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.

项目概要/摘要 儿童急性胰腺炎（AP）的发病率已上升至1/10,000例。糖尿病 (DM) 可能是由部分患者的 AP 引起的，这会导致发病率增加，特别是在诊断不足的情况下， 鉴于目前尚无针对儿科人群进行 AP 后 DM 筛查的方法。 AP 后 DM 的研究仍未充分，其结果尚不明确。以往关于 DM post AP 的研究大多是 本质上是单中心和回顾性的，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期或 AP 后糖尿病，其中一部分 患者在 AP 后的胰岛自身抗体 (Ab) 检测呈阳性，但这并不总是意味着完全 糖尿病的诊断。这就引出了一个问题：这些抗体是否会影响 β 细胞（β 细胞）功能并在 DM 的进展以及 AP 之后是什么类型的 DM。 DM 类型或 β 细胞功能的标志物尚未确定 AP后学习儿科。因此，这项拟议的研究利用了我们之前的工作，进行了新颖的设计， 允许系统地生成新颖的机械数据来定义 DM 类型，以及胰岛自动 Abs 和 β细胞功能障碍是相关因素。 R03 的主要目标是研究 DM 的类型和程度 辛辛那提前瞻性 AP 登记处和生物样本库中样本和受试者的 β 细胞功能障碍 儿童医院医疗中心 (CCHMC) 根据我们的 NIDDK K23DK118190 设计建造 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，这将导致改进 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 将通过测试定义 DM 的子类型以及与 Pre DM 和 DM post AP 的时间相关的时间变化 不同时间点（AP 后 3 个月和 12 个月）的 1 型、2 型和 3c 型 DM 标记物。具体目标2 将测试在 3 个月时对患者进行标准化混合膳食耐受性测试 (MMTT) 的可行性 AP 后 12 个月，构建模型来定义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，以及刺激测试的数据点是否提供超越 简单的空腹 C 肽和血糖水平。后者很重要，因为 MMTT 对于 儿科检查比简单的抽血更重要。我们还将研究胰岛抗体阳性对 β 细胞功能的作用。我们的 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 后糖尿病的进展，以填补这一知识空白。 成功完成这项研究有可能提高对机制和 Pre-DM和DM的危险因素，指导DM的最终预防和及时治疗及其效果 关于儿童后美联社。