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TCDD-Induced Insulin Resistance

Objective/Hypothesis:

This projects will examine the role of environmental dioxin exposure in the development of insulin-resistance, a pre-diabetic state in which normal blood glucose levels are maintained by high circulating levels of insulin. The most toxic of the dioxin compounds is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD was the primary dioxin component of "Agent Orange" and has been found in numerous toxic waste sites including the Vertac Superfund site in Jacksonville, Arkansas. Thus, the problem is not limited to Vietnam veterans; many Americans have been exposed to TCDD.

Two recent studies have suggested a link between diabetes and TCDD; one found an increase in the prevalence of diabetes and among veterans who loaded Agent Orange onto planes during the Vietnam conflict, and the other includes preliminary data from our group which examined subjects living near the  Vertac Superfund site. Our data suggest that non-diabetic individuals exposed to TCDD have a marked insulin-resistance. The objectives of this project are to further document this pathology in humans and to use an animal model to determine if the toxic mechanism includes effects on TNF-alpha, glucose transporters, lipase activities or PPAR-gamma.

Approach:

Goal 1. Quantitation of insulin sensitivity and insulin secretion in TCDD-exposed humans:

These studies will determine more precisely the nature of the insulin-resistance in TCDD-exposed subjects. To accomplish this, we will recruit human subjects with blood lipid TCDD levels >10 ppt for insulin sensitivity testing and match each "high TCDD" subject to two control subjects with low TCDD levels. The questions to be answered include:

1. Do TCDD-exposed subjects demonstrate insulin-resistance when other factor (age, weight, gender, etc.) are controlled?
2. What is the quantitative difference in insulin sensitivity?
3. Does TCDD affect insulin secretion?

Goal 2. Examination of the mechanism of insulin-resistance in a rat model.

We have recently demonstrated that rats given TCDD develop elevated blood insulin levels. Using this rat model we will examine the mechanism of TCDD-Induced insulin-resistance. Questions to be asked include:

1. Does TCDD elicit insulin-resistance in rats as measured by euglycemic clamping?
2. What is the dose and time-dependency of TCDD-Induced insulin-resistance?
3. Does obesity or a high-fat diet promote TCDD-Induced insulin-resistance?
4. Does TCDD treatment of lean or obese rats affect tissues levels of TNF-alpha, glucose transports, lipase activities or PPAR-gamma?

Expected Results:

We expect to see a TCDD-Induced insulin-resistance in both humans and rats with the animal model showing both dose- and time-dependencies. In addition, it is anticipated that the insulin-resistance will be facilitated by obesity or a high-fat diet and will be mediated by effects on PPAR-gamma and TNF-alpha that decrease glucose transporters and lipase activity.

Improvements in Risk Management:

By providing a better understanding of the mechanism of TCDD-Induced insulin-resistance, this study will provide the foundation required to develop better preventative and-or therapeutic approaches for the insulin-resistance and diabetes in individuals exposed to TCDD.