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

环境卫生领域的一个重要而未解决的问题是，接触常见的环境毒物是否会增加患糖尿病的风险，特别是在与肥胖等其他常见代谢应激源结合的情况下。虽然铅（Pb）暴露和血液水平在过去十年中有所下降，但在环境和生活方式因素与持久性环境毒物（如Pb）暴露共存的美国大部分人口中，肥胖和铅暴露之间的相互作用是一个相关问题。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压力因素之间的合作相互作用，将对描述疾病/毒物病因以及为那些最危险的人群建立早期干预措施具有重大意义。本项目的目的是表征铅暴露对代谢应激啮齿动物糖尿病风险的影响，并确定铅影响代谢平衡的体外机制。对肥胖大鼠的初步研究表明，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，铅干扰胰岛素抑制肝脏葡萄糖生成的能力，从而导致体内高血糖的发生。综上所述，这些结果形成了本提案的假设：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)表征铅暴露导致糖尿病的程度，在一个完善的肥胖啮鼠模型中，Zucker糖尿病脂肪（ZDF）大鼠，2)建立体外细胞模型，研究铅影响胰岛素信号和肝脏葡萄糖稳态的机制。我们将利用瘦肉大鼠和肥胖大鼠的肝癌细胞和原代肝细胞，研究铅对代谢正常细胞和应激细胞胰岛素敏感性和葡萄糖代谢的影响机制。标准的体外mRNA分离和基因表达分析技术将用于建立体外细胞模型。

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.