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.

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Zhao, Lue Ping; Bolouri, Hamid; Zhao, Michael et al. (2016) An Object-Oriented Regression for Building Disease Predictive Models with Multiallelic HLA Genes. Genet Epidemiol 40:315-32
Hao, Wei; Greenbaum, Carla J; Krischer, Jeffrey P et al. (2015) The Effect of DPT-1 Intravenous Insulin Infusion and Daily Subcutaneous Insulin on Endogenous Insulin Secretion and Postprandial Glucose Tolerance. Diabetes Care 38:891-6
Brooks-Worrell, Barbara M; Boyko, Edward J; Palmer, Jerry P (2014) Impact of islet autoimmunity on the progressive ?-cell functional decline in type 2 diabetes. Diabetes Care 37:3286-93
Eringsmark Regnéll, S; Lernmark, A (2013) The environment and the origins of islet autoimmunity and Type 1 diabetes. Diabet Med 30:155-60
Brooks-Worrell, B M; Palmer, J P (2013) Attenuation of islet-specific T cell responses is associated with C-peptide improvement in autoimmune type 2 diabetes patients. Clin Exp Immunol 171:164-70
Skoglund, Camilla; Chéramy, Mikael; Casas, Rosaura et al. (2012) GAD autoantibody epitope pattern after GAD-alum treatment in children and adolescents with type 1 diabetes. Pediatr Diabetes 13:244-50
Nepom, Gerald T (2012) MHC class II tetramers. J Immunol 188:2477-82
Oak, S; Radtke, J; Torn, C et al. (2011) Immunoglobulin subclass profiles of anti-idiotypic antibodies to GAD65Ab differ between type 1 diabetes patients and healthy individuals. Scand J Immunol 74:363-7
Brooks-Worrell, Barbara M; Reichow, Jessica L; Goel, Amit et al. (2011) Identification of autoantibody-negative autoimmune type 2 diabetic patients. Diabetes Care 34:168-73
Hänninen, Arno; Soilu-Hänninen, Merja; Hampe, Christiane S et al. (2010) Characterization of CD4+ T cells specific for glutamic acid decarboxylase (GAD65) and proinsulin in a patient with stiff-person syndrome but without type 1 diabetes. Diabetes Metab Res Rev 26:271-9

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