Methods to reduce beta-cell loss after islet isolation and transplantation must be developed if islet transplantation is to become a preferred treatment for diabetes. Most recent research has focused on the reduction of toxicity from immunosuppressants and the enhancement of revascularization by growth factors such as vascular endothelial growth factor. Cytoglobin is an intracellular oxygen-binding protein found in islet beta-cells, inducible by hypoxia. It is our hypothesis that cytoglobin induction and overexpression may improve survival and function of transplanted islets by preventing ischemic cell death. Lewis rat islets and MIN6 cells were transfected with the cytoglobin gene. Control and transfected cells and islets were held for 4 hours at 20% oxygen before glucose challenge. Another group of islets and cells was held for 4 hours at 20% and then 1% oxygen prior to glucose challenge. Untreated or transfected Lewis rat islets (n = 800) were transplanted beneath the renal capsule of streptozotocin diabetic Lewis rats. In another study, Sprague-Dawley islets were transfected and transplanted into streptozotocin diabetic Lewis rats. Fasting blood glucose was used as an indicator of islet function and survival. Cytoglobin transfected islets and cells retained the ability to secrete insulin at low oxygen concentrations in contrast to controls. Cytoglobin over expression reduced the development of central islet necrosis after 5 days in tissue culture. Cytoglobin inhibited the onset of immunorejection (14 +/- 2 days) as compared with controls islets (5 +/- 2 days). Cytoglobin induction may be a useful adjunct to islet transplantation.