Mechanisms of preventing type 1diabetes with inactive insulin

The long-term goal of this study is to develop immune therapy for the prevention of type 1 diabetes. The goal of the current study is to optimize protective regulatory T cell responses using insulin analogs, along with a potent intestinal insulinotropic hormone to expand islet cell mass to prevent or reverse the development of type 1 diabetes in animal models. Our hypothesis is that the combination of inactive insulin analog therapy, with insulinotropic hormones will be have synergistic effects for the prevention of type 1 diabetes. We have demonstrated that metabolically-inactive insulin analogs prevent the development of diabetes. In addition, our recent studies show that a basal insulin analog (glargine) which is now in clinical use, also prevents the development of diabetes in NOD mice. Furthermore, we demonstrate that the dose of insulin is a critical factor for the prevention of type 1 diabetes. Using the same dose of insulin as was used in the recently completed Diabetes Prevention Trial, DPT-1, we were unable to prevent diabetes. It was necessary to use a dose of insulin which was twenty times greater (5 units/kg) than the dose used in the DPT-1. To reduce the risk of hypoglycemia we utilized either basal insulin, with minimal peak effect, or the metabolically-inactive insulin. Our latest data demonstrates that we are inducing a CD4+FoxP3+ regulatory T cell response with long term insulin analog therapy to prevent diabetes. In the current study, we will monitor the CD4+FoxP3+ T cell response to insulin analog to assess the effectiveness of the therapy. The FDA has recently approved a GLP-1 analog, exendin-4, for the treatment of type 2 diabetes. This hormone improves post-prandial blood glucose but also has been shown to increase islet beta cell mass in rodent models of diabetes when given at very large doses which greatly exceed the doses approved for use in humans. We will determine if lower doses of exenatide can expand beta cell mass using doses that would be more acceptable for clinical therapy. We will then evaluate the ability of the combination insulin analog therapy with exendin-4 for the prevention of immune-mediated diabetes in an effort to obtain a synergistic response. Our ultimate goal is to reduce the destruction of beta cells with antigen-specific immune therapy, and expand beta cell mass with hormonal therapy to induce a remission of type 1 diabetes. Karounos D.G. Page 29