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：郎格汉斯胰岛β细胞胰岛素分泌不足对 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T2D患者β细胞功能障碍的重要机制。我们合作小组的新数据显示，相当大比例的T2D患者有多种胰岛自身免疫表现--包括胰岛反应性T细胞、胰岛自身抗体和缺乏抗独特型抗体--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。基于仔细的自然病史研究和T2D患者全身性和胰岛炎症的证据，我们假设早期和持续的胰岛损伤是T2D的主要特征。在易感患者中，这会导致免疫耐受性崩溃，随之而来的是胰岛特异性T细胞反应性和具有疾病特异性表位模式的自身抗体。GRADE试验计划每年重复进行口服葡萄糖耐量试验和胰岛素测量，提供了一个无与伦比的机会，可以研究纵向追踪的T2D患者β细胞功能丧失的这些免疫调节机制，以及不同作用模式的抗糖尿病药物对这些机制的影响。为了验证这一假设，我们将实现以下具体目标：1.在参加分级试验的T2D患者中，确定T细胞对胰岛自身抗原的反应性与β细胞功能随时间和治疗反应的丧失之间的关系；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β细胞功能随时间和治疗反应丧失之间的关系。 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，并确定它们与随时间推移的β细胞功能丧失和治疗反应的关系；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细胞功能丧失的关系。本项目希望回答的重要问题是：1)胰岛自身免疫在T2D患者中的所有表现有多普遍？2)胰岛自身免疫是否预示着T2D患者β细胞功能下降的更快速度？3)任何分级干预措施能否减轻自身免疫相关的β细胞功能下降的速度？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物蛋白、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，纵向跟踪大规模、异质性的T2D人群中的β细胞功能，并使用创新的统计建模方法来分析和整合数据，并发现这些生物标记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