Autoimmune-mediated destruction of beta cells is the predominant cause of Type I diabetes (TIDM). Beta cell replacement through pancreatic islet cell transplantation is a theoretically attractive treatment for type 1 diabetes. Indeed recent clinical successes support this notion, but also reveal significant limitations of this therapy. These limitations include the recurrence of autoimmunity, risks associated with systemic immunosuppression to control alloreactivity, the limited availability of pancreatic islets for transplantation, and the relative transient reversal of diabetes. Indeed, while 1-year rates of insulin independence after islet transplantation is approximately 80%, only 10% of patients maintaining insulin independence after 5 years. Multiple solutions are therefore necessary to effectively cure type 1 diabetes, including the need to cure autoimmunity, limit alloreactivity, and restore beta-cell mass. My laboratory research has focused on the latter issue of restoration of beta-cell mass through islet transplantation and beta-cell regeneration.
Indeed, the limited supply of beta-cells and the need for continued immunosuppression to control alloreactivity has prompted recent investigations into the natural ability of beta-cells to regenerate and restore glucose homeostasis. Prompted by reports that spleen cells could be used to produce beta-cells, we set out to test whether adult mice severely depleted of islet beta-cells could regenerate islet beta cells to levels capable of maintaining normal glycemia, and whether this regeneration is dependent on the conversion of spleen cells into beta-cells. We have developed two successful models of functional beta-cell regeneration that restored normoglycemia in autoimmune and chemically-induced diabetic mice (1, 2). Using mice generated by Dr. Manami Hara (Section of Endocrinology), we were unable to observe the presence of spleen-derived beta-cells, and concluded that the regenerated beta-cells were host-derived. In collaboration with Dr. Louis Philipson (Section of Endocrinology), we are using these models to investigate the mechanisms of beta-cell regeneration, and to identify therapeutic targets for enhancing regeneration.