PATHOGENESIS OF TYPE 1.5 DIABETES IN GENERAL POPULATiION

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Diabetes is comprised primarily of two clinically separate diseases: type 1 and type 2 diabetes. The diagnosis of type 1 versus type 2 diabetes is usually made using criteria such as age at onset, abruptness of hyperglycemic symptoms, presence of ketosis, degree of obesity and the perceived need for insulin replacement. The pathogenesis of type 1 and type 2 diabetes is different. Type 1 diabetes is a cell-mediated autoimmune disease directed against the beta cells and characterized by autoantibody and T cell reactivity to islet proteins. In contrast, classic type 2 diabetes is not autoimmune, but rather results from both insulin resistance, and a non-autoimmune insulin secretory defect. However, there isa subgroup of phenotypic type 2 diabetes patients who have autoantibodies and T cells responsive to islet cell proteins similar to type 1 patients (type 1.5 diabetes). Patients demonstrating type 1.5 diabetes have been hypothesized to have a more "chronic" form of autoimmunity compared to "classic" type 1 diabetes. Understanding the differences in autoantibody, T cell subpopulations, genetics, T cell proliferative and cytokine response patterns to islet proteins between type 1 and type 1.5 patients may be pertinent to the understanding of diabetes disease progression and the mechanisms responsible for development of autoimmune diabetes later in life. In this proposal we will investigate whether the progression of type 1.5 diabetes versus progression of type 1 diabetes is characterized by increased regulation of islet specific responses and/or a decrease in effector cell populations. We will accomplish this goal through comparisons of antigen spreading of islet specific T cell proliferative and cytokine responses, phenotypic analysis of cell populations, and precursor frequency of islet reactive cells between type 1 and type 1.5 diabetes patients. Moreover, we will also investigate the underlying mechanisms of regulation between type 1 and type 1.5 subjects. These studies should help us to identify immunologic mechanisms that may be applicable for delaying or preventing autoimmune diabetes. Moreover, early detection of type 1.5 diabetes patients is important due to the fact that approximately 80% of type 1.5 diabetes patients eventually require insulin replacement. The outcome of these studies could have important implications not only for our understanding of the pathogenesis of autoimmune diabetes but also in characterizing the regulatory mechanisms responsible for protection from or delay in the onset of autoimmune diabetes.