title: The S20G substitution in hIAPP is more amyloidogenic and cytotoxic than wild-type hIAPP in mouse islets.
abstract: The S20G human islet amyloid polypeptide (hIAPP) substitution is associated with an earlier onset of type 2 diabetes in humans. Studies of synthetic S20G hIAPP in cell-free systems and immortalised beta cells have suggested that this may be due to increased hIAPP amyloidogenicity and cytotoxicity. Thus, using primary islets from mice with endogenous S20G hIAPP expression, we sought to determine whether the S20G gene mutation leads to increased amyloid-induced toxicity, beta cell loss and reduced beta cell function.
  
  
  
  Islets from mice in which mouse Iapp was replaced with human wild-type or S20G hIAPP were isolated and cultured in vitro under amyloid-forming conditions. Levels of insulin and hIAPP mRNA and protein, amyloid deposition and beta cell apoptosis and area, as well as glucose-stimulated insulin and hIAPP secretion, were quantified.
  
  
  
  Islets expressing S20G hIAPP cultured in 16.7 mmol/l glucose demonstrated increased amyloid deposition and beta cell apoptosis, reduced beta cell area, decreased insulin content and diminished glucose-stimulated insulin secretion, compared with islets expressing wild-type hIAPP. Amyloid deposition and beta cell apoptosis were also increased when S20G islets were cultured in 11.1 mmol/l glucose (the concentration that is thought to be physiological for mouse islets).
  
  
  
  S20G hIAPP reduces beta cell number and function, thereby possibly explaining the earlier onset of type 2 diabetes in individuals carrying this gene mutation.
authors.affiliation: VA Puget Sound Health Care System, 1660 S. Columbian Way, Seattle, WA, 98108, USA.|University of Washington, Seattle, WA, USA.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Meier
authors.affiliation: VA Puget Sound Health Care System, 1660 S. Columbian Way, Seattle, WA, 98108, USA.|University of Washington, Seattle, WA, USA.
authors.forename: Leon
authors.initials: L
authors.lastname: Entrup
authors.affiliation: VA Puget Sound Health Care System, 1660 S. Columbian Way, Seattle, WA, 98108, USA.|University of Washington, Seattle, WA, USA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Templin
authors.affiliation: VA Puget Sound Health Care System, 1660 S. Columbian Way, Seattle, WA, 98108, USA.|University of Washington, Seattle, WA, USA.
authors.forename: Meghan F
authors.initials: MF
authors.lastname: Hogan
authors.affiliation: VA Puget Sound Health Care System, 1660 S. Columbian Way, Seattle, WA, 98108, USA.|University of Washington, Seattle, WA, USA.
authors.forename: Mahnaz
authors.initials: M
authors.lastname: Mellati
authors.affiliation: VA Puget Sound Health Care System, 1660 S. Columbian Way, Seattle, WA, 98108, USA.|University of Washington, Seattle, WA, USA.
authors.forename: Sakeneh
authors.initials: S
authors.lastname: Zraika
authors.affiliation: VA Puget Sound Health Care System, 1660 S. Columbian Way, Seattle, WA, 98108, USA.|University of Washington, Seattle, WA, USA.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Hull
authors.affiliation: VA Puget Sound Health Care System, 1660 S. Columbian Way, Seattle, WA, 98108, USA. skahn@uw.edu.|University of Washington, Seattle, WA, USA. skahn@uw.edu.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Kahn
mesh_terms: D000682:Amyloid / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D005260:Female; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D058228:Islet Amyloid Polypeptide / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics
chemical_list: D000682:Amyloid; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D005947:Glucose
keywords: Amylin; Amyloid; Beta cell; Insulin secretion; Islet; Islet amyloid polypeptide; Toxicity; Type 2 diabetes