University of Minnesota Clinical Center for the Study of Acute Pancreatitis and Diabetes

明尼苏达大学急性胰腺炎和糖尿病临床研究中心

基本信息

  • 批准号:
    10458669
  • 负责人:
  • 金额:
    $ 27.13万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-09-17 至 2025-07-31
  • 项目状态:
    未结题

项目摘要

Abstract Patients with a history of acute pancreatitis (AP) are at high risk for developing diabetes mellitus (DM), affecting about 1 in 4 patients after AP. Clinical risk factors are poorly understood, and mechanisms leading to development of DM after AP are unknown. We propose to study risk for and mechanisms underlying development of DM after AP; specifically we will study the contributions of beta cell autoimmunity, defects in insulin secretion, and insulin resistance to DM after AP. In type 1 diabetes mellitus (T1DM) insulin deficiency results from targeted autoimmune destruction of the islet β-cells; this autoimmunity is triggered by unknown environmental exposures in genetically susceptible individuals. We hypothesize that tissue injury combined with an altered inflammatory milieu during AP activates β-cell autoimmunity (T1DM) in a subset of patients with AP-related DM. Our preliminary data collectively suggests an increased signal of β-cell autoimmunity in patients with recurrent AP or chronic pancreatitis and DM. We hypothesize that patients who develop DM after AP will have reduced insulin secretion (due to pancreatic injury), reduced insulin sensitivity, and a subset will have β-cell autoimmunity. Our overall goal is to establish a carefully phenotyped multi-center longitudinal cohort of adults diagnosed with AP to determine clinical risk factors for DM, define metabolic dysfunction in AP-DM, and determine the immunologic contributions to AP-DM. The University of Minnesota-Clinical Center investigators are leaders in the fields of AP, DM, and T1DM immunology and are ideally suited to address the consortium objectives. In Aim 1, we will identify, recruit, and enroll adults (N=1250) consortium-wide at 0 to 3 months after a first episode of acute pancreatitis for a longitudinal study to advance our understanding of progression to DM after AP. We will determine clinical risk factors for DM after AP. In Aim 2, we will define mechanistic mechanisms of AP-related DM by studying 250 patients after AP (from Aim 1) with mixed meal tolerance and frequent sample intravenous glucose tolerance tests to measure insulin secretion and insulin sensitivity. In Aim 3, we will define immunologic mechanisms of disease by determining the contribution of β-cell autoimmunity in development of DM after AP. We will perform HLA-typing and β-cell autoantibodies in the entire cohort from Aim 1 and assess cellular autoimmunity with T-cell and B-cell tetramers in a subset of 60 subjects selected by DM and AAb status. A separate tissue biobank will be used to evaluate islet infiltrates in recurrent AP. This work will contribute significantly to both our understanding of pancreatogenic DM and T1DM. In the setting of AP, better defining the pathophysiologic mechanisms of disease is critical to improving treatment and delaying or preventing progression to DM. For T1DM, this work provides an avenue to better identify an important role for islet β-cells as a key trigger for the self-reactive immune cells causing autoimmunity.
摘要 有急性胰腺炎(AP)病史的患者患糖尿病(DM)的风险较高, 影响AP后约四分之一的患者。临床风险因素知之甚少,导致 AP后DM的发展尚不清楚。我们建议研究的风险和机制, AP后DM的发展;具体而言,我们将研究β细胞自身免疫的贡献, 胰岛素分泌和AP后对DM的胰岛素抵抗。 在1型糖尿病(T1 DM)中,胰岛素缺乏是由胰岛的靶向自身免疫破坏引起的 β细胞;这种自身免疫性是由遗传易感性中未知的环境暴露引发的。 个体我们假设AP期间组织损伤与炎症环境的改变相结合激活了 AP相关DM患者亚组中的β细胞自身免疫(T1 DM)。我们的初步数据 提示复发性AP或慢性胰腺炎患者β细胞自身免疫信号增加, DM.我们假设AP后发生DM的患者胰岛素分泌减少(由于 胰腺损伤)、胰岛素敏感性降低,并且一个子集将具有β细胞自身免疫性。 我们的总体目标是建立一个仔细分型的多中心纵向队列的成人诊断为 AP以确定DM的临床危险因素,定义AP-DM的代谢功能障碍,并确定 免疫学对AP-DM的贡献。明尼苏达大学临床中心的研究人员是 AP、DM和T1 DM免疫学领域,非常适合解决联盟目标。在 目标1,我们将在首次研究后0至3个月在整个联盟范围内识别、招募和入组成人(N=1250)。 急性胰腺炎发作的纵向研究,以提高我们对糖尿病进展的理解, AP.我们将确定AP后DM的临床危险因素。在目标2中,我们将定义 通过研究250例AP后患者(来自目标1)的混合餐耐量和频繁样本, 静脉内葡萄糖耐量试验,以测量胰岛素分泌和胰岛素敏感性。在目标3中,我们 通过确定β细胞自身免疫在疾病中的作用, AP后发生DM。我们将在整个队列中进行HLA分型和β细胞自身抗体检测, 目的1和评估细胞自身免疫与T细胞和B细胞四聚体在一个子集的60名受试者选择, DM和AAb状态。将使用单独的组织生物库来评价复发性AP中的胰岛浸润。 这项工作将大大有助于我们对胰源性DM和T1 DM的了解。背景下 更好地定义疾病的病理生理机制对于改善治疗和 延缓或阻止糖尿病的进展。对于T1 DM,这项工作提供了一种更好地识别 胰岛β细胞作为引起自身免疫的自反应免疫细胞的关键触发因素,发挥着重要作用。

