title: Abnormal endocrine pancreas function at birth in cystic fibrosis ferrets.
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.
authors.affiliation: Department of Pathology, College of Public Health, and Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Alicia K
authors.initials: AK
authors.lastname: Olivier
authors.forename: Yaling
authors.initials: Y
authors.lastname: Yi
authors.forename: Xingshen
authors.initials: X
authors.lastname: Sun
authors.forename: Hongshu
authors.initials: H
authors.lastname: Sui
authors.forename: Bo
authors.initials: B
authors.lastname: Liang
authors.forename: Shanming
authors.initials: S
authors.lastname: Hu
authors.forename: Weiliang
authors.initials: W
authors.lastname: Xie
authors.forename: John T
authors.initials: JT
authors.lastname: Fisher
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Keiser
authors.forename: Diana
authors.initials: D
authors.lastname: Lei
authors.forename: Weihong
authors.initials: W
authors.lastname: Zhou
authors.forename: Ziying
authors.initials: Z
authors.lastname: Yan
authors.forename: Guiying
authors.initials: G
authors.lastname: Li
authors.forename: Turan I A
authors.initials: TI
authors.lastname: Evans
authors.forename: David K
authors.initials: DK
authors.lastname: Meyerholz
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Zoe A
authors.initials: ZA
authors.lastname: Stewart
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Norris
authors.forename: John F
authors.initials: JF
authors.lastname: Engelhardt
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D002478:Cells, Cultured / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics / Q000503:physiopathology*; D003920:Diabetes Mellitus / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D004108:Dilatation, Pathologic / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005289:Ferrets / Q000235:genetics / Q000502:physiology*; D005355:Fibrosis; D055786:Gene Knockout Techniques; D005934:Glucagon / Q000096:biosynthesis / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D018149:Glucose Intolerance / Q000209:etiology; D006943:Hyperglycemia / Q000209:etiology; D007328:Insulin / Q000096:biosynthesis / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D046790:Pancreas, Exocrine / Q000473:pathology / Q000503:physiopathology; D010183:Pancreatic Ducts / Q000473:pathology; D010195:Pancreatitis / Q000151:congenital / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D013045:Species Specificity
chemical_list: D007328:Insulin; D005934:Glucagon; D005947:Glucose