title: Glycaemic regulation and insulin secretion are abnormal in cystic fibrosis pigs despite sparing of islet cell mass.
abstract: Diabetes is a common and significant co-morbidity in cystic fibrosis (CF). The pathogenesis of cystic fibrosis related diabetes (CFRD) is incompletely understood. Because exocrine pancreatic disease is similar between humans and pigs with CF, the CF pig model has the potential to contribute significantly to the understanding of CFRD pathogenesis. We determined the structure of the endocrine pancreas in fetal, newborn and older CF and non-CF pigs and assessed endocrine pancreas function by intravenous glucose tolerance test (IV-GTT). In fetal pigs, pancreatic insulin and glucagon density was similar between CF and non-CF. In newborn and older pigs, the insulin and glucagon density was unchanged between CF and non-CF per total pancreatic area, but increased per remnant lobular tissue in CF reflecting exocrine pancreatic loss. Although fasting glucose levels were not different between CF and non-CF newborns, CF newborns demonstrated impaired glucose tolerance and increased glucose area under the curve during IV-GTT. Second phase insulin secretion responsiveness was impaired in CF newborn pigs and significantly lower than that observed in non-CF newborns. Older CF pigs had elevated random blood glucose levels compared with non-CF. In summary, glycaemic abnormalities and insulin secretion defects were present in newborn CF pigs and spontaneous hyperglycaemia developed over time. Functional changes in CF pig pancreas were not associated with a decline in islet cell mass. Our results suggest that functional islet abnormalities, independent of structural islet loss, contribute to the early pathogenesis of CFRD.
authors.affiliation: *Department of Pediatrics, University of Iowa, Iowa City, IA, U.S.A.
authors.forename: Aliye
authors.initials: A
authors.lastname: Uc
authors.affiliation: †Department of Pathology, University of Iowa, Iowa City, IA, U.S.A.
authors.forename: Alicia K
authors.initials: AK
authors.lastname: Olivier
authors.affiliation: *Department of Pediatrics, University of Iowa, Iowa City, IA, U.S.A.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Griffin
authors.affiliation: †Department of Pathology, University of Iowa, Iowa City, IA, U.S.A.
authors.forename: David K
authors.initials: DK
authors.lastname: Meyerholz
authors.affiliation: *Department of Pediatrics, University of Iowa, Iowa City, IA, U.S.A.
authors.forename: Jianrong
authors.initials: J
authors.lastname: Yao
authors.affiliation: ‡Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, U.S.A.
authors.forename: Maisam
authors.initials: M
authors.lastname: Abu-El-Haija
authors.affiliation: *Department of Pediatrics, University of Iowa, Iowa City, IA, U.S.A.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Buchanan
authors.affiliation: *Department of Pediatrics, University of Iowa, Iowa City, IA, U.S.A.
authors.forename: Oriana G
authors.initials: OG
authors.lastname: Vanegas Calderón
authors.affiliation: §University of Texas Medical Branch at Galveston, Galveston, TX, U.S.A.
authors.forename: Marwa
authors.initials: M
authors.lastname: Abu-El-Haija
authors.affiliation: ∥Department of Internal Medicine, University of Iowa, Iowa City, IA, U.S.A.
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Pezzulo
authors.affiliation: ∥Department of Internal Medicine, University of Iowa, Iowa City, IA, U.S.A.
authors.forename: Leah R
authors.initials: LR
authors.lastname: Reznikov
authors.affiliation: ∥Department of Internal Medicine, University of Iowa, Iowa City, IA, U.S.A.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Hoegger
authors.affiliation: ∥Department of Internal Medicine, University of Iowa, Iowa City, IA, U.S.A.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Rector
authors.affiliation: ∥Department of Internal Medicine, University of Iowa, Iowa City, IA, U.S.A.
authors.forename: Lynda S
authors.initials: LS
authors.lastname: Ostedgaard
authors.affiliation: ∥Department of Internal Medicine, University of Iowa, Iowa City, IA, U.S.A.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Taft
authors.affiliation: ∥Department of Internal Medicine, University of Iowa, Iowa City, IA, U.S.A.
authors.forename: Nick D
authors.initials: ND
authors.lastname: Gansemer
authors.affiliation: ∥Department of Internal Medicine, University of Iowa, Iowa City, IA, U.S.A.
authors.forename: Paula S
authors.initials: PS
authors.lastname: Ludwig
authors.affiliation: ∥Department of Internal Medicine, University of Iowa, Iowa City, IA, U.S.A.
authors.forename: Emma E
authors.initials: EE
authors.lastname: Hornick
authors.affiliation: ∥Department of Internal Medicine, University of Iowa, Iowa City, IA, U.S.A.
authors.forename: David A
authors.initials: DA
authors.lastname: Stoltz
authors.affiliation: *Department of Pediatrics, University of Iowa, Iowa City, IA, U.S.A.
authors.forename: Katie L
authors.initials: KL
authors.lastname: Ode
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Welsh
authors.affiliation: **Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA, U.S.A.
authors.forename: John F
authors.initials: JF
authors.lastname: Engelhardt
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Norris
mesh_terms: D000818:Animals; D001786:Blood Glucose; D003550:Cystic Fibrosis / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D003920:Diabetes Mellitus / Q000378:metabolism* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D018149:Glucose Intolerance; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D013552:Swine
chemical_list: D001786:Blood Glucose; D007328:Insulin