TY - JOUR
T1 - Dysregulated insulin in pancreatic insufficient cystic fibrosis with post-prandial hypoglycemia
AU - Kilberg, Marissa J.
AU - Sheikh, Saba
AU - Stefanovski, Darko
AU - Kubrak, Christina
AU - De Leon, Diva D.
AU - Hadjiliadis, Denis
AU - Rubenstein, Ronald C.
AU - Rickels, Michael R.
AU - Kelly, Andrea
N1 - Funding Information:
We would like to thank the CF subjects for their participation; the nursing and dietary staff of the Penn and CHOP Clinical & Translational Research Centers for their subject care and technical assistance; Russel Localio, PhD of the University of Pennsylvania Department of Biostatistics, Epidemiology and Informatics for assistance with statistical analyses; Heather Collins, PhD of the University of Pennsylvania Diabetes Research Center for performance of the radioimmunoassays; Samir Sayed of the Children's Hospital of Philadelphia Translational Core Laboratory for performance of the enzyme-linked immunosorbent assays; and Huong-Lan Nguyen of the Human Metabolism Resource of the University of Pennsylvania Institute for Diabetes, Obesity & Metabolism for laboratory assistance.
Funding Information:
This work was supported by grants from the Cystic Fibrosis Foundation (to A.K., M.R.R. and M.J.K.), Public Health Services Research Grants R01 DK97830 (to A.K. and M.R.R), UL1 TR000003 (Penn and CHOP Clinical & Translational Research Centers), P30 DK19525 (University of Pennsylvania Diabetes Research Center), and K23 DK107937 (to S.S.), and the Human Metabolism Resource of the University of Pennsylvania Institute for Diabetes, Obesity & Metabolism.
Publisher Copyright:
© 2019 European Cystic Fibrosis Society.
PY - 2020/3
Y1 - 2020/3
N2 - Background: Post-prandial and oral glucose tolerance test-related hypoglycemia is common in cystic fibrosis (CF); however, the underlying mechanisms are unclear. Methods: To understand the relationship of hypoglycemia with meal-related glucose excursion and insulin secretion, we analyzed plasma glucose, insulin, C-peptide, glucagon and incretins obtained during standardized mixed-meal tolerance tests (MMTT) in non-diabetic adolescents and young adults with pancreatic insufficient CF (PI-CF). Results: Hypoglycemia, defined as glucose <70 mg/dL, occurred in 9/34 subjects at 150 (range:120–210) minutes following initial meal ingestion. Hypoglycemia[+] and hypoglycemia[−] groups did not differ in gender, age, lung function, HbA1c, or BMI. While 11/14 hypoglycemia[−] individuals displayed normal glucose tolerance (NGT), only 2/9 hypoglycemia[+] had NGT. Peak glucose was higher in hypoglycemia[+] vs hypoglycemia[−]. Compared to hypoglycemia[−] NGT, hypoglycemia[+] exhibited lower early-phase insulin secretion (ISR-AUC0-30min). ISR-AUC120–180min was not different in hypoglycemia[+] vs hypoglycemia[−] with abnormal glucose tolerance (AGT); however, glucose-AUC120–180min was lower in hypoglycemia[+] vs hypoglycemia[−] AGT. After adjusting for glucose-AUC, hypoglycemia[+] subjects tended to have higher ISR-AUC120–180min than hypoglycemia[−] AGT. Glucagon concentration did not differ between groups. Lower GLP-1-AUC30min and AUC180min and higher GIP-AUC30min were present in hypoglycemia[+] individuals. Conclusion: Hypoglycemia is common in PI-CF following MMTT and is associated with early glucose dysregulation (higher peak glucose), more impaired early-phase insulin secretion (lower ISR-AUC30min), and possibly late compensatory hyperinsulinemia. Further study is required to understand whether absence of glucagon difference in the hypoglycemia[+] individuals signals counterregulatory impairment, to delineate the role of incretins in hypoglycemia, and to determine the relationship of hypoglycemia to emergence of CFRD.
AB - Background: Post-prandial and oral glucose tolerance test-related hypoglycemia is common in cystic fibrosis (CF); however, the underlying mechanisms are unclear. Methods: To understand the relationship of hypoglycemia with meal-related glucose excursion and insulin secretion, we analyzed plasma glucose, insulin, C-peptide, glucagon and incretins obtained during standardized mixed-meal tolerance tests (MMTT) in non-diabetic adolescents and young adults with pancreatic insufficient CF (PI-CF). Results: Hypoglycemia, defined as glucose <70 mg/dL, occurred in 9/34 subjects at 150 (range:120–210) minutes following initial meal ingestion. Hypoglycemia[+] and hypoglycemia[−] groups did not differ in gender, age, lung function, HbA1c, or BMI. While 11/14 hypoglycemia[−] individuals displayed normal glucose tolerance (NGT), only 2/9 hypoglycemia[+] had NGT. Peak glucose was higher in hypoglycemia[+] vs hypoglycemia[−]. Compared to hypoglycemia[−] NGT, hypoglycemia[+] exhibited lower early-phase insulin secretion (ISR-AUC0-30min). ISR-AUC120–180min was not different in hypoglycemia[+] vs hypoglycemia[−] with abnormal glucose tolerance (AGT); however, glucose-AUC120–180min was lower in hypoglycemia[+] vs hypoglycemia[−] AGT. After adjusting for glucose-AUC, hypoglycemia[+] subjects tended to have higher ISR-AUC120–180min than hypoglycemia[−] AGT. Glucagon concentration did not differ between groups. Lower GLP-1-AUC30min and AUC180min and higher GIP-AUC30min were present in hypoglycemia[+] individuals. Conclusion: Hypoglycemia is common in PI-CF following MMTT and is associated with early glucose dysregulation (higher peak glucose), more impaired early-phase insulin secretion (lower ISR-AUC30min), and possibly late compensatory hyperinsulinemia. Further study is required to understand whether absence of glucagon difference in the hypoglycemia[+] individuals signals counterregulatory impairment, to delineate the role of incretins in hypoglycemia, and to determine the relationship of hypoglycemia to emergence of CFRD.
KW - Cystic fibrosis
KW - Glucose tolerance
KW - Hypoglycemia
KW - Insulin secretion
KW - Pancreatic insufficiency
UR - http://www.scopus.com/inward/record.url?scp=85070195694&partnerID=8YFLogxK
U2 - 10.1016/j.jcf.2019.07.006
DO - 10.1016/j.jcf.2019.07.006
M3 - Article
C2 - 31402215
AN - SCOPUS:85070195694
VL - 19
SP - 310
EP - 315
JO - Journal of Cystic Fibrosis
JF - Journal of Cystic Fibrosis
SN - 1569-1993
IS - 2
ER -