This project is concerned with islet transplantation, which has the potential to normalize plasma glucose levels in people with diabetes. There are important obstacles that must be overcome. The source of islet tissue, and its function and viability once grafted, are major issues. Immune destruction from rejection and autoimmunity poses other problems. The proposed experiments focus upon the function and viability of transplanted islets and how immune destruction can be limited by immunobarrier devices and/or modulation of immune reaction. The specific aims include: Transplanted islets in immunobarrier devices will be studied to develop strategies to optimize their function and viability. The benefits of prevascularized membrane devices will be assessed. The potential benefits of oxygen-carrying molecules such as polymerized hemoglobin will be explored. The effects of hyperglycemia and hypoglycemia upon graft function will be examined. Angiogenesis of normal and transplanted islets will be studied. Angiogenesis is critical for the viability of transplanted islets. It may now be possible to understand why normal islets have such a rich vascular supply. The hypothesis will be examined that vascular endothelial growth factor (VEGF) plays a key role in islet angiogenesis, and that the genetic expression of VEGF is linked to the oxygen consumption of glucose-induced insulin secretion. The cytokine interleukin-1 (IL-1) is thought to play an important role in the destruction of islets by autoimmunity and transplant rejection. The naturally occurring IL-1 receptor antagonist protein (IRAP) can protect against the toxic effects of IL-1. IRAP will be overexpressed in beta cells by the genetic manipulations of transfection and the production of transgenic mice to determine if transplanted islets can be protected at the site of attack from immune injury.