Departments of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
Department of Medical Biophysics, Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, ON, Canada.
Am J Transplant. 2015 Jun;15(6):1519-30. doi: 10.1111/ajt.13134. Epub 2015 Apr 1.
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.
胰岛移植是治疗糖尿病患者的一种有前途的疗法，但它的长期成功受到许多因素的限制，包括胰岛淀粉样沉积物的形成。肝素在临床胰岛移植中被用于减少凝血，但也促进了淀粉样蛋白原纤维的形成。我们假设，在移植前培养过程中对胰岛进行肝素处理可能会增强淀粉样形成，导致β细胞损失和移植物功能障碍。肝素促进人胰岛淀粉样多肽（IAPP）的纤维形成，并增强其对 INS-1β细胞的毒性。肝素增加了培养的人胰岛中的淀粉样沉积，但令人惊讶的是，它降低了胰岛细胞的凋亡。在移植前用肝素处理人胰岛会增加移植物失败的可能性。用肝素酶处理去除 2 型糖尿病中与胰岛淀粉样沉积物结合的胰岛硫酸乙酰肝素糖胺聚糖，可减少淀粉样沉积并防止胰岛细胞死亡。这些发现提示，在移植前用肝素处理人胰岛可能会增强 IAPP 聚集和淀粉样形成，并可能对随后的移植物功能有害。
