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: 9768465
• 负责人: ASHOK BALASUBRAMANYAM
• 金额: $ 32.26万
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9768465
• 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：Langerhans胰岛的β细胞分泌不足的胰岛素分泌对 2型糖尿病（T2D）的发展。我们建议针对胰岛细胞的自身免疫过程构成了导致T2D患者β细胞功能障碍的重要机制。来自我们协作小组的新兴数据表明，T2D患者的很大比例具有多种体现自身免疫性的表现，包括胰岛反应性T细胞，胰岛自身抗体和缺乏抗IDiotypic抗体 - 与加速β细胞的加速β细胞功能障碍有关。识别不同形式的胰岛自身免疫性对于理解T2D中β细胞功能障碍的原因和自然病史以及靶向治疗方法至关重要。根据仔细的自然史研究和T2D患者全身注射的证据，我们假设，早期和持续的胰岛损伤是T2D的基本特征。在易感患者中，这会导致免疫耐受性破裂，然后发展具有特异性表位模式的胰岛特异性T细胞反应性和自身抗体。该年级试验及其每年对胰岛素测量的每年重复口服葡萄糖耐受性测试的时间表，为研究这些免疫介导的T2D患者的免疫介导的机制损失提供了无与伦比的机会，以及对具有不同动作模式的抗糖尿病药物的这些机制的影响。为了检验这一假设，我们将达到以下特定目的：1。确定，在参加年级试验的T2D患者中，T细胞对胰岛自身抗原的反应性与随着时间的时间和对治疗响应的反应之间的关系与β细胞功能的丧失。 2。在与AIM 1同一患者中确定胰岛自身抗体，它们的表位，抗IDIOTYPIC抗体和β细胞功能的丧失以及对响应于β细胞功能的损失 治疗; 3。在与AIM 1的同一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流逝和治疗响应的β细胞功能丧失的关系； 4：发现目标1-3中测得的标记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大问题是：1）在T2D患者中，胰岛自动免疫的普遍性 - 在其所有表现中有多普遍？ 2）胰岛自身免疫会预示T2D中β细胞功能下降的速度更快吗？ 3）任何等级干预措施是否可以减轻与自身免疫相关的β细胞功能下降的速率？ 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 employee innovative统计建模方法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。

项目成果

Type 1 Diabetes Genetic Risk Score Differentiates Subgroups of Ketosis-Prone Diabetes.

1 型糖尿病遗传风险评分可区分酮症倾向糖尿病的亚组。

• DOI: 10.2337/dc23-0622
• 发表时间: 2023
• 期刊: Diabetes care
• 影响因子: 16.2
• 作者: Osafehinti,Deborah;Mulukutla,SuryaN;Hampe,ChristianeS;Gaba,Ruchi;Ram,Nalini;Weedon,MichaelN;Oram,RichardA;Balasubramanyam,Ashok
• 通讯作者: Balasubramanyam,Ashok