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

基本信息

  • 批准号:
    9768465
  • 负责人:
  • 金额:
    $ 32.26万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

 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.
 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.

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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:
  • 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
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ASHOK BALASUBRAMANYAM其他文献

ASHOK BALASUBRAMANYAM的其他文献

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{{ truncateString('ASHOK BALASUBRAMANYAM', 18)}}的其他基金

Center for Identification and Study of Individuals with Atypical Diabetes Mellitus (U54)
非典型糖尿病个体识别和研究中心 (U54)
  • 批准号:
    10660916
  • 财政年份:
    2018
  • 资助金额:
    $ 32.26万
  • 项目类别:
Center for Identification and Study of Individuals with Atypical Diabetes Mellitus (U54)
非典型糖尿病个体识别和研究中心 (U54)
  • 批准号:
    9597055
  • 财政年份:
    2018
  • 资助金额:
    $ 32.26万
  • 项目类别:
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
  • 财政年份:
    2015
  • 资助金额:
    $ 32.26万
  • 项目类别:
Adipose Tissue is a significant reservoir for HIV
脂肪组织是艾滋病毒的重要储存库
  • 批准号:
    8842411
  • 财政年份:
    2014
  • 资助金额:
    $ 32.26万
  • 项目类别:
Arginine and nitric oxide synthesis in the pathogenesis of ketosis-prone diabetes
酮症糖尿病发病机制中的精氨酸和一氧化氮合成
  • 批准号:
    8813384
  • 财政年份:
    2014
  • 资助金额:
    $ 32.26万
  • 项目类别:
Adipose Tissue is a significant reservoir for HIV
脂肪组织是艾滋病毒的重要储存库
  • 批准号:
    9291547
  • 财政年份:
    2014
  • 资助金额:
    $ 32.26万
  • 项目类别:
Adipose Tissue is a significant reservoir for HIV
脂肪组织是艾滋病毒的重要储存库
  • 批准号:
    8914490
  • 财政年份:
    2014
  • 资助金额:
    $ 32.26万
  • 项目类别:
DIET/EXERCISE, NIACIN, FENOFIBRATE FOR HIV LIPODYSTROPHY
饮食/运动、烟酸、非诺贝特治疗 HIV 脂肪代谢障碍
  • 批准号:
    8356764
  • 财政年份:
    2010
  • 资助金额:
    $ 32.26万
  • 项目类别:
THE EFFECT OF LEPTIN THERAPY ON LIPID METABOLISM IN HIV-LIPODYSTROPHY
瘦素治疗对 HIV 脂肪代谢障碍患者脂质代谢的影响
  • 批准号:
    8356763
  • 财政年份:
    2010
  • 资助金额:
    $ 32.26万
  • 项目类别:
ESTIMATION OF BETA CELL MASS EVOLUTION IN KETOSIS-PRONE DIABETES
酮症倾向糖尿病中 β 细胞质量进化的估计
  • 批准号:
    8356774
  • 财政年份:
    2010
  • 资助金额:
    $ 32.26万
  • 项目类别:

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