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

摘要：青少年发病的2型糖尿病(T2D)在美国的患病率正在上升(例如 在2002年至2015年之间，其表型与成人起病的T2 DM不同，因为它伴有 胰岛素抵抗程度越高，β细胞功能恶化越快，生命开始得越早- 危险的并发症。这些发现表明，青少年发病的T2D的个人和社会成本将是 比成人发病的疾病严重得多。青年起病表型较重的原因 T2D尚不清楚，需要进一步调查。为了开发治疗靶点来延迟，减少 青年T2 DM的严重程度或预防，需要更准确的预测模型。这只能是 通过对T2 DM高危青年的前瞻性队列研究确定特征或 谁进步最快的生物标志物。这将使我们能够评估可能的风险因素，包括： 遗传因素、心理社会和环境因素、炎症和其他来源的β细胞衰竭。 晚期糖基化终产物可溶性受体(SRAGE)与胰岛素抵抗 以及成人T2D患者的β细胞功能障碍。然而，年龄/愤怒轴还没有得到很好的研究。 青年发病的T2D。它在更快的β细胞衰竭和增加并发症发生率中的潜在作用 青春期起病的T2D特点值得研究。也有越来越多的证据表明 代谢干扰物暴露与肥胖、胰岛素抵抗和β细胞之间的关系 功能障碍。值得注意的是，MDC暴露对某些人群的影响不成比例，包括黑人、Latinx和 低收入社区，反映了受T2D影响最大的人群。非化学环境 暴露和心理社会功能也会改变疾病风险，包括建筑环境、社会 环境，以及生活方式/饮食环境。我们建议使用远程数据采集和生态 评估是跟踪环境暴露的新方法。我们认为，这些因素的相互作用 内部和外部暴露是青少年发病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提供了相当多的专业知识， 用于制定最终方案的科学和临床专业知识，以及利益相关者参与的流程，使用 以制定我们的建议，并可用于最后敲定研究议定书。纽约大学朗格尼健康中心是一家 综合系统，将使用其主要医院和做法，与超过11,500名青年组成的不同群体 BMI&GT；95%年龄在7-14岁之间，需要我们为这项研究进行筛查。我们将与 财团和主要利益攸关方设计和实施研究议定书；并为 在其他因素的背景下进行评价，例如年龄/愤怒轴，包括：健康的社会决定因素， 体力活动、食物选择、抑郁和mdc暴露对胰岛素抵抗进展的影响，β细胞 失败，以及青春期T2D的发展。

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.