Natural History and Mechanisms of Exocrine Pancreatic Dysfunction in Pre-Type 1 Diabetes

1 型糖尿病前期外分泌胰腺功能障碍的自然史和机制

• 批准号: 10483133
• 负责人: Brittany Bruggeman
• 金额: $ 10.68万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-07 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10483133
• 关键词: Affect; Antibodies; Atrophic; Autoantibodies; Autoimmune Diseases; Autoimmunity; Beta Cell; Biological Markers; Birth; Cells; Childhood; Clinical; Cohort Studies; Data; Development; Diabetes Mellitus; Diagnosis; Digestion; Disease; Early identification; Elastases; Endocrine; Endocrinologist; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Evaluation; Event; Exocrine pancreas; Exocrine pancreatic insufficiency; Fat-Soluble Vitamin; Fibrosis; First Degree Relative; Fluorescent Antibody Technique; Functional disorder; Funding; Future; Goals; Heterogeneity; Immune; Immune mediated destruction; Immunohistochemistry; Individual; Inflammatory Infiltrate; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention Trial; Investigation; Knowledge; Learning; Lipids; Magnetic Resonance Imaging; Measures; Mediating; Mentors; Metabolic; Natural History; Nutritional; Organ Donor; Organ Size; Pancreas; Pathogenesis; Patients; Persons; Play; Prevention strategy; Prevention trial; Proteome; Research; Research Design; Research Personnel; Research Technics; Risk; Role; Sampling; Scientist; Serum; Serum Markers; Study Subject; TimeLine; Tissues; Tumor-infiltrating immune cells; Vitamin Deficiency; autoimmune pathogenesis; career; cohort; design; diabetes pathogenesis; diabetes risk; early detection biomarkers; experience; functional loss; high risk; imaging biomarker; improved; insulin dependent diabetes mellitus onset; islet; islet cell antibody; lipidome; microbiome; novel; pre-clinical; predictive marker; prognostic value; prospective; research clinical testing; stool sample; treatment response

PROJECT SUMMARY. Type 1 diabetes (T1D) is historically described as an endocrine (β-cell) specific autoimmune disease. However, a substantial reduction in pancreatic exocrine cell mass is also present at T1D diagnosis resulting in a 20-50% reduction in pancreas organ size and subclinical exocrine pancreatic insufficiency. The mechanisms, natural history, and role of reduced exocrine pancreatic mass in T1D pathogenesis remains unclear. Evaluation of pancreatic volume and function by magnetic resonance imaging (MRI) and fecal elastase (FE-1) has shown that exocrine atrophy may even precede the onset of multiple islet autoantibodies (Stage 1 T1D) in some subjects, signifying that these measures could be helpful early T1D biomarkers. The primary objective of this proposal is to investigate the natural history of exocrine loss in T1D by measuring FE-1 throughout the course of pre-T1D within TEDDY (The Environmental Determinants of Diabetes in the Young) subject banked samples (Aim 1A). We hypothesize that FE-1 levels will be reduced even prior to Stage 1 T1D in those destined to develop T1D and that the rate of decline in FE-1 can be used as a disease-predictive biomarker. FE-1 will be the first studied marker of exocrine pancreatic function to inform the large body of data already collected within TEDDY. This will allow for future collaborative studies of potential mechanisms and downstream effects of a decline in pancreatic function within pre-T1D, including associations with nutritional changes such as fat-soluble vitamin deficiencies or lipid abnormalities and with other changes in the lipidome, proteome or microbiome of at-risk TEDDY subjects. An upcoming R01-funded study of TrialNet (TN) subjects (Campbell-Thompson and Haller, mPIs) will prospectively examine pancreas volume by MRI and serum markers of pancreatic exocrine function in single islet autoantibody positive (AAb+), multiple AAb+, and AAb- first degree relatives (FDRs) of T1D patients to evaluate the prognostic utility of these measures. Herein we propose to add evaluation of FE-1 to this trial in order to examine its efficacy as a disease predictive biomarker (Aim 1B). Lastly, the mechanisms underlying reduced exocrine pancreatic mass and function in T1D remain unclear. Previous studies have found exocrine pancreas Aabs and immune infiltrates to be present in subjects with T1D, making autoimmune destruction of both exocrine and endocrine tissue a plausible mechanism worth further investigation. The secondary objective of this study is to use samples from the Network for Pancreatic Organ donors with Diabetes (nPOD) cohort to investigate exocrine autoimmunity as a potential mechanism for the changes in pancreatic size and function seen in T1D (Aim 2). We hypothesize that exocrine autoimmunity is present in subjects with multiple islet AAb+ without dysglycemia as well as those with clinical T1D and that it is associated with exocrine histopathologic changes. If we find that autoimmunity plays a role in the pancreatic exocrine changes seen within T1D subjects, this will represent a paradigm shift in our traditional understanding of the pathogenesis of T1D as an endocrine-specific autoimmune disease.

项目总结。