title: Exendin-4 increases islet amyloid deposition but offsets the resultant beta cell toxicity in human islet amyloid polypeptide transgenic mouse islets.
abstract: OBJECTIVE
  In type 2 diabetes, aggregation of islet amyloid polypeptide (IAPP) into amyloid is associated with beta cell loss. As IAPP is co-secreted with insulin, we hypothesised that IAPP secretion is necessary for amyloid formation and that treatments that increase insulin (and IAPP) secretion would thereby increase amyloid formation and toxicity. We also hypothesised that the unique properties of the glucagon-like peptide-1 (GLP-1) receptor agonist exendin-4 to maintain or increase beta cell mass would offset the amyloid-induced toxicity.
  
  
  METHODS
  Islets from amyloid-forming human IAPP transgenic and control non-transgenic mice were cultured for 48 h in 16.7 mmol/l glucose alone (control) or with exendin-4, potassium chloride (KCl), diazoxide or somatostatin. Human IAPP and insulin release, amyloid deposition, beta cell area/islet area, apoptosis and AKT phosphorylation levels were determined.
  
  
  RESULTS
  In control human IAPP transgenic islets, amyloid formation was associated with increased beta cell apoptosis and beta cell loss. Increasing human IAPP release with exendin-4 or KCl increased amyloid deposition. However, while KCl further increased beta cell apoptosis and beta cell loss, exendin-4 did not. Conversely, decreasing human IAPP release with diazoxide or somatostatin limited amyloid formation and its toxic effects. Treatment with exendin-4 was associated with an increase in AKT phosphorylation compared with control and KCl-treated islets.
  
  
  CONCLUSIONS
  IAPP release is necessary for islet amyloid formation and its toxic effects. Thus, use of insulin secretagogues to treat type 2 diabetes may result in increased islet amyloidogenesis and beta cell death. However, the AKT-associated anti-apoptotic effects of GLP-1 receptor agonists such as exendin-4 may limit the toxic effects of increased islet amyloid.
authors.affiliation: Division of Metabolism, Endocrinology and Nutrition, VA Puget Sound Health Care System (151), 1660 South Columbian Way, Seattle, WA 98108, USA. astonk@u.washington.edu
authors.forename: K
authors.initials: K
authors.lastname: Aston-Mourney
authors.forename: R L
authors.initials: RL
authors.lastname: Hull
authors.forename: S
authors.initials: S
authors.lastname: Zraika
authors.forename: J
authors.initials: J
authors.lastname: Udayasankar
authors.forename: S L
authors.initials: SL
authors.lastname: Subramanian
authors.forename: S E
authors.initials: SE
authors.lastname: Kahn
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003981:Diazoxide / Q000494:pharmacology; D000077270:Exenatide; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects*; D058228:Islet Amyloid Polypeptide / Q000235:genetics / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013004:Somatostatin / Q000494:pharmacology; D014688:Venoms / Q000494:pharmacology*
chemical_list: D000682:Amyloid; D007004:Hypoglycemic Agents; D058228:Islet Amyloid Polypeptide; D010455:Peptides; D014688:Venoms; D013004:Somatostatin; D000077270:Exenatide; D051057:Proto-Oncogene Proteins c-akt; D003981:Diazoxide