Does Chronic Low-Level Lead (Pb) Exposure Increase Diabetes Susceptibility?

描述(申请人提供)：环境健康领域中一个重要且悬而未决的问题是，暴露在常见环境毒物中是否会增加患糖尿病的风险，特别是与其他常见代谢应激因素，如肥胖结合在一起时。尽管铅暴露和血液水平在过去十年中有所下降，但在大部分美国人口中，肥胖和铅暴露之间的相互作用是一个相关的问题，在那里，环境和生活方式因素与持久性环境毒物(如铅)共存。了解毒物暴露与可能促进代谢不稳定和疾病的额外身体和社会应激源之间的合作相互作用，对于描绘疾病/毒物病因以及为那些最危险的人群建立早期干预将具有巨大的意义。该项目的目标是确定铅暴露对代谢应激啮齿动物患糖尿病风险的影响，并确定铅影响代谢平衡的体外机制。肥胖大鼠的初步研究结果表明，铅暴露会促进代谢不稳定和糖尿病。体外培养的肝细胞数据显示，铅干扰了胰岛素抑制肝脏葡萄糖产生的能力，这可能有助于体内高血糖的发展。这些结果综合起来形成了这一建议的假设：与肥胖相结合，铅暴露会增加糖尿病的易感性和/或严重程度。有两个特定的目的：1)在一个已建立的肥胖啮齿动物模型Zucker糖尿病脂肪(ZDF)大鼠中表征铅暴露导致糖尿病的程度；2)建立体外细胞模型来研究铅影响肝脏胰岛素信号转导和血糖稳态的机制。我们将用瘦肥胖ZDF大鼠的肝癌细胞和原代肝细胞来鉴定铅影响代谢正常和应激细胞的胰岛素敏感性和葡萄糖代谢的机制。将利用标准的体外mRNA分离和基因表达分析技术来建立这种体外细胞模型。 公共卫生相关性：这项工作的结果可能对我们如何看待环境毒物与人类行为和生活方式应激源的相互作用产生重大影响，并可能迫使其他人开展流行病学研究，以直接评估代谢和营养压力人群中毒物暴露的风险。这里开发的体内模型可能被证明在开发治疗方法以减少铅暴露对高危人类的有害影响方面是有用的。最后，我们建立的体外系统将对研究其他环境毒物与新陈代谢应激个体的相互作用具有普遍意义。

DESCRIPTION (provided by applicant): An important and unresolved question in the environmental health field is whether exposure to common environmental toxicants increases the risk of developing diabetes, especially in combination with other common metabolic stressors, such as obesity. Although lead (Pb) exposure and blood levels have declined over the past decade, the interaction between obesity and Pb exposure is a relevant issue in large sections of the US population where environmental and lifestyle factors co-exist with exposure to persistent environmental toxicants, such as Pb. Understanding the cooperative interaction between toxicant exposure and additional physical and social stressors that may promote metabolic instability and disease will be of enormous significance in delineating disease/toxicant etiology as well as establishing earlier interventions for those populations most at risk. The goals of this project are to characterize the effect of Pb exposure on diabetes risk in metabolically stressed rodents and to identify the in vitro mechanisms by which Pb affects metabolic balance. Preliminary findings in obese rats suggest that Pb exposure promotes metabolic instability and diabetes. In vitro data from cultured hepatocytes show that Pb interferes with the ability of insulin to suppress hepatic glucose production, which would contribute to the development of hyperglycemia in vivo. Together these results form the hypothesis of this proposal: In combination with obesity, Pb exposure increases diabetes susceptibility and/or severity. There are two specific aims: 1) Characterize the extent to which Pb exposure causes diabetes in a well-established rodent model of obesity, Zucker Diabetic Fatty (ZDF) rats, and 2) establish in vitro cellular models to study the mechanism by which Pb affects insulin signaling and glucose homeostasis in liver. Hepatoma cells and primary hepatocytes prepared from lean and obese ZDF rats will be used to identify the mechanism by which Pb affects insulin sensitivity and glucose metabolism in metabolically normal and stressed cells. Standard in vitro techniques for mRNA isolation and gene expression analysis will be utilized to establish this in vitro cell model. PUBLIC HEALTH RELEVANCE: Results from this work could have a significant impact on how we view the interaction of environmental toxicants with behavioral and lifestyle stressors in humans, and may compel others to carry out epidemiological studies to directly assess the risks of toxicant exposure in metabolically and nutritionally stressed populations. The in vivo models developed here may prove useful in developing therapies to reduce the deleterious effects of Pb exposure in at-risk humans. Finally, the in vitro systems that we establish will be of general utility for research on the interaction of other environmental toxicants and metabolically stressed individuals.