title: Spontaneous diabetes in hemizygous human amylin transgenic mice that developed neither islet amyloid nor peripheral insulin resistance.
abstract: OBJECTIVE
  We sought to 1) Determine whether soluble-misfolded amylin or insoluble-fibrillar amylin may cause or result from diabetes in human amylin transgenic mice and 2) determine the role, if any, that insulin resistance might play in these processes.
  
  
  METHODS
  We characterized the phenotypes of independent transgenic mouse lines that display pancreas-specific expression of human amylin or a nonaggregating homolog, [(25,28,29)Pro]human amylin, in an FVB/n background.
  
  
  RESULTS
  Diabetes occurred in hemizygous human amylin transgenic mice from 6 weeks after birth. Glucose tolerance was impaired during the mid- and end-diabetic phases, in which progressive beta-cell loss paralleled decreasing pancreatic and plasma insulin and amylin. Peripheral insulin resistance was absent because glucose uptake rates were equivalent in isolated soleus muscles from transgenic and control animals. Even in advanced diabetes, islets lacked amyloid deposits. In islets from nontransgenic mice, glucagon and somatostatin cells were present mainly at the periphery and insulin cells were mainly in the core; in contrast, all three cell types were distributed throughout the islet in transgenic animals. [(25,28,29)Pro]human amylin transgenic mice developed neither beta-cell degeneration nor glucose intolerance.
  
  
  CONCLUSIONS
  Overexpression of fibrillogenic human amylin in these human amylin transgenic mice caused beta-cell degeneration and diabetes through mechanisms independent from both peripheral insulin resistance and islet amyloid. These findings are consistent with beta-cell death evoked by misfolded but soluble cytotoxic species, such as those formed by human amylin in vitro.
authors.affiliation: School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand.
authors.forename: Winifred P S
authors.initials: WP
authors.lastname: Wong
authors.forename: David W
authors.initials: DW
authors.lastname: Scott
authors.forename: Chia-Lin
authors.initials: CL
authors.lastname: Chuang
authors.forename: Shaoping
authors.initials: S
authors.lastname: Zhang
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Athena
authors.initials: A
authors.lastname: Ferreira
authors.forename: Etuate L
authors.initials: EL
authors.lastname: Saafi
authors.forename: Yee Soon
authors.initials: YS
authors.lastname: Choong
authors.forename: Garth J S
authors.initials: GJ
authors.lastname: Cooper
mesh_terms: D000682:Amyloid / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001786:Blood Glucose / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D004797:Enzyme-Linked Immunosorbent Assay; D005934:Glucagon / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006801:Humans; D007150:Immunohistochemistry; D007333:Insulin Resistance / Q000502:physiology*; D058228:Islet Amyloid Polypeptide; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D013004:Somatostatin / Q000378:metabolism
chemical_list: D000682:Amyloid; D001786:Blood Glucose; D058228:Islet Amyloid Polypeptide; D013004:Somatostatin; D005934:Glucagon; D005947:Glucose