PATHOGENESIS OF TYPE 1.5 DIABETES IN THE GENERAL POPULATION

糖尿病主要由两种临床独立的疾病组成：1型和2型糖尿病。1型糖尿病和2型糖尿病的诊断通常使用诸如发病年龄、高血糖症状的突然性、酮症的存在、肥胖程度和胰岛素替代的感知需求等标准。1型和2型糖尿病的发病机制不同。1型糖尿病是一种针对β细胞的细胞介导的自身免疫性疾病，以自身抗体和T细胞对胰岛蛋白的反应性为特征。相比之下，典型的2型糖尿病不是自身免疫性的，而是胰岛素抵抗和非自身免疫性胰岛素分泌缺陷的结果。然而，有一小群表型为2型糖尿病的患者，其自身抗体和T细胞对胰岛细胞蛋白的反应与1型糖尿病患者相似（1.5型糖尿病）。与“经典”1型相比，1.5型糖尿病患者被认为具有更“慢性”的自身免疫

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.