title: Islet amyloid-associated diabetes in obese A(vy)/a mice expressing human islet amyloid polypeptide.
abstract: We have previously shown that hemizygous transgenic mice expressing human islet amyloid polypeptide (hIAPP) in pancreatic beta-cells have no diabetic phenotype, whereas in the homozygous state, they developed severe, early-onset hyperglycemia associated with impaired insulin secretion and beta-cell death. We investigated the possibility that when the hemizygous mice are crossed onto an obese, insulin-resistant strain such as agouti viable yellow (A(vy)/a), they would exhibit a phenotype more akin to human type 2 diabetes. The hIAPP-expressing A(vy) males (TG-Y) displayed fasting hyperglycemia at 90 days of age and by 1 year progressed to severe hyperglycemia relative to their nontransgenic counterparts. Plasma insulin concentrations and pancreatic insulin content dropped 10- to 20-fold, suggesting severe impairment of beta-cell function. Histopathological findings revealed beta-cell degeneration and loss consistent with the drop in the plasma insulin concentration. In addition, large deposits of IAPP amyloid were present in TG-Y islets. We conclude that in transgenic mice expressing hIAPP, insulin resistance can induce overt, slow-onset diabetes associated with islet amyloid and decreased beta-cell mass.
authors.affiliation: Department of Molecular Sciences, Central Research Division, Pfizer, Groton, Connecticut 06340, USA. soellerwc@pfizer.com
authors.forename: W C
authors.initials: WC
authors.lastname: Soeller
authors.forename: J
authors.initials: J
authors.lastname: Janson
authors.forename: S E
authors.initials: SE
authors.lastname: Hart
authors.forename: J C
authors.initials: JC
authors.lastname: Parker
authors.forename: M D
authors.initials: MD
authors.lastname: Carty
authors.forename: R W
authors.initials: RW
authors.lastname: Stevenson
authors.forename: D K
authors.initials: DK
authors.lastname: Kreutter
authors.forename: P C
authors.initials: PC
authors.lastname: Butler
mesh_terms: D000375:Aging / Q000378:metabolism; D000682:Amyloid / Q000032:analysis*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000502:physiology; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D058228:Islet Amyloid Polypeptide; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009765:Obesity; D010641:Phenotype
chemical_list: D000682:Amyloid; D001786:Blood Glucose; D058228:Islet Amyloid Polypeptide