Role of Islet Injury and Autoimmunity in T2D Beta Cell Dysfunction

胰岛损伤和自身免疫在 T2D β 细胞功能障碍中的作用

• 批准号: 9330149
• 负责人: ASHOK BALASUBRAMANYAM
• 金额: $ 35.35万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-16 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9330149
• 关键词: Address; Amyloid; Anti-Idiotypic Antibodies; Antidiabetic Drugs; Antigens; Attenuated; Autoantibodies; Autoantigens; Autoimmune Process; Autoimmunity; Beta Cell; Biological Markers; Cell physiology; Cells; Characteristics; Data; Defect; Development; Disease; Early treatment; Enrollment; Epitopes; Factor Analysis; Failure; Functional disorder; Future; Goals; Human; Immune; Immune Tolerance; Inflammation; Injury; Insulin; Intervention; Investigation; Islet Cell; Islets of Langerhans; Langerhans cell; Lead; Measurement; Measures; Mediating; Metabolic; Metabolic Control; Methods; Modification; Natural History; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Oxidative Stress; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pattern; Population; Proteins; Research; Role; Schedule; Serum Proteins; Statistical Models; Structure of beta Cell of islet; T cell response; T-Lymphocyte; Testing; Time; United States National Institutes of Health; Wit; attenuation; base; cell injury; clinically significant; endocrine pancreas development; functional decline; improved; innovation; insulin mediators; insulin secretion; islet; loss of function; novel therapeutic intervention; protein biomarkers; public health relevance; response; targeted treatment; treatment response

 DESCRIPTION: Deficient insulin secretion by β cells of the islets of Langerhans is critical to the development of type 2 diabetes (T2D). We propose that autoimmune processes directed against islet cells comprise a significant mechanism leading to β cell dysfunction in patients wit T2D. Emerging data from our collaborative group indicate that a substantial proportion of patients with T2D have multiple manifestations of islet autoimmunity - including islet-reactive T cells, islet autoantibodies and absence of anti-idiotypic antibodies - associated with accelerated beta cell dysfunction. Identification of different forms of islet autoimmunity is crucial to understanding the causes and natural history of β cell dysfunction in T2D, as well as for targeted treatment approaches. We hypothesize, based on careful natural history studies and evidence for systemic and islet inflammation in T2D patients, that early and ongoing islet injury is a cardinal feature of T2D. In susceptible patients, this leads to breakdown of immune tolerance, followed by the development of islet-specific T cell reactivity and autoantibodies with disease-specific epitope patterns. The GRADE Trial, with its schedule of annually repeated oral glucose tolerance tests with insulin measurements, provides a matchless opportunity to investigate these immune-mediated mechanisms of β cell function loss in longitudinally-tracked T2D patients, as well as the impact on these mechanisms of antidiabetic drugs with different modes of action. To test this hypothesis, we will achieve the following Specific Aims: 1. Determine, in T2D patients enrolled in the GRADE Trial, the relationship between T cell reactivity to islet autoantigens and loss of β cell function over time and in response to treatmen; 2. Determine, in the same patients as in Aim 1, the relationship between islet autoantibodies, their epitopes, anti-idiotypic antibodies and loss of β cell function over time and in response to treatment; 3. Discover and confirm, in the same patients as in Aim 1, serum proteins related to islet cell injury, and determine their relationship to loss of β cell function over time and in response to treatment; 4: Discover a network of interactions among the markers measured in Aims 1-3, as well as their association with loss of β cell function. The significant questions thi project hopes to answer are: 1) How prevalent is islet autoimmunity - in all its manifestations - among patients with T2D? 2) Does islet autoimmunity portend a faster rate of β cell function decline in T2D? 3) Can any GRADE interventions attenuate the autoimmunity-associated rate of β cell function decline? To answer these questions, our collaborative research group will utilize state-of-the-art methods to measure islet injury marker proteins, anti-idiotypic antibodies, epitope-specific islet autoantibodies, and islet- specific T cell reactivity to delineate pathways f β cell dysfunction, track β cell function longitudinally in the large, heterogeneous GRADE T2D population, and employ innovative statistical modeling methods to analyze and integrate the data and discover a network of interactions among these biomarkers.

 描述：朗格罕斯岛 β 细胞胰岛素分泌不足对于胰岛素抵抗至关重要。 2 型糖尿病 (T2D) 的发展。我们认为，针对胰岛细胞的自身免疫过程是导致 2 型糖尿病患者 β 细胞功能障碍的重要机制。我们合作小组的最新数据表明，相当一部分 T2D 患者具有多种胰岛自身免疫表现，包括胰岛反应性 T 细胞、胰岛自身抗体和抗独特型抗体缺乏，与加速的 β 细胞功能障碍相关。识别不同形式的胰岛自身免疫对于了解 T2D β 细胞功能障碍的原因和自然史以及有针对性的治疗方法至关重要。基于仔细的自然史研究以及 T2D 患者全身和胰岛炎症的证据，我们假设早期和持续的胰岛损伤是 T2D 的一个主要特征。在易感患者中，这会导致免疫耐受性崩溃，随后出现胰岛特异性 T 细胞反应性和具有疾病特异性表位模式的自身抗体。 GRADE 试验的时间表是每年重复进行口服葡萄糖耐量测试和胰岛素测量，为研究纵向跟踪的 T2D 患者中 β 细胞功能丧失的免疫介导机制，以及不同作用模式的抗糖尿病药物对这些机制的影响提供了无与伦比的机会。为了检验这一假设，我们将实现以下具体目标： 1. 在参加 GRADE 试验的 T2D 患者中，确定 T 细胞对胰岛自身抗原的反应性与随着时间的推移和对治疗的反应而丧失的 β 细胞功能之间的关系； 2. 在与目标 1 相同的患者中，确定胰岛自身抗体、其表位、抗独特型抗体与随时间推移和响应的 β 细胞功能丧失之间的关系 治疗; 3. 在与目标 1 相同的患者中发现并确认与胰岛细胞损伤相关的血清蛋白，并确定它们与随着时间的推移和对治疗的反应而丧失的 β 细胞功能的关系； 4：发现目标 1-3 中测量的标记物之间的相互作用网络，以及它们与 β 细胞功能丧失的关联。该项目希望回答的重要问题是：1) 胰岛自身免疫（各种表现形式）在 T2D 患者中有多普遍？ 2) 胰岛自身免疫是否预示着 T2D 中 β 细胞功能衰退速度更快？ 3) 任何 GRADE 干预措施都可以减轻自身免疫相关的 β 细胞功能下降率吗？为了回答这些问题，我们的合作研究小组将利用最先进的方法来测量胰岛损伤标记蛋白、抗独特型抗体、表位特异性胰岛自身抗体和胰岛特异性 T 细胞反应性，以描绘 β 细胞功能障碍的途径，在大型、异质 GRADE T2D 群体中纵向跟踪 β 细胞功能，并采用创新的统计方法 建模方法来分析和整合数据并发现这些生物标志物之间的相互作用网络。