Environmental Chemical Exposures and Longitudinal Changes of Glucose Metabolism, Insulin Sensitivity and B Cell Function in Youth

摘要 年轻发病的2型糖尿病(T2D)是一个优先的公共卫生问题，因为它通常没有被认识到，回答说 治疗效果差，导致微血管和大血管并发症进展迅速。因此， 更好地了解触发年轻发病的T2D发展和病理的因素 进步是必要的。这在西班牙裔青年中尤其重要，这是一个发病率很高的少数群体 T2D。动物研究表明，即使在低水平暴露下，持久性有机污染物(POP)，包括 有机氯化合物、全氟烷基物质和溴化阻燃剂对T2D有贡献 发病机制。人类接触持久性有机污染物的情况很普遍，个人接触的不仅仅是一种化学品 而且还涉及可能具有协同作用的环境化学品的混合物。然而，证据来自 人体研究是不确定的，而且主要是基于检查单一暴露的横断面成人研究。 重要的是，以前还没有研究过多次接触化学物质对纵向影响。 疾病发展前的葡萄糖代谢和胰岛素分泌的变化，这是一个关键时期 干预有可能阻止或推迟T2D的发展。我们最重要的假设是， 接触多种环境化学品可能会增加年轻人对T2D的易感性。这一假设是 基于我们强大的初步数据和来自实验模型的令人信服的先前证据。我们的 多学科研究团队建议在一项发现纵向队列中检验这一假说 西班牙裔青少年存在患T2D的风险，现有的血糖稳态黄金标准临床评估， 胰岛素分泌和β细胞功能(对有糖尿病风险的拉丁裔青少年的研究，SOLAR)，并复制 在具有代表性的样本中，对类似设计的纵向队列的发现和概括性进行检验 西班牙裔和非西班牙裔青年(儿童健康研究，CHS)。此外，高分辨率代谢组学 简档将促进我们对持久性有机污染物糖尿病致病作用的机制的理解。在这两个地方 队列，我们将使用新的统计和生物信息学方法来预测风险增加的青年亚群 根据他们对环境化学品的暴露和代谢组学特征，对T2D进行评估。我们的具体目标是 确定持久性有机污染物暴露单独和/或联合与以下方面相关联的程度：1)纵向 青年糖代谢、胰岛素敏感性和β细胞功能的改变(目标1)，和2)损害 与T2D易感性增加相关的脂和氨基酸代谢途径的调节(AIM 2)。最终，我们的目标是基于他们的POP来预测T2D易感性增加的青年亚组 使用新的统计方法的暴露和代谢组学概况(目标3)。这项研究具有创新性， 提供了一个独特的机会，促进我们对环境对T2D的贡献的理解，并打开新的 预防青少年糖尿病的途径。

ABSTRACT Young-onset type 2 diabetes (T2D) is a priority public health issue, since it is often unrecognized, responds poorly to treatment, and results in rapid progression of microvascular and macrovascular complications. Thus, an improved understanding of the factors that trigger young-onset T2D development and pathological progression is needed. This is especially important among Hispanic youth, a minority group with high rates of T2D. Animal studies show that even at low levels of exposure, persistent organic pollutants (POPs), including organochlorine compounds, perfluoroalkyl substances, and brominated flame retardants, contribute to T2D pathogenesis. Human exposure to POPs is widespread and individuals are exposed not only to a single chemical but also to a mixture of environmental chemicals that may have synergistic actions. However, evidence from human studies is inconclusive and largerly based on cross-sectional adult studies examining single exposures. Importantly, no previous study has examined the effects of multiple chemical exposures on longitudinal alterations of glucose metabolism and insulin secretion prior to disease development, a critical period in which interventions have the potential to stop or delay T2D development. Our overarching hypothesis is that the burden of exposure to multiple environmental chemicals may increase susceptibility to T2D in youth. This hypothesis is based on our strong preliminary data and compelling prior evidence from experimental models. Our multidisciplinary team of investigators proposes to test this hypothesis in a discovery longitudinal cohort of Hispanic adolescents at risk for T2D with existing gold standard clinical assessments of glucose homeostasis, insulin secretion, and β-cell function (the Study of Latino Adolescents at Diabetes Risk, SOLAR), and to replicate findings and examine generalizability in a longitudinal cohort of similar design with a representative sample of Hispanic and non-Hispanic youth (Children Health Study, CHS). In addition, high resolution metabolomics profiles will advance our understanding of the mechanisms underlying the diabetogenic effects of POPs. In both cohorts, we will use novel statistical and bioinformatics methods to predict subgroups of youth at increased risk for T2D based on their exposure to environmental chemicals and metabolomics profiles. Our specific aims are to determine the extent to which POPs exposures are individually and/or jointly associated with: 1) longitudinal alterations of glucose metabolism, insulin sensitivity, and β-cell function in youth (Aim 1), and 2) impairment in the regulation of lipid and amino acid metabolism pathways associated with increased susceptibility to T2D (Aim 2). Ultimately, we aim to predict subgroups of youth with increased susceptibility to T2D based on their POPs exposure and metabolomics profiles using novel statistical approaches (Aim 3). The study is innovative and offers a unique opportunity to advance our understanding on environmental contributions to T2D and open new avenues for diabetes prevention in youth.