Approaches to Enhance the Growth and Function of Transplanted Islets

Since 1990, islet transplantation has led to insulin-independence in humans with type 1 diabetes mellitus, but these grafts usually fail in several weeks or months, only a few have functioned successfully for more than a year. The reasons for the failure of these transplants are not well understood. Either a limitation in the growth capacity or an increased death rate of transplanted islets could lead to continuous loss of β-cell mass and failure of the graft. To improve the outcome of clinical islet transplantation, we have investigated the following approaches to improve the growth and function of islet grafts. 1. Influence of islet mass on the outcome of islet transplantation Obtaining sufficient islet mass is a major problem to achieve successful human islet transplantation. To know the influence of islet mass on transplantation, we observed the outcome of diabetic mice transplanted with different number of islets. All recipients with a large number of islets became normoglycemia soon after transplantation. Surprisingly, the majority of recipients with a small number of islets could also achieve normal blood glucose after a long period of hyperglycemia. These data indicate: (1) islet mass has a great impact in the outcome of transplantation; (2) limited islets transplanted into diabetic recipients can catch up the performance of larger number of islets; and (3) a period of hyperglycemia dose not result in significant destruction or loss of transplanted β-cells. 2. Influence of donor age on the outcome of islet transplantation Old donor age has traditionally been considered a risk factor and relative contraindication for transplantation. To expand the donor source, we studied the characteristics and function of islets isolated from old or young mice. We isolated more and larger islets which contained higher insulin from old mice than those from young mice. However, the diabetic recipients transplanted with islets from old or young donors had similar metabolic changes. These data indicate: (1) the islets isolated from donors with different ages have different characteristics and junction; and (2) donor age does not influence the outcome of islet transplantation. 3. Effects of glycemic control upon the growth and function of transplanted islets To known the beneficial effects of normal or near-normal glucose levels on islet transplantation, we transplanted an insufficient number of islets into diabetic mice in which temporary normoglycemia was maintained by either additional islets or exogenous insulin. After a period of normo- or near-normoglycemia, the growth and function of the transplanted islets were significantly enhanced. This finding indicates maintaining normoglycemic environment is important for diabetic recipients after islet transplantation. 4. Effects of hyperbaric oxygen (HBO) on islet transplantation To improve the oxygenation and neovascularization of islet grafts, we treated diabetic mice with HBO during peritransplant period. The results showed HBO therapy, twice/day before and after islet transplantation, could enhance the growth and function of transplanted islets. This suggests HBO therapy can be used in clinical islet transplantation to improve its outcome. 5. Effects of vascular endothelial growth factor (VEGF) and pentoxyphyline on islet transplantation Islet anoxia and death after transplantation may contribute to the early graft failure. It has been shown VEGF can enhance tissue neovascularization and pentoxiphylline can improve tissue microcirculation. To investigate their effects on islet grafts, we either cultured islets with VEGF before syngeneic transplantation, or treated diabetic recipients with pentoxiphylline after syngeneic transplantation. We found VEGF pretreatment had no effect on the neovascularization or function of islet grafts. However, pentoxiphyllinetreated group had lower blood glucose and higher insulin content of the graft than controls after transplantation. These results indicates posttransplant pentoxiphylline treatment for diabetic recipients could improve their metabolic status and islet graft function. 6. Effect of 15-deoxyspergualin (DSG) on islet transplantation Nonspecific inflammation is one of the factors in the destruction or dysfunction of islet grafts. To examine the significance of the macrophage-mediated injury to islet grafts, we treated diabetic mice with DSG, a macrophage immunomodulatory agent, after syngeneic transplantation. The results showed DSG could improve the growth and function of the islet graft. We concluded that: (l) the DSG treatment was beneficial for islet transplantation; (2) the nonspecific, macrophage-mediated injury might play an important role in the destruction of transplanted islets. 7. Effect of sulfonylureas on islet transplantation Gliclazide is a second generation of sulfonylurea which can stimulate insulin secretion from pancreatic beta-cells. To investigate its effect on transplanted islets, we injected gliclazide to the diabetic recipients after syngeneical transplantation with insufficient number of islets. At day 28, the recipients’ blood glucose and insulin content of the graft were not significantly different between the gliclazide and control groups. Our data indicate posttranaplant administration of gliclazide had little effect on the outcome of islet transplantation.

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transplanted islets

國際替代計量

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