title: Amyloid formation in human islets is enhanced by heparin and inhibited by heparinase.
abstract: Islet transplantation is a promising therapy for patients with diabetes, but its long-term success is limited by many factors, including the formation of islet amyloid deposits. Heparin is employed in clinical islet transplantation to reduce clotting but also promotes fibrillization of amyloidogenic proteins. We hypothesized that heparin treatment of islets during pre-transplant culture may enhance amyloid formation leading to beta cell loss and graft dysfunction. Heparin promoted the fibrillization of human islet amyloid polypeptide (IAPP) and enhanced its toxicity to INS-1 beta cells. Heparin increased amyloid deposition in cultured human islets, but surprisingly decreased islet cell apoptosis. Treatment of human islets with heparin prior to transplantation increased the likelihood of graft failure. Removal of islet heparan sulfate glycosaminoglycans, which localize with islet amyloid deposits in type 2 diabetes, by heparinase treatment decreased amyloid deposition and protected against islet cell death. These findings raise the possibility that pretransplant treatment of human islets with heparin could potentiate IAPP aggregation and amyloid formation and may be detrimental to subsequent graft function.
authors.affiliation: Departments of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: K J
authors.initials: KJ
authors.lastname: Potter
authors.affiliation: Departments of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: I
authors.initials: I
authors.lastname: Werner
authors.affiliation: Departments of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: H C
authors.initials: HC
authors.lastname: Denroche
authors.affiliation: Departments of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Montane
authors.affiliation: Departments of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Plesner
authors.affiliation: Department of Medical Biophysics, Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, ON, Canada.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Departments of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Lei
authors.affiliation: Departments of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Soukhatcheva
authors.affiliation: Surgery, Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: G L
authors.initials: GL
authors.lastname: Warnock
authors.affiliation: Surgery, and Bioengineering, University of Illinois, Chicago, IL.
authors.forename: J
authors.initials: J
authors.lastname: Oberholzer
authors.affiliation: Department of Medical Biophysics, Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, ON, Canada.
authors.forename: P E
authors.initials: PE
authors.lastname: Fraser
authors.affiliation: Departments of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.|Surgery, Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: C B
authors.initials: CB
authors.lastname: Verchere
mesh_terms: D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000601:surgery; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006084:Graft Rejection / Q000378:metabolism; D006493:Heparin / Q000494:pharmacology*; D019763:Heparin Lyase / Q000494:pharmacology*; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D016381:Islets of Langerhans Transplantation / Q000379:methods; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D013311:Streptozocin / Q000009:adverse effects
chemical_list: D000682:Amyloid; D006493:Heparin; D019763:Heparin Lyase; D006497:Heparan Sulfate; D058228:Islet Amyloid Polypeptide; D013311:Streptozocin
keywords: basic (laboratory) research/science; cell death: apoptosis; diabetes: type 1; drug toxicity; endocrinology/diabetology; islet transplantation; islets of Langerhans; organ perfusion; preservation; translational research/science