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

优先研究：从预测到预防青少年发病的 2 型糖尿病

• 批准号: 10583291
• 负责人: SHEELA NATESH MAGGE
• 金额: $ 6.38万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-22 至 2029-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583291
• 关键词: 13 year old; 14 year old; Adolescent; Adult; Adult Children; Affect; African ancestry; Age; Asian; B-Lymphocytes; Baltimore; Behavioral; Beta Cell; Black Populations; Black race; Blood Pressure; Body Composition; Body mass index; Cardiovascular system; Cell physiology; Cell secretion; Child; Childhood; Chronic stress; Clinic; Clinical Research; Clinical Trials; Communities; Continuous Glucose Monitor; Coupled; Development; Diagnosis; Diet; Disease; Dual-Energy X-Ray Absorptiometry; Early treatment; Education; Endocrinology; Enrollment; Epigenetic Process; Ethnic Origin; European ancestry; Failure; Family; Family history of; Fatty Liver; Fatty acid glycerol esters; Florida; Functional disorder; Future; Genetic; Glucagon; Glucose; Glycosylated hemoglobin A; Health system; Hepatic; High Density Lipoproteins; Hispanic; Hispanic Populations; Hour; Impaired fasting glycaemia; Impairment; Incidence; Income; Inflammatory; Insulin; Insulin Resistance; Kinetics; Learning; Life; Lipids; Longitudinal cohort; Low income; Measures; Metabolic; Metformin; Methodology; Microvascular Dysfunction; Minority; Minority Groups; Minority Health Research; Modeling; Morbidity - disease rate; Neighborhoods; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Not Hispanic or Latino; OGTT; Obesity; Outcome; Overweight; Pacific Islander; Parents; Patient Self-Report; Pharmacotherapy; Phenotype; Physical activity; Physiological; Prediabetes syndrome; Prevalence; Prevention; Prevention strategy; Primary Care; Puberty; Public Health; Race; Recording of previous events; Risk; Risk Factors; Site; Source; South Asian; Techniques; Testing; Treatment Failure; Trust; Visceral; Youth; adipokines; adverse childhood events; boys; cardiovascular risk factor; care providers; children of color; clinically relevant; cohort; depressive symptoms; diabetes prevention program; diabetes risk; early onset; ethnic diversity; ethnic minority; experience; fasting glucose; fitness; genetic risk factor; girls; health care availability; health care disparity; high school; impaired glucose tolerance; improved; in vivo; innovation; mathematical model; metabolic phenotype; minority children; multidisciplinary; neighborhood disadvantage; novel; obesity in children; pandemic disease; particle; pediatrician; predictive modeling; preservation; progression risk; racial diversity; racial minority; recruit; retention rate; risk variant; social; social health determinants; socioeconomic disadvantage; socioeconomic disparity; socioeconomics; statistics; stressor; treatment strategy; trustworthiness

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.

项目摘要/摘要 小儿肥胖的增加导致青年发作（YO）2型糖尿病（T2D）的燃烧增加， 不成比例地影响弱势青年。 YOT2D的特征是极端胰岛素抵抗，胰岛素 相比 生命很早就发病。但是，导致某些机制和风险因素 具有糖尿病前期（PERP）的青少年发展到YOT2D，而其他人则不了解。 该建议将研究有可能有Yot2d风险的早期青年青年，以开发更精确的预测范例 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，通常具有多种社会经济压力源，以及社会决定健康的影响 （SDOH）必须澄清YOT2D的进展。 Sheela N. Magge博士（PI）已经组装了一个高度的 来自巴尔的摩和佛罗里达州的约翰·霍普金斯网站的经验丰富的团队，包括初级保健儿科医生 （Perrin，Polk，Showell，Hernandez）在诊所，为大型黑人和西班牙裔人口提供社会经济 劣势。少数群体参与研究受到健康的可信度的影响 系统和研究招聘将通过利用这些值得信赖的护理提供者来帮助。玛格博士提议 创新方法，从3个不同来源招募：1。儿科专科诊所（内分泌学和 肥胖），2。为低收入有色子女提供服务的一般儿科诊所，3。成年人的后代 发病（40年）T2D。该研究将纵向遵循9-13岁女孩和10-的该队列（总n = 2250） 由HBA1C，禁食葡萄糖和/或2小时定义的BMI≥85％IL和PERPM的14岁男孩（现场n = 150）和Predm 在3年或T2D诊断的口服葡萄糖耐受性测试（OGTT）上进行葡萄糖，首先发生。他们 将收集人体测量学，心血管，行为和遗传危险因素以及SDOH测量。 生理测试，包括使用3-的胰岛素动力学和游离脂肪酸通量（FFA）的数学建模 将收集小时OGTT，体内连续葡萄糖监测（CGM）和身体组成。目的：1）到 根据PEDM的青年，总体以及根据风险因素概况的估计，对YOT2D风险进行可靠的估计 基于他们的进展风险YOT2D，2）表征早期的病理生理学 Yot2d的驱动程序。一个。研究胰岛素动力学（分泌，灵敏度，清除率）的差异，FFA通量，CGM， 异位脂肪（内脏，肝脏）和YOT2D的年轻人与那些年轻人之间的心血管风险 不要。 b。确定这些病理生理差异是否因AIM中确定的风险因素群体而有所不同 1。该提议采用了一个多学科团队 参与和代谢病理生理学，一种创新的招聘方法以及尖端，新颖 研究预测并导致yot2d的危险因素和病理生理驱动因素的方法 为了告知未来的预防和治疗策略。