Understanding, Predicting and Preventing Type 2 Diabetes in Youth, Boston Clinical Center (UPP Study)

了解、预测和预防青少年 2 型糖尿病，波士顿临床中心（UPP 研究）

• 批准号: 10583740
• 负责人: Amy Debra Fleischman
• 金额: $ 16.68万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-10 至 2029-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583740
• 关键词: Address; Adolescent; Adrenal Glands; Adult; Affect; Age; Androgens; Area; B-Lymphocytes; Basal metabolic rate; Beta Cell; Biological; Blood Vessels; Body Composition; Body mass index; Boston; COVID-19 pandemic; Cell physiology; Characteristics; Child; Childhood; Clinical; Clinical Research; Clinical assessments; Collaborations; Color; Communities; Continuous Glucose Monitor; Data; Data Collection; Detection; Development; Diabetes Mellitus; Diagnosis; Diet Surveys; Disease; Dual-Energy X-Ray Absorptiometry; Early Diagnosis; Environmental Risk Factor; Epigenetic Process; Evaluation; Evolution; Family history of; Fatty acid glycerol esters; Feces; Future; General Hospitals; Genomics; Geography; Glucose; Glycosylated hemoglobin A; Gonadal Hormones; Growth; Hair; Hand Strength; Hepatic; Home; Hormonal; Hormones; Hyperglycemia; Impairment; Incidence; Insulin Resistance; Insulin-Like Growth Factor I; Light; Massachusetts; Measurable; Measures; Mediator; Metabolic; Neighborhood Health Center; Neighborhoods; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oral; Participant; Pathogenesis; Pediatric Hospitals; Peripheral Blood Mononuclear Cell; Phenotype; Physical activity; Physiological; Plasma; Prediabetes syndrome; Prevention; Puberty; Public Health; Research; Risk; Risk Factors; Risk Reduction; Running; Sampling; Shapes; Somatotropin; Stress; Systems Biology; Techniques; Testing; Triglycerides; Ultrasonography; Urine; VO2max; Visceral fat; Youth; actigraphy; biobank; blood glucose regulation; clinical center; cohort; community setting; data repository; diabetes pathogenesis; fasting plasma glucose; fitness; high body mass index; high risk; incretin hormone; indexing; insulin secretion; insulin sensitivity; macrovascular disease; marginalized community; marginalized population; metabolomics; modifiable risk; multiple omics; predictive marker; predictive modeling; prevent; progression marker; progression risk; recruit; remote assessment; repository; sample collection; social factors; social health determinants; trend; type 2 diabetes in children; ultrasound; waist circumference; wearable device; Address; Adolescent; Adrenal Glands; Adult; Affect; Age; Androgens; Area; B-Lymphocytes; Basal metabolic rate; Beta Cell; Biological; Blood Vessels; Body Composition; Body mass index; Boston; COVID-19 pandemic; Cell physiology; Characteristics; Child; Childhood; Clinical; Clinical Research; Clinical assessments; Collaborations; Color; Communities; Continuous Glucose Monitor; Data; Data Collection; Detection; Development; Diabetes Mellitus; Diagnosis; Diet Surveys; Disease; Dual-Energy X-Ray Absorptiometry; Early Diagnosis; Environmental Risk Factor; Epigenetic Process; Evaluation; Evolution; Family history of; Fatty acid glycerol esters; Feces; Future; General Hospitals; Genomics; Geography; Glucose; Glycosylated hemoglobin A; Gonadal Hormones; Growth; Hair; Hand Strength; Hepatic; Home; Hormonal; Hormones; Hyperglycemia; Impairment; Incidence; Insulin Resistance; Insulin-Like Growth Factor I; Light; Massachusetts; Measurable; Measures; Mediator; Metabolic; Neighborhood Health Center; Neighborhoods; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oral; Participant; Pathogenesis; Pediatric Hospitals; Peripheral Blood Mononuclear Cell; Phenotype; Physical activity; Physiological; Plasma; Prediabetes syndrome; Prevention; Puberty; Public Health; Research; Risk; Risk Factors; Risk Reduction; Running; Sampling; Shapes; Somatotropin; Stress; Systems Biology; Techniques; Testing; Triglycerides; Ultrasonography; Urine; VO2max; Visceral fat; Youth; actigraphy; biobank; blood glucose regulation; clinical center; cohort; community setting; data repository; diabetes pathogenesis; fasting plasma glucose; fitness; high body mass index; high risk; incretin hormone; indexing; insulin secretion; insulin sensitivity; macrovascular disease; marginalized community; marginalized population; metabolomics; modifiable risk; multiple omics; predictive marker; predictive modeling; prevent; progression marker; progression risk; recruit; remote assessment; repository; sample collection; social factors; social health determinants; trend; type 2 diabetes in children; ultrasound; waist circumference; wearable device

