Prohormone processing in pancreatic islet transplantation

Islet transplantation is a promising treatment for diabetes; however, most transplant recipients exhibit progressive loss of graft function. Islet function in transplant recipients shares similarities with subjects with type 2 diabetes including impaired glucose-stimulated insulin secretion, decreased beta-cell mass associated with amyloid formation, and defective proinsulin processing resulting in disproportionate secretion of intact proinsulin and proinsulin intermediates. We hypothesized that processing of the beta-cell prohormones, proinsulin and pro-islet amyloid polypeptide (proIAPP), will be impaired in islet transplant recipients as in patients with type 2 diabetes. Human islet transplant recipients were found to have impaired proinsulin processing manifest as elevated proinsulin/C-peptide ratios (TP/CP). The TP/CP ratio was significantly elevated in both islet allo- and auto-transplant recipients relative to controls. Furthermore, the TP/CP was greater in those recipients that received sub-optimal numbers of islets transplanted, suggesting that beta-cell dysfunction is exacerbated in the face of increased secretory demand due to insufficient islet mass. In a mouse model of islet transplantation, proinsulin processing was found to decline over time following transplantation, resulting in elevated proinsulin/insulin ratios. Amyloid deposits, a common pancreatic lesion in type 2 diabetes, were also found in human islet transplants and were associated with reduced beta-cell mass. Since IAPP, like insulin, is also processed within the beta cell from its precursor proIAPP, and since proinsulin processing is impaired in islet transplants and type 2 diabetes, we hypothesized that proIAPP processing will also be impaired in these conditions. To quantify proIAPP levels in humans, an immunoassay was developed. Circulating proIAPP levels in normal subjects were found to be in the low picomolar range and the ratio of proIAPP/IAPP was approximately 30%. In a small cohort of type 2 diabetic subjects, the proIAPP/IAPP ratio tended to be lower. These studies demonstrate that impaired proinsulin processing is a characteristic of transplanted islets and that the proinsulin/insulin or proinsulin/C-peptide ratios may serve as markers of graft dysfunction in islet transplantation. In addition, the proIAPP/IAPP ratio can now also be evaluated as a marker of beta-cell dysfunction in islet transplants and type 2 diabetes.Medicine, Faculty ofPathology and Laboratory Medicine, Department ofGraduat