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

青少年环境化学物质暴露与葡萄糖代谢、胰岛素敏感性和 B 细胞功能的纵向变化

• 批准号: 9815831
• 负责人: VAIA LIDA CHATZI
• 金额: $ 63.74万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9815831
• 关键词: Adolescent; Adult; Amino Acid Metabolism Pathway; Amino Acids; Animals; Arginine; B-Lymphocytes; Beta Cell; Biochemical; Bioinformatics; Caucasians; Cell physiology; Cells; Chemical Exposure; Chemicals; Child Health; Chlorinated Hydrocarbons; Clinical assessments; Cohort Studies; Data; Development; Diabetes Mellitus; Diabetes prevention; Dichlorodiphenyl Dichloroethylene; Diet; Dioxins; Disease; Disease Progression; Early Intervention; Endocrine Disruptors; Environmental Pollutants; Epidemic; Experimental Models; Exposure to; Fatty acid glycerol esters; Flame Retardants; Glutamates; Goals; Gold; Health; Health Benefit; Hexachlorobenzene; Hispanics; Human; Impairment; Incidence; Individual; Insulin Resistance; Intervention; Islets of Langerhans; Life; Link; Lipids; Longitudinal Studies; Longitudinal cohort; Measures; Metabolic; Metabolic Pathway; Methods; Microvascular Dysfunction; Minority; Minority Groups; Modeling; Non-Insulin-Dependent Diabetes Mellitus; Not Hispanic or Latino; OGTT; Obesity; Overweight; Palmitic Acids; Pancreas; Participant; Pathogenesis; Pathologic; Patients; Plasma; Poly-fluoroalkyl substances; Polychlorinated Biphenyls; Population; Predisposition; Prevalence; Prospective cohort; Public Health; Regulation; Research Personnel; Resolution; Risk; Risk Factors; Sampling; Serine; Study of Latinos; Subgroup; Sulfonic Acids; Testing; Tetrachlorodibenzodioxin; Time; Tyrosine; Work; Youth; aged; base; blood glucose regulation; cohort; critical period; data archive; design; diabetes risk; diabetogenic; disease phenotype; environmental chemical; environmental chemical exposure; exposed human population; follow-up; glucose metabolism; high risk; improved; innovation; insulin secretion; insulin sensitivity; interest; intravenous glucose tolerance test; lipid metabolism; macrovascular disease; metabolomics; modifiable risk; multidisciplinary; novel; perfluorohexane; perfluorooctane sulfonate; perfluorooctanoic acid; persistent organic pollutants; polybrominated diphenyl ether; public health intervention; public health priorities; sugar; young adult

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.

抽象的 年轻发病的 2 型糖尿病 (T2D) 是一个优先的公共卫生问题，因为它常常未被认识到， 治疗效果不佳，导致微血管和大血管并发症快速进展。 更好地了解触发年轻发病 T2D 发展和病理的因素 这对于西班牙裔青年这一比例较高的少数群体来说尤其重要。 T2D。动物研究表明，即使接触水平较低，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会导致 T2D 人类接触持久性有机污染物的情况很普遍，而且个人不仅接触单一化学物质。 但也有可能具有协同作用的环境化学物质的混合物。 人类研究尚无定论，并且很大程度上基于检查单次暴露的成人横断面研究。 重要的是，之前没有研究检验过多次化学暴露对纵向的影响。 疾病发生前葡萄糖代谢和胰岛素分泌的改变，这是疾病发展的关键时期 我们的首要假设是，干预措施有可能阻止或延缓 T2D 的发展。 接触多种环境化学物质可能会增加青少年对 T2D 的易感性。 基于我们强有力的初步数据和来自实验模型的令人信服的先前证据。 多学科研究小组建议在纵向发现队列中检验这一假设 根据现有的葡萄糖稳态临床评估金标准，西班牙裔青少年面临 T2D 风险， 胰岛素分泌和 β 细胞功能（糖尿病风险拉丁裔青少年研究，SOLAR），并复制 结果并检查具有代表性样本的类似设计的纵向队列的普遍性 西班牙裔和非西班牙裔青少年（儿童健康研究，CHS）此外，高分辨率代谢组学。 概况将加深我们对持久性有机污染物对糖尿病影响的机制的理解。 队列中，我们将使用新颖的统计和生物信息学方法来预测风险增加的青少年亚组 我们的具体目标是根据他们接触的环境化学品和代谢组学概况来确定 T2D。 确定持久性有机污染物暴露与以下因素单独和/或共同相关的程度： 1) 纵向 青少年葡萄糖代谢、胰岛素敏感性和 β 细胞功能的改变（目标 1）和 2） 与 T2D 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 POP 来预测对 T2D 易感性增加的青年亚群。 使用新颖的统计方法进行暴露和代谢组学分析（目标 3）。 提供了一个独特的机会来加深我们对 T2D 环境贡献的理解并开辟新的领域 青少年预防糖尿病的途径。