PATHOGENESIS OF TYPE 1.5 DIABETES IN THE GENERAL POPULATION

一般人群中 1.5 型糖尿病的发病机制

• 批准号: 7468453
• 负责人: JERRY P PALMER
• 金额: $ 20.46万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7468453
• 关键词: Adult; Age; Antigens; Autoantibodies; Autoimmune Diabetes; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Beta Cell; Blood; Cell surface; Cells; Childhood; Chronic; Defect; Development; Diabetes Mellitus; Diagnosis; Disease; Disease Progression; Early Diagnosis; Effector Cell; Frequencies; General Population; Genetic; Goals; Hyperglycemia; Immunologic Factors; Immunologic Markers; Immunologics; In Vitro; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Islet Cell; Islets of Langerhans; Ketoses; Ketosis; Life; Lymphocyte; Measures; Mediating; Names; Non-Insulin-Dependent Diabetes Mellitus; Numbers; Obesity; Outcome Study; Pathogenesis; Patients; Pattern; Phenotype; Population; Production; Proteins; Regulation; Relative (related person); Research Personnel; Subgroup; Symptoms; T cell regulation; T-Lymphocyte; To autoantigen; autoreactive T cell; cell type; cytokine; in vivo; islet; prevent; programs; response; type I and type II diabetes

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.

糖尿病主要由两种不同的临床疾病组成：1型糖尿病和2型糖尿病。1型糖尿病与2型糖尿病的诊断通常使用的标准包括发病年龄、高血糖症状的突然出现、酮症的存在、肥胖程度以及是否需要胰岛素替代。1型和2型糖尿病的发病机制是不同的。1型糖尿病是一种针对β细胞的细胞介导性自身免疫性疾病，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的，而是胰岛素抵抗和非自身免疫的胰岛素分泌缺陷共同作用的结果。然而，有一组表型2型糖尿病患者的自身抗体和T细胞对胰岛细胞蛋白的反应类似于1型糖尿病患者(1.5型糖尿病)。与典型的1型糖尿病患者相比，患有1.5型糖尿病的患者被认为是一种更慢性的自身免疫。 糖尿病。了解自身抗体、T细胞亚群、遗传学、T细胞的差异 1型和1.5型患者之间对胰岛蛋白的增殖和细胞因子反应模式可能与了解糖尿病疾病的进展和日后发生自身免疫性糖尿病的机制有关。 在这项建议中，我们将研究1.5型糖尿病的进展与1型糖尿病的进展是否以胰岛特异性反应的调节增加和/或效应细胞数量的减少为特征。我们将通过比较1型和1.5型糖尿病患者胰岛特异性T细胞增殖和细胞因子反应的抗原扩散，细胞群体的表型分析和胰岛反应细胞的前体频率来实现这一目标。此外，我们还将调查1型和1.5型受试者之间的潜在调节机制。这些研究应该有助于我们确定可能适用于延缓或预防自身免疫性糖尿病的免疫学机制。此外，早期发现1.5型糖尿病患者也很重要 由于大约80%的1.5型糖尿病患者最终需要胰岛素 替补。这些研究的结果可能不仅对我们的 不仅要了解自身免疫性糖尿病的发病机制，还要确定预防或延缓自身免疫性糖尿病发病的调控机制。