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.