Project Summary / Abstract Rising obesity has led to an unprecedented increase in pre-diabetes (preD) and type 2 diabetes (T2D) incidence in children and adolescents, a worrisome trend amplified by the COVID 19 pandemic. Based on current evidence, it remains difficult to predict whether children and adolescents with preD will progress to T2D. Our proposal aims to address key questions in the pathogenesis of T2D, focusing on modifiable risk factors. Leveraging a collaboration between Boston Children’s Hospital, Joslin Diabetes Center, and Massachusetts General Hospital, in partnership with community health centers in the Greater Boston area, we propose to recruit a diverse cohort of early pubertal youth (ages 7-15, n=300) with preD, elevated BMI (≥95th percentile), a positive family history of diabetes, and one or more additional risk factors. We propose to combine rigorous annual clinical studies with convenient remote assessments, to gain a granular understanding of metabolic, hormonal and environmental factors contributing to T2D pathogenesis. In Aim 1, we will test whether measures of glucose homeostasis and beta cell function differ between youth with preD who progress to T2D versus those who revert to normoglycemia or remain preD. We propose to analyze glycemia and beta cell function using oral GTT and incretin hormone levels, and assessments adaptable to community settings, e.g., continuous glucose monitors and home A1c kits. In Aim 2, we will test whether fitness level and amount of physical activity differ between youth with preD who progress to T2D versus those who revert to normoglycemia or remain preD. We propose to evaluate fitness level using detailed clinical assessments, including VO2 max, assessments adaptable to community settings including grip strength, and free-living assessments using wearables and app-based activity tracking. In Aim 3, we will test whether evolution of body composition during growth and puberty predicts progression to T2D. We propose to analyze body composition (total and visceral fat) using DXA, and hepatic fat using echography-based assessments, gonadal hormones, adrenal androgens, and mediators of growth hormone action, as well as assessments adaptable to community settings, e.g., BMI and app-based dietary surveys. As secondary aims, we propose to create a data repository to allow evaluation of social and environmental factors contributing to T2D onset at a consortium level, with measures including social determinants of health, neighborhood and geographic characteristics (using geocoding techniques), and the environmental exposome. We also propose the creation of a biological repository to allow multi-omics studies to identify genomic, epigenetic, and/or metabolomic markers for progression from preD to T2D in youth at a consortium level. We propose to collect a rich biorepository of longitudinal samples (i.e., plasma, PBMCs, urine, stool, hair) from all participants that will set the stage for future systems biology-driven studies. Together, these studies will permit development of a predictive model based on variables easily measurable at the community level, which can then be applied to the detection and treatment of youth at highest risk of T2D.

项目摘要 /摘要 肥胖的上升导致糖尿病前（PRED）和2型糖尿病（T2D）发病率的前所未有的增加 在儿童和青少年中，covid 19大流行所扩大的可怕趋势。基于当前证据， 很难预测患有PER的儿童和青少年是否会发展为T2D。我们的建议目标 为了解决T2D发病机理中的关键问题，重点是可修改的危险因素。利用 波士顿儿童医院，乔斯林糖尿病中心和马萨诸塞州综合医院之间的合作 与大波士顿地区的社区卫生中心合作，我们建议招募潜水员队列 早期青春期（7-15岁，n = 300），BMI升高（≥95％），这是一个积极的家族史 糖尿病和一个或多个其他危险因素。我们建议将严格的年度临床研究与 方便的远程评估，以获得对代谢，荷尔蒙和环境的细腻理解 导致T2D发病机理的因素。在AIM 1中，我们将测试葡萄糖稳态和 beta细胞功能与pred的年轻人不同，他会发展为T2D与那些还原为正常血糖的年轻人的功能 或保持pred。我们建议使用口服GTT和增加激素分析血糖和β细胞功能 水平和评估可适应社区环境，例如连续的葡萄糖监测器和家庭A1C套件。 在AIM 2中，我们将测试适应水平和体育锻炼的数量是否不同 进展到T2D与恢复到正常血糖或保持pred的人相比。我们建议评估健身水平 使用详细的临床评估，包括VO2 Max，可适应社区环境的评估 使用可穿戴设备和基于应用程序的活动跟踪来抓住强度和自由生活评估。在AIM 3中，我们将测试 人体成分在生长和青春期预测过程中的进化是否发展到T2D。我们建议 使用DXA分析人体成分（总和内脏脂肪），以及使用基于电子检查的肝脂肪 评估，性腺恐怖，肾上腺雄激素，增长骑马动作的介体以及 作为次要目标， 我们建议创建一个数据存储库，以评估有助于的社会和环境因素 T2D在财团层面的发作，并采取了措施，包括卫生，社区和 地理特征（使用地理编码技术）和环境展示体。我们也建议 创建生物存储库，以允许多摩学研究识别基因组，表观遗传和/或 在财团水平的青年中，在青年中从pred到T2D的代谢标记。我们建议收集 所有参与者的纵向样品（即等离子体，PBMC，尿液，粪便，头发）的丰富生物座 为未来的系统生物学驱动的研究奠定了基础。这些研究一起将允许开发 基于变量的预测模型在社区层面上很容易测量，然后可以将其应用于 检测和治疗T2D风险最高的年轻人。