Amyloid Formation in Human Islets Is Enhanced by Heparin and Inhibited by Heparinase
| Autor: | D. Lei, C. B. Verchere, Jose Oberholzer, Garth L. Warnock, Isa Werner, Joel Montane, Kathryn J. Potter, Paul E. Fraser, Heather C. Denroche, Y.S. Chen, Galina Soukhatcheva, Annette Plesner |
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| Rok vydání: | 2015 |
| Předmět: |
Graft Rejection
Amyloid endocrine system medicine.medical_specialty Programmed cell death endocrine system diseases Islets of Langerhans Transplantation Apoptosis Mice SCID Streptozocin Diabetes Mellitus Experimental Islets of Langerhans chemistry.chemical_compound Mice Inbred NOD Internal medicine medicine Animals Humans Immunology and Allergy Pharmacology (medical) Cells Cultured Transplantation geography Heparinase geography.geographical_feature_category Dose-Response Relationship Drug Heparin business.industry Heparan sulfate Islet Islet Amyloid Polypeptide 3. Good health Disease Models Animal Endocrinology Heparin Lyase chemistry Heparitin Sulfate Beta cell business medicine.drug |
| Zdroj: | American Journal of Transplantation. 15:1519-1530 |
| ISSN: | 1600-6135 |
| DOI: | 10.1111/ajt.13134 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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