Using the spontaneously diabetic, insulin-dependent BB/E rat as a model for human insulin-dependent diabetes mellitus (IDDM) three possible new approaches to the treatment of this disorder have been studied. The first study was concerned with assessing the function of isolated pancreatic islets encapsulated in alginate-poly-L-lysine-alginate microcapsules designed to protect transplanted islets from both graft rejection and autoimmune destruction. The glucose-induced insulin secretory response of (1) freshly isolated free (i.e. non-encapsulated), and (2) free and encapsulated islets cultured for different periods of time, was investigated using a multichannel perifusion system. Insulin secretion by freshly isolated free islets was shown to be significantly higher than that of free cultured and encapsulated cultured islets. A slight delay was observed in the first phase insulin response to glucose in encapsulated islets. Insulin secretion by free cultured and encapsulated cultured islets was optimal after six and seven days culture respectively and diminished thereafter. A precisely timed recovery period in culture prior to implantation appears to be important for optimal function of encapsulated islet grafts. In the second study, metabolic control and patterns of food intake were compared in BB/E rats with spontaneous, autoimmune, insulin-dependent diabetes and rats with streptozotocin-induced diabetes (STZ-diabetes) which were treated either with conventional insulin therapy (CIT) in the form of daily subcutaneous injections of insulin, or with sustained release insulin implants (SRII). In the final study, the effect of a short course (14 days) of treatment with non-depleting and depleting monoclonal antibodies specific for T lymphocyte subsets on preventing rejection and autoimmune destruction of intraportal islet allografts was investigated in BB/E rats with established, insulin-dependent diabetes.