title: The glucagon-like peptide-1 receptor agonist exenatide restores impaired pro-islet amyloid polypeptide processing in cultured human islets: implications in type 2 diabetes and islet transplantation.
abstract: OBJECTIVE
  Islet amyloid, formed by aggregation of human islet amyloid polypeptide (hIAPP), is associated with beta cell death in type 2 diabetes as well as in cultured and transplanted human islets. Impaired prohIAPP processing due to beta cell dysfunction is implicated in hIAPP aggregation. We examined whether the glucagon-like peptide-1 receptor (GLP-1R) agonist exenatide can restore impaired prohIAPP processing and reduce hIAPP aggregation in cultured human islets and preserve beta cell function/mass during culture conditions used in clinical islet transplantation.
  
  
  METHODS
  Isolated human islets (n = 10 donors) were cultured with or without exenatide in normal or elevated glucose for 2 or 7 days. Beta cell apoptosis, proliferation, mass, function, cJUN N-terminal kinase (JNK) and protein kinase B (PKB) activation and amyloid formation were assessed. ProhIAPP, its intermediates and mature hIAPP were detected.
  
  
  RESULTS
  Exenatide-treated islets had markedly lower JNK and caspase-3 activation and beta cell apoptosis, resulting in higher beta/alpha cell ratio and beta cell area than non-treated cultured islets. Exenatide improved beta cell function, manifested as higher insulin response to glucose and insulin content, compared with non-treated cultured islets. Phospho-PKB immunoreactivity was detectable in exenatide-treated but not untreated cultured islets. Islet culture caused impaired prohIAPP processing with decreased mature hIAPP and increased NH(2)-terminally unprocessed prohIAPP levels resulting in higher release of immature hIAPP. Exenatide restored prohIAPP processing and reduced hIAPP aggregation in cultured islets.
  
  
  CONCLUSIONS
  Exenatide treatment enhances survival and function of cultured human islets and restores impaired prohIAPP processing in normal and elevated glucose conditions thereby reducing hIAPP aggregation. GLP-1R agonists may preserve beta cells in conditions associated with islet amyloid formation.
authors.affiliation: Department of Surgery, Faculty of Medicine, University of British Columbia, Jim Pattison Pavilion, Vancouver General Hospital, 910 W 10th Avenue, Vancouver, BC V5Z 4E3, Canada.
authors.forename: Y J
authors.initials: YJ
authors.lastname: Park
authors.forename: Z
authors.initials: Z
authors.lastname: Ao
authors.forename: T J
authors.initials: TJ
authors.lastname: Kieffer
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.forename: N
authors.initials: N
authors.lastname: Safikhan
authors.forename: D M
authors.initials: DM
authors.lastname: Thompson
authors.forename: M
authors.initials: M
authors.lastname: Meloche
authors.forename: G L
authors.initials: GL
authors.lastname: Warnock
authors.forename: L
authors.initials: L
authors.lastname: Marzban
mesh_terms: D000328:Adult; D000682:Amyloid / Q000378:metabolism*; D053148:Caspase 3; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism / Q000628:therapy*; D000077270:Exenatide; D005260:Female; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism*; D016381:Islets of Langerhans Transplantation; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000494:pharmacology*; D018027:Receptors, Glucagon / Q000819:agonists*; D014688:Venoms / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D000682:Amyloid; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; C422904:pro-islet amyloid polypeptide; D000077270:Exenatide; D053148:Caspase 3