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: 10458669
• 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/10458669
• 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; Clinics and Hospitals; Data; Defect; Development; Diabetes Mellitus; Diabetes autoantibodies; Diagnosis; Disease; Endocrine; Enrollment; Environmental Exposure; Epidemiology; Event; Exhibits; Exocrine pancreas; Frequencies; Functional disorder; Genetic Markers; Glucose; Goals; Health; Hospitalization; Hyperglycemia; Immune; Immunologics; Immunology; Individual; Inflammation; Injury; Insulin Resistance; Insulin deficiency; Insulin-Dependent Diabetes Mellitus; International; Intravenous; Longitudinal Studies; Longitudinal cohort; Longitudinal observational study; 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; Prevalence; Recording of previous events; Recurrence; Research Personnel; Risk; Risk Factors; Role; Sampling; Self Tolerance; Serum; Signal Transduction; Stimulus; 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; macrophage; 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.

摘要