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
• 负责人: Melena D. Bellin
• 金额: $ 27.13万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10671610
• 关键词: Abate; Accident and Emergency department; Acinar Cell; Address; Adult; Affect; American; Antibodies; Antigens; Autoantibodies; Autoimmunity; B-Lymphocytes; Beta Cell; Bioinformatics; Biological Markers; CD8-Positive T-Lymphocytes; Cell Death; Cell physiology; Cells; Cellular Stress; Cessation of life; Childhood; Clinic; Data; Defect; Development; Diabetes Mellitus; Diagnosis; Disease; Endocrine; Enrollment; Environmental Exposure; Epidemiology; Event; Exhibits; Exocrine pancreas; Frequencies; Functional disorder; Genetic Markers; Glucose; Goals; Health; Hospitalization; Hospitals; Hyperglycemia; Immune; Immunologics; Immunology; Individual; Infiltration; Inflammation; Injury; Insulin Resistance; Insulin deficiency; Insulin-Dependent Diabetes Mellitus; International; Intravenous; Longitudinal Studies; Longitudinal cohort; Longitudinal, observational study; Macrophage; Measures; Metabolic; Metabolic dysfunction; Minnesota; Oral; Oxidative Stress; Pancreas; Pancreatic Injury; Pancreatitis; Participant; Patient Recruitments; Patients; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Post-Translational Protein Processing; Predisposition; Prevalence; Recording of previous events; Recurrence; Research Personnel; Risk; Risk Factors; Role; Sampling; Self Tolerance; Serum; Signal Transduction; Stimulus; Subjects Selections; T-Lymphocyte; Testing; Tissues; Universities; Work; acute pancreatitis; autoimmune pathogenesis; autoreactive T cell; biobank; chronic pancreatitis; clinical center; clinical risk; cohort; cytokine; diabetes risk; experience; gastrointestinal; high risk; human leukocyte antigen testing; improved; inflammatory milieu; injured; insulin secretion; insulin sensitivity; intravenous glucose tolerance test; islet; medical specialties; multimodality; neoantigens; neutrophil; patient subsets; prevent; recruit; response; tissue injury

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.

抽象的 有急性胰腺炎（AP）病史的患者患糖尿病（DM）的风险很高， 影响大约四分之一的 AP 后患者。对临床危险因素知之甚少，并且导致的机制 AP 后 DM 的发展尚不清楚。我们建议研究风险及其背后的机制 AP后发展为DM；具体来说，我们将研究 β 细胞自身免疫的贡献、 AP 后的胰岛素分泌和对 DM 的胰岛素抵抗。 在 1 型糖尿病 (T1DM) 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；这种自身免疫是由遗传易感人群的未知环境暴露引发的 个人。我们假设 AP 激活期间组织损伤与炎症环境改变相结合 AP 相关 DM 患者亚群中的 β 细胞自身免疫 (T1DM)。我们的初步数据汇总 提示复发性 AP 或慢性胰腺炎患者的 β 细胞自身免疫信号增强， DM。我们假设 AP 后出现 DM 的患者胰岛素分泌会减少（由于 胰腺损伤），胰岛素敏感性降低，并且一部分人会出现 β 细胞自身免疫。 我们的总体目标是建立一个经过仔细表型分析的多中心纵向队列，其中的成年人被诊断为 AP 确定 DM 的临床危险因素，定义 AP-DM 的代谢功能障碍，并确定 AP-DM 的免疫学贡献。明尼苏达大学临床中心的研究人员是以下领域的领导者 AP、DM 和 T1DM 免疫学领域，非常适合实现联盟目标。在 目标 1，我们将在第一次合作后 0 到 3 个月内确定、招募和登记整个联盟的成年人 (N=1250) 急性胰腺炎发作后进行一项纵向研究，以加深我们对糖尿病进展的理解 美联社。我们将在 AP 后确定 DM 的临床危险因素。在目标 2 中，我们将定义以下机制： 通过研究 250 名 AP 后患者（来自目标 1）具有混合膳食耐受性和频繁样本的 AP 相关 DM 静脉内葡萄糖耐量试验可测量胰岛素分泌和胰岛素敏感性。在目标 3 中，我们将 通过确定 β 细胞自身免疫在疾病中的贡献来定义疾病的免疫机制 AP后DM的发展。我们将对整个队列进行 HLA 分型和 β 细胞自身抗体检测 目标 1 并在由 60 名受试者组成的子集中评估 T 细胞和 B 细胞四聚体的细胞自身免疫性 DM 和 AAB 状态。一个单独的组织生物库将用于评估复发性 AP 中的胰岛浸润情况。 这项工作将极大地促进我们对胰源性糖尿病和 T1DM 的理解。在设置中 AP，更好地定义疾病的病理生理机制对于改善治疗和治疗至关重要 延缓或预防进展为 DM。对于 T1DM，这项工作提供了一个更好地识别 T1DM 的途径 胰岛β细胞作为引起自身免疫的自身反应性免疫细胞的关键触发因素发挥着重要作用。