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.

项目总结/摘要 儿童肥胖的增加导致青年发病（Yo）2型糖尿病（T2 D）的负担增加， 对弱势青年的影响尤为严重。YoT 2D的特征是极端的胰岛素抵抗，胰岛素抵抗。 与成人2型糖尿病相比，分泌过多、B细胞快速衰竭和并发症增加， 在生命早期就有严重的发病率。然而，导致某些疾病的机制和风险因素 糖尿病前期（PreDM）青少年发展为YoT 2D，而其他人则没有，仍然知之甚少。 该提案将研究处于YoT 2D风险中的青春期早期青年，以开发更精确的YoT 2D预测模式。 发展到YoT 2D，并研究病理生理驱动因素。YoT 2D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，以及健康的社会决定因素的影响 （SDoH）对YoT 2D进展的影响必须予以澄清。Sheela N.博士马奇（PI）组装了一个高度- 来自巴尔的摩和佛罗里达约翰霍普金斯研究中心的经验丰富的团队，包括初级保健儿科医生 （Perrin，Polk，Showell，埃尔南德斯）在诊所服务于大量黑人和西班牙裔人口， 劣势少数群体参与研究受到卫生部门可信度的影响。 系统和研究招募将通过利用这些值得信赖的护理提供者来帮助。Magge博士提出了一个 创新的方法，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.普通儿科诊所，为低收入的有色人种儿童提供服务; 3.成年早期 发病（40岁）T2 D。该研究将纵向跟踪9-13岁女孩和10- 14岁女孩的队列（总N=2250）。 BMI ≥ 85%ile和PreDM的14岁男孩（研究中心n=150），定义为HbA 1c、空腹血糖和/或2小时血糖 口服葡萄糖耐量试验（OGTT）血糖超过3年或诊断为T2 D，以先发生者为准。他们 将收集人体测量，心血管，行为和遗传风险因素，以及SDoH措施。 生理测试，包括胰岛素动力学和游离脂肪酸流量（FFA）的数学建模，使用3- 将收集24小时OGTT、体内连续葡萄糖监测（CGM）和身体组成。目的：1） 总体上并根据风险因素特征，对PreDM青年患者的YoT 2D风险进行可靠估计， 根据其进展为YoT 2D的风险区分组，2）表征早期病理生理学特征， YoT 2D的驱动程序。a.研究胰岛素动力学（分泌、敏感性、清除率）、FFA通量、CGM， 异位脂肪（内脏，肝脏）和心血管风险之间的青年谁进展到YoT 2D和那些谁 不要。B.确定这些病理生理学差异是否因目的中确定的风险因素组而异 1.该提案采用了一个多学科团队，该团队在SDoH、利益相关者 参与，和代谢病理生理学，创新的招聘方法，和尖端的，新颖的 研究预测和导致YoT 2D的风险因素和病理生理驱动因素的方法， 以便为今后的预防和治疗战略提供信息。