Logo image
Back
Abnormal endocrine pancreas function at birth in cystic fibrosis ferrets
Journal article   Open access   Peer reviewed

Abnormal endocrine pancreas function at birth in cystic fibrosis ferrets

Alicia K Olivier, Yaling Yi, Xingshen Sun, Hongshu Sui, Bo Liang, Shanming Hu, Weiliang Xie, John T Fisher, Nicholas W Keiser, Diana Lei, …
The Journal of clinical investigation, Vol.122(10), pp.3755-3768
10/2012
DOI: 10.1172/JCI60610
PMCID: PMC3534166
PMID: 22996690
url
https://doi.org/10.1172/JCI60610View
Published (Version of record) Open Access

Abstract

Diabetes is a common comorbidity in cystic fibrosis (CF) that worsens prognosis. The lack of an animal model for CF-related diabetes (CFRD) has made it difficult to dissect how the onset of pancreatic pathology influences the emergence of CFRD. We evaluated the structure and function of the neonatal CF endocrine pancreas using a new CFTR-knockout ferret model. Although CF kits are born with only mild exocrine pancreas disease, progressive exocrine and endocrine pancreatic loss during the first months of life was associated with pancreatic inflammation, spontaneous hyperglycemia, and glucose intolerance. Interestingly, prior to major exocrine pancreas disease, CF kits demonstrated significant abnormalities in blood glucose and insulin regulation, including diminished first-phase and accentuated peak insulin secretion in response to glucose, elevated peak glucose levels following glucose challenge, and variably elevated insulin and C-peptide levels in the nonfasted state. Although there was no difference in lobular insulin and glucagon expression between genotypes at birth, significant alterations in the frequencies of small and large islets were observed. Newborn cultured CF islets demonstrated dysregulated glucose-dependent insulin secretion in comparison to controls, suggesting intrinsic abnormalities in CF islets. These findings demonstrate that early abnormalities exist in the regulation of insulin secretion by the CF endocrine pancreas.
 Diabetes Mellitus - blood Glucagon - biosynthesis Dilatation, Pathologic - genetics Species Specificity Diabetes Mellitus - genetics Cystic Fibrosis - physiopathology Pancreas, Exocrine - pathology Male Pancreatic Ducts - pathology Insulin - biosynthesis Pancreatitis - congenital Pancreatitis - genetics Dilatation, Pathologic - pathology Glucose Intolerance - etiology Islets of Langerhans - physiopathology Female Ferrets - genetics Insulin Secretion Pancreatitis - physiopathology Disease Models, Animal Animals, Newborn Islets of Langerhans - pathology Glucose - pharmacology Gene Knockout Techniques Disease Progression Insulin - metabolism Animals Diabetes Mellitus - physiopathology Cystic Fibrosis - genetics Fibrosis Glucagon - metabolism Pancreatitis - pathology Cells, Cultured - metabolism Hyperglycemia - etiology Pancreas, Exocrine - physiopathology Ferrets - physiology Apoptosis

Details

Metrics

31 Record Views
123 Times Cited - Web of Science
Logo image