomics to assess the short-chain fatty acid (SCFA) composition. Ten healthy matched controls were included as a comparison. Inflammatory calprotectin levels and patient symptoms were also investigated. No significant differences were observed in overall gut microbiota characteristics between any of the study stages, extended also across intestinal inflammation, gut symptoms, and SCFA-targeted metabolomics. However, microbiota and SCFA metabolomic compositions, in pwCF, were significantly different from controls in all study treatment stages. CFTR modulator therapy with Tezacaftor/Ivacaftor had negligible effects on both the gut microbiota and SCFA composition across the course of the study and did not alter toward compositions observed in healthy controls. Future longitudinal CFTR modulator studies will investigate more effective CFTR modulators and should use prolonged sampling periods, to determine whether longer-term changes occur in the CF gut microbiome. IMPORTANCE People with cystic fibrosis (pwCF) experience persistent gastrointestinal (GI) symptoms throughout life. The research question "how can we relieve gastrointestinal symptoms, such as stomach pain, bloating, and nausea?" remains a top priority for clinical research in CF. While CF transmembrane conductance regulator (CFTR) modulator therapies are understood to correct underlying issues of CF disease and increasing the numbers of pwCF are now receiving some form of CFTR modulator treatment. It is not known how these therapies affect the gut microbiome or GI system. In this pilot study, we investigated, for the first time, effects of the dual combination CFTR modulator medicine, Tezacaftor/Ivacaftor. We found it had negligible effects on patient GI symptoms, intestinal inflammation, or gut microbiome composition and functioning. Our findings are important as they fill important knowledge gaps on the relative effectiveness of these widely used treatments. We are now investigating triple combination CFTR modulators with prolonged sampling periods.

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

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