title: Loss of prohormone convertase 2 promotes beta cell dysfunction in a rodent transplant model expressing human pro-islet amyloid polypeptide.
abstract: A contributor to beta cell failure in type 2 diabetes and islet transplants is amyloid formation by aggregation of the beta cell peptide, islet amyloid polypeptide (IAPP). Similar to the proinsulin processing pathway that generates insulin, IAPP is derived from a prohormone precursor, proIAPP, which requires cleavage by prohormone convertase (PC) 1/3 and PC2 in rodent pancreatic beta cells. We hypothesised that loss of PC2 would promote beta cell death and dysfunction in a rodent model of human beta cell proIAPP overexpression.
  
  
  
  We generated an islet transplant model wherein immune-deficient mouse models of diabetes received islets expressing amyloidogenic human proIAPP and lacking PC2, leading to restoration of normoglycaemia accompanied by increased secretion of human proIAPP. Blood glucose levels were analysed for up to 16 weeks in transplant recipients and grafts were assessed for islet amyloid and beta cell number and death.
  
  
  
  Hyperglycaemia (blood glucose >16.9 mmol/l) returned in 94% of recipients of islets expressing human proIAPP and lacking PC2, whereas recipients of islets that express human proIAPP and normal PC2 levels remained normoglycaemic for at least 16 weeks. Islet graft failure was accompanied by a ∼20% reduction in insulin-positive cells, yet the degree of amyloid deposition and beta cell apoptosis was similar to those of controls expressing human proIAPP with functional PC2 levels.
  
  
  
  PC2 deficiency in transplanted mouse islets expressing human proIAPP promotes beta cell loss and graft failure. Our data suggest that impaired NH2-terminal processing and increased secretion of human proIAPP promote beta cell failure.
authors.affiliation: Research Institute, BC Children's Hospital, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Jaques A
authors.initials: JA
authors.lastname: Courtade
authors.affiliation: Research Institute, BC Children's Hospital, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Evan Y
authors.initials: EY
authors.lastname: Wang
authors.affiliation: Research Institute, BC Children's Hospital, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Yen
authors.affiliation: Research Institute, BC Children's Hospital, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Derek L
authors.initials: DL
authors.lastname: Dai
authors.affiliation: Research Institute, BC Children's Hospital, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Galina
authors.initials: G
authors.lastname: Soukhatcheva
authors.affiliation: Research Institute, BC Children's Hospital, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Orban
authors.affiliation: Research Institute, BC Children's Hospital, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada. bverchere@cfri.ca.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada. bverchere@cfri.ca.|Department of Surgery, University of British Columbia, Vancouver, BC, Canada. bverchere@cfri.ca.
authors.forename: C Bruce
authors.initials: CB
authors.lastname: Verchere
mesh_terms: D000682:Amyloid / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D058228:Islet Amyloid Polypeptide / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D011384:Proinsulin / Q000378:metabolism; D045664:Proprotein Convertase 1 / Q000235:genetics / Q000378:metabolism; D045706:Proprotein Convertase 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000682:Amyloid; D001786:Blood Glucose; D058228:Islet Amyloid Polypeptide; C422904:pro-islet amyloid polypeptide; D011384:Proinsulin; D045664:Proprotein Convertase 1; D045706:Proprotein Convertase 2
keywords: Beta cell; Islet amyloid; Islet transplant; Prohormone processing