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（T2 D）是一个优先的公共卫生问题，因为它往往是不认识的，响应 治疗效果差，并导致微血管和大血管并发症的快速进展。因此，在本发明中， 更好地了解触发T2 D发展和病理的因素， 需要进步。这在西班牙裔青年中尤为重要，这是一个少数群体， 2型糖尿病动物研究表明，即使在低水平的接触下，持久性有机污染物，包括 有机氯化合物，全氟烷基物质和溴化阻燃剂，有助于T2 D 发病机制人类广泛接触持久性有机污染物，而且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，证据显示， 人类研究没有结论，主要是基于对单一接触的成人横断面研究。 重要的是，以前的研究没有检查过多次化学暴露对纵向的影响。 在疾病发展之前葡萄糖代谢和胰岛素分泌的改变，这是一个关键时期， 干预措施有可能阻止或延迟T2 D的发展。我们的首要假设是 暴露于多种环境化学物质可能会增加青年对T2 D的易感性。这种假设是 基于我们强大的初步数据和令人信服的先前实验模型证据。我们 一个多学科的研究小组建议在一个发现纵向队列中检验这一假设， 具有T2 D风险的西班牙裔青少年，现有葡萄糖稳态的金标准临床评估， 胰岛素分泌和β细胞功能（拉丁裔青少年糖尿病风险研究，SOLAR），并复制 调查结果和检查的一般性，在纵向队列的类似设计与代表性样本， 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 这些特征将促进我们对持久性有机污染物致糖尿病效应的机制的理解。无论是 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组 根据他们暴露于环境化学物质和代谢组学特征，我们的具体目标是 确定持久性有机污染物接触在多大程度上单独和/或共同与以下方面相关： 青年人葡萄糖代谢、胰岛素敏感性和β细胞功能的改变（目的1），以及2） 与T2 D易感性增加相关的脂质和氨基酸代谢途径的调节（目的 2）。最终，我们的目标是根据他们的持久性有机污染物来预测对T2 D易感性增加的青年亚组。 暴露和代谢组学概况使用新的统计方法（目标3）。该研究具有创新性， 提供了一个独特的机会，以促进我们对T2 D的环境贡献的理解，并打开新的 预防青年糖尿病的途径。

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.