Understanding and Targeting the Pathophysiology of Youth-onset Type 2 Diabetes- NYU Clinical Center

了解并针对青年发病 2 型糖尿病的病理生理学 - 纽约大学临床中心

基本信息

批准号：
10584108
负责人：
Mary Patricia Gallagher
金额：
$ 10.88万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-17 至 2029-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10584108
关键词：
19 year old Address Adult Advanced Glycosylation End Products Affect Age Animals Area Automobile Driving Basic Science Beta Cell Biological Markers Black race Body mass index Caring Cell physiology Characteristics Chemical Exposure Chemicals Child Clinical Collaborations Communities Complex Data Data Collection Deterioration Development Diabetes Mellitus Disease Disease Progression Enrollment Ensure Environmental Exposure Environmental Hazards Environmental Risk Factor Evaluation Exposure to Failure Family Family health status Food Functional disorder Genetic Health Healthcare Systems High Prevalence Hospitals Human Human Subject Research Incidence Individual Inflammation Institution Insulin Resistance Insulin-Dependent Diabetes Mellitus Intervention Investigation Kidney Diseases Latinx Learning Life Life Style Long Island Longitudinal Studies Low income Measurement Measures Mental Depression Metabolism Microvascular Dysfunction Modification Neighborhoods Non-Insulin-Dependent Diabetes Mellitus Obesity Onset of illness Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phenotype Physical activity Population Population Heterogeneity Poverty Prevalence Process Prospective, cohort study Proteome Protocols documentation Psychosocial Factor Public Health Research Research Methodology Research Personnel Risk Risk Factors Role Seminal Severities Site Social Environment Source Systems Integration Therapeutic United States Youth behavioral economics built environment cardiometabolism chemical association clinical center cohort community based participatory research design diabetes risk disorder risk early onset environmental chemical epigenome experience food environment food resource gene environment interaction high risk interest meetings metabolome microbiome novel novel marker obesity risk pharmacologic predictive marker predictive modeling prevent prognostic psychosocial receptor for advanced glycation endproducts recruit response safety net social health determinants societal costs success therapeutic target transcriptome urban setting

项目摘要

Abstract: Youth-onset type 2 diabetes (T2D) in the United States is increasing in prevalence (e.g. 4.8% per year between 2002 and 2015, and its phenotype is distinct from adult-onset T2DM in that it is accompanied by a greater degree of insulin resistance, more rapid deterioration of β-cell function, and earlier onset of life- threatening complications. These findings suggest the personal and societal costs of youth-onset T2D will be substantially greater than in adult-onset disease. The reasons for the more severe phenotype of youth-onset T2D are unclear and require further investigation. In order to develop therapeutic targets to delay, decrease the severity of, or prevent T2DM in youth, a more accurate predictive model is needed. This can only be determined through a prospective cohort study of youth at high risk for T2DM to identify characteristics or biomarkers of who progresses most rapidly. This will allow us to evaluate putative risk factors including: genetic factors, psychosocial and environmental factors, inflammation, and other sources of beta cell failure. Soluble receptors of Advanced Glycation End Products (sRAGE) have been associated with insulin resistance and β-cell dysfunction in adults with T2D. However, the AGE/RAGE axis has not been well researched in youth-onset T2D. Its potential role in the more rapid β-cell failure and increased rate of complications characteristic of youth-onset T2D warrants investigation. There is also mounting evidence of an association between exposure to metabolism disrupting chemicals (MDC) and obesity, insulin resistance, and β-cell dysfunction. Of note, MDC exposures disproportionately affect certain populations, including Black, Latinx, and low-income communities, mirroring the populations most affected by T2D. Non-chemical environmental exposures and psychosocial functioning also modify disease risk, including the built environment, social environment, and lifestyle/food environment. We propose to use remote data collection and ecological assessments as novel ways to track environmental exposures. We propose that the interaction of these internal and external exposures is responsible for the development of youth-onset T2D.The NYU Clinical Center team brings considerable expertise in engaging children and their families in longitudinal studies, scientific and clinical expertise to develop the final protocol, and a process for stakeholder engagement, used to develop our proposal, and which can be utilized in finalizing the study protocol. NYU Langone Health is an integrated system that will use its main hospitals and practices with a diverse group of over 11,500 youth with a BMI >95th %ile between the ages of 7-14 in our care to screen for this study. We will collaborate with the Consortium and key stakeholders to design and implement the study protocol; and suggest novel targets for evaluation, such as the AGE/RAGE axis, in the context of other factors including: social determinants of health, physical activity, food choices, depression, and MDC exposures on the progression of insulin resistance, β-cell failure, and the development of youth-onset T2D.

摘要：美国的青年2型糖尿病（T2D）的患病率正在增加（例如，每人4.8％ 2002年至2015年之间的一年，其表型与成人发作的T2DM不同，因为它伴随着更大程度的胰岛素抵抗，对β细胞功能的更快定义以及生命的早期发作威胁并发症。这些发现表明，青年发作的T2D的个人和社会成本将是大大比成人发病的疾病大得多。青年发作更严重表型的原因 T2D不清楚，需要进一步研究。为了开发治疗目标以延迟，请减少需要更准确的预测模型或预防T2DM的严重性或预防T2DM。这只能是通过对T2DM高风险的年轻人的前瞻性队列研究确定，以识别特征或谁进步最快的生物标志物。这将使我们能够评估推定的风险因素，包括：遗传因素，社会心理和环境因素，创新以及β细胞衰竭的其他来源。晚期糖基化最终产物（SRAGE）的可溶受体与胰岛素抵抗有关 T2D成年人中的β细胞功能障碍。但是，年龄/愤怒轴尚未得到很好的研究青年发t2d。它在更快速的β细胞衰竭和并发症率提高中的潜在作用青年发行的特征T2D保证投资。也有关联的越来越多的证据在破坏化学物质（MDC）的代谢和肥胖，胰岛素抵抗和β细胞之间的暴露之间功能障碍。值得注意的是，MDC暴露不成比例地影响某些人群，包括黑色，拉丁裔和低收入社区，反映了受T2D影响最大的人群。非化学环境暴露和社会心理功能还改变了疾病风险，包括建筑环境，社会环境和生活方式/食物环境。我们建议使用远程数据收集和生态评估是跟踪环境暴露的新方法。我们建议这些相互作用内部和外部暴露是造成青年发作T2D的发展。纽约大学临床中心团队在使儿童及其家人参与纵向研究方面具有丰富的专业知识，开发最终协议的科学和临床专业知识，以及利益相关者参与的过程为了制定我们的建议，可以用来最终确定研究方案。 NYU Langone Health是综合系统将使用其主要医院和实践，由11,500多名年轻人组成 BMI> 95％的年龄在7-14岁之间，在我们的护理中筛选这项研究。我们将与联盟和主要利益相关者设计和实施研究方案；并提出新的目标在其他因素的情况下，评估（例如年龄/愤怒轴），包括：卫生的社会决定者，体育锻炼，食物的选择，抑郁和MDC暴露于胰岛素抵抗进展的β细胞进展失败和青年发育T2D的发展。