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.

项目总结/摘要 儿童急性胰腺炎（Acute Pancreatitis，AP）的发病率已上升至1/10，000。糖尿病（DM） 在一部分患者中可能由AP引起，这会导致发病率增加，特别是在诊断不足的情况下， 鉴于目前还没有方法在儿科人群中进行AP后的DM筛查。 AP后糖尿病的研究仍然不足，结局定义不明确。既往对AP后DM的研究大多是 单一中心和追溯性的性质，从而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期或糖尿病后期AP，并且其中一部分 患者在AP后检测胰岛自身抗体（Ab）阳性，但这并不总是转化为完全的 DM的诊断这就引出了一个问题，这些抗体是否影响β细胞（β细胞）功能，并在 糖尿病的进展以及AP后的糖尿病类型。糖尿病类型或β细胞功能的标志物尚未被确定。 在儿科进修过因此，这项拟议的研究利用了我们以前的工作，在一个新的设计， 允许系统地生成新的机制数据以定义DM类型，以及胰岛自身抗体和 β细胞功能障碍为参与因素。本R 03的主要目标是调查DM的类型和程度 来自辛辛那提前瞻性AP登记研究和生物储存库的样本和受试者的β细胞功能障碍 儿童医院医疗中心（CCHMC）根据我们的NIDDK K23 DK 118190生成，旨在构建 AP后糖尿病的预测模型。 该项目的主要目标是提高对AP DM后的理解，这将导致改善 患者的结果。这将通过我们的前瞻性纵向研究设计来实现。具体目标1 将通过检测来定义DM的亚型以及与DM前和DM后AP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DM标志物。具体目标2 将测试在3个月时对患者进行标准化混合餐耐受性试验（MMTT）的可行性 AP后12个月，构建模型以确定测量所需的最佳样本收集时间点 β细胞对刺激试验的反应，以及刺激试验的数据点是否提供了超出 简单的空腹C肽和血糖水平。后者很重要，因为MMTT对于 比简单的抽血要简单我们还将研究胰岛Ab阳性对β细胞功能的作用。我们 该提案将帮助我们更好地定义糖尿病前期的进展，然后是AP后的糖尿病，以填补这一知识空白。 成功完成这项研究有可能导致更好地了解机制， 糖尿病前期和糖尿病的危险因素，从而指导糖尿病的最终预防和及时治疗及其效果 关于AP后的儿童