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 年轻发作的2型糖尿病（T2D）是优先的公共卫生问题，因为通常无法认识到它会做出回应 治疗不佳，导致微血管和大血管并发症的快速发展。那， 对触发年轻T2D发展和病理的因素有了改进的了解 需要进程。这在西班牙裔青年中尤其重要，这是一个少数群体 T2D。动物研究表明，即使在暴露水平较低时，持续的有机污染物（POP），包括 有机氯化合物，全氟烷基物质和阻燃剂损坏，有助于T2D 发病。人类对流行音乐的暴露是普遍的，个人不仅暴露于一种化学物质 而且还结合了可能具有协同作用的环境化学物质。但是，来自 人类研究尚无定论，并且基于检查单一暴露的横断面成人研究。 重要的是，以前没有研究检查多种化学暴露对纵向的影响 疾病发育前的葡萄糖代谢和胰岛素分泌的改变，这是一个关键时期 干预措施有可能停止或延迟T2D开发。我们的总体假设是负担 暴露于多种环境化学物质可能会增加对青年T2D的敏感性。这个假设是 基于我们强大的初步数据和实验模型中令人信服的先前证据。我们的 研究人员的多学科团队在发现纵向队列中检验这一假设的建议 西班牙裔青少年有T2D的风险，具有葡萄糖稳态的现有黄金标准临床评估， 胰岛素分泌和β细胞功能（研究糖尿病风险的拉丁裔青少年，太阳能），并复制 调查结果并检查类似设计的纵向队列中的普遍性，并具有代表性样本 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 概况将提高我们对POP糖尿病作用的机制的理解。在这两个中 队列，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年亚组 对于T2D，基于它们暴露于环境化学物质和代谢组学概况。我们的具体目标是 确定弹出式暴露在多大程度上是单独和/或共同关联的：1）纵向 葡萄糖代谢，胰岛素敏感性和β细胞功能的改变（AIM 1）和2）在 调节脂质和氨基酸代谢途径与提高T2D易感性有关的调节（AIM） 2）。最终，我们旨在根据他们的流行音乐来预测对T2D敏感性提高的青年子组 使用新型统计方法的暴露和代谢组学特征（AIM 3）。这项研究是创新的， 提供了一个独特的机会来促进我们对T2D的环境贡献的理解，并开放了新的贡献 青年预防糖尿病的途径。