项目成果

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Melena D. Bellin其他文献

Recurrent Acute Pancreatitis: Many Faces(/Facets) of a Challenging Disease
复发性急性胰腺炎:这种具有挑战性疾病的多面性
  • DOI:
    10.1053/j.gastro.2025.01.249
  • 发表时间:
    2025-07-01
  • 期刊:
  • 影响因子:
    25.100
  • 作者:
    Dhiraj Yadav;Nicholas J. Zyromski;David C. Whitcomb;Melena D. Bellin;Gregory A. Cote;Anil Dasyam
  • 通讯作者:
    Anil Dasyam
Sustained benefits of islet transplants for T1DM
胰岛移植对 1 型糖尿病的持续益处
  • DOI:
    10.1038/nrendo.2015.126
  • 发表时间:
    2015-08-04
  • 期刊:
  • 影响因子:
    40.000
  • 作者:
    Bernhard J. Hering;Melena D. Bellin
  • 通讯作者:
    Melena D. Bellin
Pancreatitis-Associated emPRSS1-PRSS2/em Haplotype Alters T-Cell Receptor Beta em(TRB)/em Repertoire More Strongly Than emPRSS1/em Expression
胰腺炎相关的 emPRSS1-PRSS2/em 单体型比 emPRSS1/em 表达更强烈地改变 T 细胞受体β em(TRB)/em 库。
  • DOI:
    10.1053/j.gastro.2022.09.036
  • 发表时间:
    2023-02-01
  • 期刊:
  • 影响因子:
    25.100
  • 作者:
    Dongni Fu;Brandon M. Blobner;Phil J. Greer;Robert Lafyatis;Melena D. Bellin;David C. Whitcomb;Melena D. Bellin;Greg Beilman;Randall E. Brand;Celeste Shelton Ohlsen;Jami L. Saloman;David C. Whitcomb;H.J. Park;Kenneth K. Lee;Alessandro Paniccia;Amer Zureikat;Samer Alkaade;Stephen Amann;Michelle A. Anderson;Peter Banks;Dhiraj Yadav
  • 通讯作者:
    Dhiraj Yadav
Transplant strategies for type 1 diabetes: whole pancreas, islet and porcine beta cell therapies
  • DOI:
    10.1007/s00125-020-05184-7
  • 发表时间:
    2020-09-07
  • 期刊:
  • 影响因子:
    10.200
  • 作者:
    Melena D. Bellin;Ty B. Dunn
  • 通讯作者:
    Ty B. Dunn
Pediatric Autologous Islet Transplantation
  • DOI:
    10.1007/s11892-015-0639-9
  • 发表时间:
    2015-08-15
  • 期刊:
  • 影响因子:
    6.400
  • 作者:
    Melena D. Bellin;Sarah J. Schwarzenberg;Marie Cook;David E. R. Sutherland;Srinath Chinnakotla
  • 通讯作者:
    Srinath Chinnakotla

