Diabetes Timing and Types and the Effect on Beta Cell Function Post-Acute Pancreatitis in Children

儿童急性胰腺炎后糖尿病发生的时间和类型以及对 β 细胞功能的影响

• 批准号: 10350091
• 负责人: Maisam Abu-El-Haija
• 金额: $ 11.37万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10350091
• 关键词: Adult; Age; Antibodies; Applications Grants; Autoimmune; Award; Beta Cell; Biological Markers; Blood; Cell physiology; Child; Childhood; Clinical; Data; Development; Diabetes Mellitus; Diagnosis; Disease; Emergency department visit; Etiology; Fasting; Functional disorder; Funding; Generations; Glucose; Goals; Guide prevention; Health Care Costs; Hospitalization; Impairment; Incidence; Infrastructure; Insulin Antibodies; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; K-Series Research Career Programs; Knowledge; Lead; Life Expectancy; Longitudinal prospective study; Measures; Medical center; Methods; Modeling; Morbidity - disease rate; Multicenter Trials; National Institute of Diabetes and Digestive and Kidney Diseases; Natural History; Nature; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Pancreatic Polypeptide; Patient-Focused Outcomes; Patients; Pattern; Pediatric Hospitals; Pediatrics; Peptides; Persons; Physiological; Play; Population; Prediabetes syndrome; Prevention; Prospective Studies; Registries; Research; Research Design; Risk; Risk Factors; Role; Sampling; Standardization; Testing; Therapeutic; Time; Translating; United States; Variant; Work; acute pancreatitis; base; biobank; chronic pancreatitis; cohort; cystic fibrosis related diabetes; design; diabetes risk; feasibility testing; gastrointestinal; glucose metabolism; improved; indexing; innovation; insulin secretion; islet; novel; patient subsets; predictive modeling; prognostic significance; prospective; response; sample collection; screening

Project Summary/Abstract The incidence of Acute Pancreatitis (AP) in children has been rising to 1/10,000 cases. Diabetes mellitus (DM) can result from AP in a subset of patients, and that leads to increased morbidity especially if underdiagnosed, given that there is no current method for DM screening post AP in the pediatric population. Post AP DM remains understudied with outcomes poorly defined. Previous studies in DM post AP are mostly single-centered and retrospective in nature, and thereby insufficient for understanding the natural history. From our previous work we have found up to 30% of children develop pre-DM or DM post AP and that a subset of patients have islet auto antibodies (Ab) positive testing post AP but that does not always translate to a full diagnosis of DM. This begs the question whether these Ab influence beta cell (β-cell) function and play a role in the progression to DM and what type of DM follows AP. Markers of DM types or β-cell function have not been studied post AP in pediatrics. Thus, this proposed study leverages our previous work in a novel design that allows for systematic generation of novel mechanistic data to define DM type, and the role of islet auto Abs and β-cell dysfunction as factors involved. The primary goal of this R03 are to investigate types of DM and extent of β-cell dysfunction from samples and subjects in prospective AP registry and biorepository at Cincinnati Children's Hospital Medical Center (CCHMC) generated under our NIDDK K23DK118190 designed to build predictive models for diabetes post AP. The primary objective of this project is to improve understanding of post AP DM, which will lead to improved patients' outcomes. This will be accomplished through our prospective longitudinal study design. Specific Aim 1 will define subtypes of DM and the temporal changes in relation to timing of Pre DM and DM post AP by testing for Type 1, Type 2 and Type 3c DM markers at different time points (3 and 12 months post AP). Specific Aim 2 will test the feasibility of conducting the standardized mixed meal tolerance testing (MMTT) in patients at 3 month and 12 month post AP, construct a model to define optimal samples collection time points needed for measuring β-cell responses to a stimulated test, and whether data points from stimulated testing provide value beyond simple fasting C peptide and glucose levels. The latter is important because MMTT is more cumbersome for pediatrics than a simple blood draw. We will also investigate the role of islet Ab positivity on β-cell function. Our proposal will help us better define progression to prediabetes then diabetes post AP to fill this knowledge gap. Successful completion of this study has the potential to lead to improved understanding of the mechanisms and risk factors for Pre-DM and DM, which will guide ultimately prevention and timely treatment of DM and its effect on children post AP.

项目摘要/摘要 儿童急性胰腺炎(AP)的发病率已上升至1/万。糖尿病(DM) 在部分患者中可由AP引起，这会导致发病率增加，特别是如果诊断不足， 鉴于目前还没有在儿科人群中筛查AP后糖尿病的方法。 急性胰腺炎后糖尿病仍未得到充分研究，其结果尚不明确。之前对糖尿病后急性胰腺炎的研究大多是 单一的中心和追溯的性质，因此不足以理解自然历史。从… 我们之前的工作发现，高达30%的儿童患有糖尿病前或糖尿病后AP，其中一部分 AP后患者胰岛自身抗体(Ab)检测呈阳性，但这并不总是转化为完全 糖尿病的诊断。这就回避了这样一个问题：这些抗体是否会影响β细胞(β细胞)的功能，并在 向DM的进展以及AP之后的DM类型。DM类型或β细胞功能的标记物尚未得到 在儿科攻读AP后。因此，这项拟议的研究在一种新颖的设计中利用了我们之前的工作 允许系统地生成新的机械数据以定义DM类型，以及胰岛自动抗体和 β-细胞功能障碍为参与因素。本R03的主要目标是调查DM的类型和范围 辛辛那提AP登记和生物信息库中样本和受试者的β细胞功能障碍 儿童医院医学中心(CCHMC)根据我们的NIDDK K23DK118190设计建造 AP后糖尿病的预测模型。 这个项目的主要目标是提高对急性胰腺炎后糖尿病的理解，这将导致改善 病人的结果。这将通过我们的前瞻性纵向研究设计来实现。具体目标1 将通过测试定义DM的亚型以及与DM前和DM后的时间相关的时间变化 在不同时间点(AP后3个月和12个月)的1型、2型和3c型糖尿病标志物。具体目标2 将在3个月后对患者进行标准化混合膳食耐量试验的可行性测试 在AP后12个月，构建模型，确定测量所需的最佳样本采集时间点 β-细胞对刺激测试的反应，以及来自刺激测试的数据点是否提供了超越 简单的空腹C肽和血糖水平。后者很重要，因为MMTT对于 儿科不是简单的抽血。我们还将研究胰岛抗体阳性对β细胞功能的影响。我们的 该提案将帮助我们更好地定义进展为糖尿病前期，然后是糖尿病后AP，以填补这一知识空白。 这项研究的成功完成有可能导致对机制和 糖尿病前期和糖尿病的危险因素，将指导糖尿病的最终预防和及时治疗及其效果 在美联社的儿童邮报上。