The PRIORITY Study: from PRedIctiOn to pReventIon of youth-onset TYpe 2 diabetes

项目摘要/摘要 儿童肥胖增加导致青年起病(YO)2型糖尿病(T2D)负担增加， 对弱势青年的影响不成比例。YoT2D的特征是极端的胰岛素抵抗，胰岛素 与成人T2D相比，高分泌、快速b细胞衰竭和更多的并发症，引起了人们对 在生命的早期就有明显的发病率。然而，机制(S)和风险因素，导致一些 患有糖尿病前期(PreDM)的青少年进展到YoT2D，而其他人没有，仍然知之甚少。 这项建议将研究青春期早期的YoT2D风险青年，以开发更准确的预测范例 进展到YoT2D，并研究病理生理驱动因素。YoT2D不成比例地影响种族和 少数民族，往往有多种社会经济压力来源，以及健康的社会决定因素的影响 (SDoH)关于向YoT2D发展的问题必须澄清。希拉·N·马格博士(PI)已经组装了一个高度- 来自约翰·霍普金斯大学位于巴尔的摩和佛罗里达的经验丰富的团队，包括初级保健儿科医生 (Perrin，Polk，Showell，Hernandez)在为大量黑人和西班牙裔人口提供社会经济服务的诊所 劣势。小规模群体参与研究受到健康可信度的影响 通过利用这些值得信赖的护理提供者，将有助于招募研究人员。Magge博士提出了一种 创新方法，从3个不同的来源招聘：1.儿科专科诊所(内分泌学和 肥胖)，2.为低收入有色人种儿童服务的普通儿科诊所，以及3.患有早产儿的成年人的后代 起病时间(GB 40年)T2D。这项研究将纵向跟踪9-13岁女孩和10-13岁女孩的队列(总计N=2250人)。 根据糖化血红蛋白、空腹血糖和/或2小时的定义，患有体重指数≥85%ILE和前DM的14岁男孩(n=150) 口服葡萄糖耐量试验(OGTT)，超过3年或诊断为T2D，以较早发生者为准。他们 将收集人体测量、心血管、行为和遗传风险因素，以及SDoH测量。 生理测试，包括胰岛素动力学和游离脂肪酸流量(FFA)的数学模型，使用3- 将收集OGTT、体内连续血糖监测(CGM)和身体成分。目标：1) 根据以下风险因素概况，全面、可靠地评估患有前期糖尿病的青少年的YoT2D风险 根据进展到YoT2D的风险区分组，2)描述早期的病理生理特征 YoT2D的驱动程序。A.研究胰岛素动力学(分泌、敏感性、清除量)、FFA流量、CGM、 进展到YoT2D的年轻人和那些患有YoT2D的年轻人之间的异位脂肪(内脏、肝脏)和心血管风险 不要这样做。B.确定这些病理生理差异是否因AIM中确定的危险因素组而不同 1.该提案使用了一个多学科团队，具有SDoH、利益相关者等方面的新颖专业知识组合 参与度和代谢病理生理学，一种创新的招聘方法，以及尖端的、新颖的 研究预测和导致YoT2D的危险因素和病理生理驱动因素的方法学 以便为今后的预防和治疗战略提供信息。

Project Summary/Abstract Increases in pediatric obesity have led to an increased burden of youth-onset (Yo) type 2 diabetes (T2D), disproportionately affecting vulnerable youth. YoT2D is characterized by extreme insulin resistance, insulin hypersecretion, rapid b cell failure, and increased complications compared to adult T2D, raising concern for significant morbidity very early in life. However, the mechanism(s) and risk factors that cause some adolescents with prediabetes (PreDM) to progress to YoT2D while others do not, remain poorly understood. This proposal will study early pubertal youth at risk for YoT2D, to develop more precise prediction paradigms of progression to YoT2D, and to investigate pathophysiologic drivers. YoT2D disproportionately affects racial and ethnic minorities, often with multiple socioeconomic stressors, and the impact of social determinants of health (SDoH) on progression to YoT2D must be clarified. Dr. Sheela N. Magge (PI) has assembled a highly- experienced team from Johns Hopkins sites in Baltimore and Florida, including primary care pediatricians (Perrin, Polk, Showell, Hernandez) at clinics serving large Black and Hispanic populations with socioeconomic disadvantage. Participation in research by minoritized groups is influenced by the trustworthiness of the health system, and study recruitment will be aided by leveraging these trusted care providers. Dr. Magge proposes an innovative approach, recruiting from 3 distinct sources: 1. pediatric subspecialty clinics (endocrinology and obesity), 2. general pediatric clinics serving low-income children of color, and 3. offspring of adults with early onset (£40yrs) T2D. The study will longitudinally follow this cohort (total N=2250) of 9-13 year old girls and 10- 14 year old boys (site n=150) with BMI ≥ 85%ile and PreDM, as defined by HbA1c, fasting glucose, and/or 2-hr glucose on oral glucose tolerance test (OGTT), over 3 years or diagnosis of T2D, whichever occurs first. They will collect anthropometric, cardiovascular, behavioral, and genetic risk factors, as well as SDoH measures. Physiologic testing, including mathematical modelling of insulin kinetics and free fatty acid flux (FFA) using a 3- hour OGTT, in vivo continuous glucose monitoring (CGM), and body composition, will be collected. Aims: 1) To develop reliable estimates of YoT2D risk in youth with PreDM, overall and according to risk factor profiles that differentiate groups based on their risk of progression to YoT2D, 2) To characterize the early pathophysiologic drivers of YoT2D. a. To study differences in insulin kinetics (secretion, sensitivity, clearance), FFA flux, CGM, ectopic fat (visceral, hepatic), and cardiovascular risk between youth who progress to YoT2D and those who do not. b. To determine whether these pathophysiologic differences differ by risk factor groups identified in Aim 1. This proposal employs a multidisciplinary team with a novel mix of expertise in SDoH, stakeholder engagement, and metabolic pathophysiology, an innovative recruitment approach, and cutting-edge, novel methodologies to investigate the risk factors and pathophysiologic drivers that predict and cause YoT2D, in order to inform future prevention and treatment strategies.