TY - JOUR
T1 - Islet hormone and incretin secretion in cystic fibrosis after four months of ivacaftor therapy
AU - Kelly, Andrea
AU - De Leon, Diva D.
AU - Sheikh, Saba
AU - Camburn, Devaney
AU - Kubrak, Christina
AU - Peleckis, Amy J.
AU - Stefanovski, Darko
AU - Hadjiliadis, Denis
AU - Rickels, Michael R.
AU - Rubenstein, Ronald C.
N1 - Funding Information:
Supported by grants from the Cystic Fibrosis Foundation (A.K. and R.C.R.), Public Health Services Research grants R01 DK97830 (A.K. and M.R.R.), K23 DK107937 (S.S.), UL1 TR001878 (University of Pennsylvania and Children’s Hospital of Philadelphia Centers for Human Phenomic Science), P30 DK19525 (University of Pennsylvania Diabetes Research Center), and the Human Metabolism Resource of the University of Pennsylvania Institute for Diabetes, Obesity and Metabolism.
Publisher Copyright:
Copyright © 2019 by the American Thoracic Society
PY - 2019/2/1
Y1 - 2019/2/1
N2 - 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 (22.4 to 1.9), and FEV 1 % 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 b-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.
AB - 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 (22.4 to 1.9), and FEV 1 % 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 b-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.
KW - Cystic fibrosis
KW - Diabetes
KW - Insulin
KW - Ivacaftor
UR - http://www.scopus.com/inward/record.url?scp=85060942441&partnerID=8YFLogxK
U2 - 10.1164/rccm.201806-1018OC
DO - 10.1164/rccm.201806-1018OC
M3 - Article
C2 - 30130412
AN - SCOPUS:85060942441
SN - 1073-449X
VL - 199
SP - 342
EP - 351
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
IS - 3
ER -