Melena D. Bellin的其他文献

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{{ truncateString('Melena D. Bellin', 18)}}的其他基金

Protein biomarkers to predict pain outcomes after total pancreatectomy with islet autotransplant
蛋白质生物标志物可预测胰岛自体移植全胰腺切除术后的疼痛结果
  • 批准号:
    10835299
  • 财政年份:
    2023
  • 资助金额:
    $ 27.13万
  • 项目类别:
Long-Term Islet Function and Impact after Total Pancreatectomy with Islet Autotransplant (LIFT)
全胰腺切除术联合胰岛自体移植 (LIFT) 后的长期胰岛功能和影响
  • 批准号:
    10540722
  • 财政年份:
    2021
  • 资助金额:
    $ 27.13万
  • 项目类别:
Long-Term Islet Function and Impact after Total Pancreatectomy with Islet Autotransplant (LIFT)
全胰腺切除术联合胰岛自体移植 (LIFT) 后的长期胰岛功能和影响
  • 批准号:
    10092263
  • 财政年份:
    2021
  • 资助金额:
    $ 27.13万
  • 项目类别:
Long-Term Islet Function and Impact after Total Pancreatectomy with Islet Autotransplant (LIFT)
全胰腺切除术联合胰岛自体移植 (LIFT) 后的长期胰岛功能和影响
  • 批准号:
    10328905
  • 财政年份:
    2021
  • 资助金额:
    $ 27.13万
  • 项目类别:
University of Minnesota Clinical Center for the Study of Acute Pancreatitis and Diabetes
明尼苏达大学急性胰腺炎和糖尿病临床研究中心
  • 批准号:
    10671610
  • 财政年份:
    2020
  • 资助金额:
    $ 27.13万
  • 项目类别:
University of Minnesota Clinical Center for the Study of Acute Pancreatitis and Diabetes
明尼苏达大学急性胰腺炎和糖尿病临床研究中心
  • 批准号:
    10265607
  • 财政年份:
    2020
  • 资助金额:
    $ 27.13万
  • 项目类别:
Anti-inflammatory therapy to improve outcomes in patients with chronic pancreatitis undergoing total pancreatectomy with islet autotransplant (TPIAT)
抗炎治疗可改善接受胰岛自体移植全胰腺切除术(TPIAT)的慢性胰腺炎患者的预后
  • 批准号:
    9335351
  • 财政年份:
    2016
  • 资助金额:
    $ 27.13万
  • 项目类别:
Advancing Treatment for Pancreatitis: A Prospective Observational Study of TPIAT
推进胰腺炎的治疗:TPIAT 的前瞻性观察研究
  • 批准号:
    9914077
  • 财政年份:
    2016
  • 资助金额:
    $ 27.13万
  • 项目类别:
Assessing Beta Cell Loss and Islet Engraftment after Islet Autotransplantation
评估胰岛自体移植后的β细胞损失和胰岛移植情况
  • 批准号:
    8851586
  • 财政年份:
    2014
  • 资助金额:
    $ 27.13万
  • 项目类别:
Sitagliptin therapy to improve outcomes after islet autotransplantation.
西他列汀治疗可改善胰岛自体移植后的结果。
  • 批准号:
    8325623
  • 财政年份:
    2010
  • 资助金额:
    $ 27.13万
  • 项目类别:
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