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

• 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
• 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

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：美国青少年发病的 2 型糖尿病 (T2D) 患病率正在上升（例如，每人 4.8%） 2002年至2015年间，其表型与成人发病的T2DM不同，因为它伴有 更大程度的胰岛素抵抗，β细胞功能更快恶化，生命开始得更早—— 这些研究结果表明，青少年发病的 T2D 所造成的个人和社会成本将是 显着大于成人发病的疾病。青年发病的表型更严重的原因。 T2D尚不清楚，需要进一步研究，以制定延迟、减少的治疗靶点。 青少年 T2DM 的严重程度或预防，需要更准确的预测模型。 通过对 T2DM 高危青少年进行前瞻性队列研究来确定特征或 谁进展最快的生物标志物这将使我们能够评估假定的风险因素，包括： 遗传因素、社会心理和环境因素、炎症以及β细胞衰竭的其他原因。 晚期糖基化终产物 (sRAGE) 可溶性受体与胰岛素抵抗有关 然而，AGE/RAGE 轴尚未得到充分研究。 青年发病的 T2D 可能会加速 β 细胞衰竭并增加并发症发生率。 青年发病的 T2D 的特征值得研究，也有越来越多的证据表明两者之间存在关联。 接触代谢干扰化学物质 (MDC) 与肥胖、胰岛素抵抗和 β 细胞之间的关系 值得注意的是，MDC 暴露对某些人群的影响尤为严重，包括黑人、拉丁裔和黑人。 低收入社区，反映了受非化学环境影响最严重的人群。 暴露和心理社会功能也会改变疾病风险，包括建筑环境、社会 我们建议使用远程数据收集和生态。 我们建议将评估作为追踪环境暴露的新方法。 内部和外部暴露是导致青少年发病的 T2D 的原因。纽约大学临床 中心团队在让儿童及其家庭参与纵向研究方面拥有丰富的专业知识， 使用科学和临床专业知识来制定最终方案以及利益相关者参与的流程 制定我们的提案，并可用于最终确定研究方案。 综合系统将利用其主要医院和诊所，为超过 11,500 名青年组成的多元化群体提供服务 我们将与我们合作筛选 7-14 岁年龄段的 BMI >95% 的儿童。 联盟和主要利益相关者设计和实施研究方案并提出新目标； 评估，例如年龄/愤怒轴，在其他因素的背景下，包括：健康的社会决定因素， 体力活动、食物选择、抑郁和 MDC 暴露对胰岛素抵抗、β 细胞进展的影响 失败以及青年发病的 T2D 的发展。