Islet amyloid deposition limits the viability of human islet grafts but not porcine islet grafts

Abstract

Islet transplantation is a promising treatment for diabetes but longterm success is limited by progressive graft loss. Aggregates of the beta cell peptide islet amyloid polypeptide (IAPP) promote beta cell apoptosis and rapid amyloid formation occurs in transplanted islets. Porcine islets are an attractive alternative islet source as they demonstrate long-term graft survival. We compared the capacity of transplanted human and porcine islets to form amyloid as an explanation for differences in graft survival. Human islets were transplanted into streptozotocin-diabetic immune-deficient mice. Amyloid deposition was detectable at 4 weeks posttransplantation and was associated with islet graft failure. More extensive amyloid deposition was observed after 8 weeks. By contrast, no amyloid was detected in transplanted neonatal or adult porcine islets that had maintained normoglycemia for up to 195 days. To determine whether differences in IAPP sequence between humans and pigs could explain differences in amyloid formation and transplant viability, we sequenced porcine IAPP. Porcine IAPP differs from the human sequence at 10 positions and includes substitutions predicted to reduce its amyloidogenicity. Synthetic porcine IAPP was considerably less amyloidogenic than human IAPP as determined by transmission electron microscopy, circular dichroism, and thioflavin T binding. Viability assays indicated that porcine IAPP is significantly less toxic to INS-1 beta cells than human IAPP. Our findings demonstrate that species differences in IAPP sequence can explain the lack of amyloid formation and improved survival of transplanted porcine islets. These data highlight the potential of porcine islet transplantation as a therapeutic approach for human diabetes.

The role of caspase-8 in amyloid-induced beta cell death in human and mouse islets

“…Islet amyloid formation in patients with type 2 diabetes contributes to progressive beta cell death [3][4][5]. Unlike in type 2 diabetes, amyloid forms rapidly in cultured [6][7][8] and transplanted human islets [9,10], and this is associated with beta cell dysfunction and death in vitro [6][7][8], and with islet graft failure leading to recurrence of hyperglycaemia in animal models of type 1 diabetes [10][11][12]. Moreover, amyloid deposition associated with reduced beta cell mass has been reported in islet grafts in patients with type 1 diabetes [13,14].…”

Morin hydrate inhibits amyloid formation by islet amyloid polypeptide and disaggregates amyloid fibers

“…23,28,29,32,[34][35][36][37][38][39][40] Recent studies also highlight a potentially important role for IAPP amyloid formation in the failure of islet cell grafts. [41][42][43] There is widespread interest in developing inhibitors of amyloid formation and compounds which can disaggregate preformed amyloid. Much of this work has focused on the Ab peptide of Alzheimer's disease or on a-synuclein, the protein which plays a central role in Parkinson's disease, but fewer inhibitors of IAPP amyloid formation have been reported.…”

Porcine islet amyloid polypeptide fragments are refractory to amyloid formation

“…The aggregation of hIAPP(1-37) and its fragments, including hIAPP (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29) and hIAPP (20)(21)(22)(23)(24)(25)(26)(27)(28)(29), has been reported to exhibit cytotoxicity [4,18,20]. MTT assay was used to investigate the cytotoxicity of IAPP fragment variants in INS-1 cells.…”

“…It has been documented that both human and feline IAPP are prone to form toxic aggregates, whereas IAPP from rodents such as rat and degu are resistant to this process [3]. In an elegant recent study, Potter et al reported that porcine IAPP (pIAPP) is significantly less amyloidogenic compared with hIAPP, thus supporting the potential application of porcine islet transplantation in T2DM therapy [4]. Sequence comparison shows 10 variation sites between hIAPP and pIAPP (bold in Fig.…”