Access Type

Open Access Dissertation

Date of Award

January 2013

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Pathology

First Advisor

Todd A. Leff

Abstract

An important and unresolved question in the environmental health field is whether exposure to common environmental toxicants, such as dioxin and heavy metals like Pb, increase the risk of developing diabetes, especially in combination with other common metabolic stressors such as obesity.

Previous studies suggested that dioxin exposure increased peripheral insulin resistance but did not appear to cause fasting hyperglycemia or elevated hepatic glucose output. In concordance with those findings we observed that dioxin treatment caused a strong suppression of the expression of the key hepatic gluconeogenic genes PEPCK and G6Pase. However, this suppression was not solely mediated by the dioxin (AhR) receptor as we observed that dioxin treatment stimulated the AMPK signaling pathway, which is known to have a suppressive effect on PEPCK gene expression.

Although Pb exposure and blood Pb 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. We characterized the effect of Pb exposure on diabetes risk in metabolically stressed rodents and attempted to identify the in vitro mechanisms by which Pb affects metabolic balance.

These findings demonstrate for the first time that, in metabolically stressed rodents, Pb exposure promotes the development of Type 2 diabetes. In ZDF rats we identified Pb-induced defects in hepatic glucose output and postprandial glucose clearance as well as key histological aspects of Pb-exposure, including islet abnormalities and increased β-cell compensation. And in hIAPP transgenic mice we demonstrated that Pb exposure, in combination with a high fat diet, caused the development of fasting hyperglycemia and glucose intolerance as well as Pb-induced islet hyperplasia and striking pancreatic amyloid plaque formation. In vitro data from cultured hepatocytes clearly showed that Pb exposure either induced the expression of genes that are required for hepatic glucose production (PEPCK, G6Pase, and PGC1-α), or blocked the ability of insulin to down-regulate those genes, which would contribute to the development of hyperglycemia in vivo. Together, these observations suggest that Pb exposure interferes with insulin signaling, inducing a hepatic insulin resistance that compromises the ability of the liver to control glucose production.

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.

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