 Col. James Walter Shugart III was diagnosed with type 1 diabetes after exposure to Agent Orange during the Vietnam War. He encourages Vietnam veterans who developed diabetes to apply to the VA for disability compensation, since the VA has recognized Agent Orange as associated with type 2 diabetes since 2001. A number of other exposed Vietnam vets who developed type 1 have not been able to get compensation, however, since the VA only recognizes type 2 as associated with Agent Orange exposure. The primary source of exposure to dioxins and dioxin-like compounds in developed countries is via food, especially meat, milk, dairy, eggs, and fish, which together make up 93% of total exposure. Inhalation, drinking water, vegetable oils, and other sources only constitute a small percentage of overall exposure (Lorber et al. 2009). The U.S. Environmental Protection Agency has concluded that "safe" levels of dioxin exposure are 300-600 times lower than current average daily exposure levels, in part due to dioxin's potential effects on the immune system (Gogal and Holladay 2008).
AutoimmunityDioxin is known to suppress the immune system of animals and possibly humans (Baccarelli et al. 2002), but can it also promote autoimmunity? In a review, Gogal and Holladay (2008) find that current evidence supports the hypothesis that exposure to dioxin in utero may indeed predispose a person to autoimmune disease later in life. How? Perhaps by interfering with the development of the immune system, especially in the thymus (see the autoimmunity page for more on the thymus and immune system development).
When mice not genetically prone to autoimmune disease were treated prenatally with TCDD during immune system development, they had immune dysregulation that included autoantibody production, and suggested an increased risk for later autoimmune disease. These findings suggest that developmental exposure to TCDD may increase the risk of autoimmune disease. These mice, however, are more sensitive than other strains of mice to the effects of dioxin (Mustafa et al. 2008).
But wait, it gets more complicated. A new study has found that chronic exposure to dioxin prevents diabetes in non-obese diabetic (NOD) mice, an animal used to model autoimmune diabetes in the laboratory. NOD mice are less susceptible to the effects of dioxin that other strains of mice (Kerkvliet et al. 2009). However, most interventions-- 195 of them so far-- delay or prevent disease in NOD mice, including some that have not shown the same effect in humans. This is one reason the usefulness of NOD mice has been questioned (Roep and Atkinson 2004) (discussed further on the of mice and men page). NOD mice, then, are probably not appropriate to use for examining the effects of environmental contaminants on type 1 diabetes in humans. It may also be that dioxin shows differing effects based on the timing of the exposure. The NOD mice were given their first dose of dioxin at 8 weeks of age, while the other mice were exposed prenatally. Prenatal exposure could perhaps increase the risk of autoimmunity, while later exposure could suppress it.
Type 2 diabetesStudies of people exposed to high levels of dioxin (TCDD) have sometimes found increased rates of type 2 diabetes. For example:
What about people exposed to lower, "background" levels of dioxin, as are generally found in the environment and in most people?
To investigate this question, Longnecker and Michalek (2000) studied the association of dioxin levels with diabetes in members of the Air Force study who were not exposed to Agent Orange. The dioxin levels in these vets were similar to those seen in the general U.S. population. They found that men with higher background dioxin levels did indeed have a higher prevalence of diabetes, as well as higher levels of insulin and glucose after a glucose tolerance test (signs of type 2 diabetes).
Another study analyzed tissue samples from the same Air Force veterans, from both vets exposed to TCDD and from vets who were not exposed. They found strong evidence that a change occurred in the tissues of vets exposed to Agent Orange that could contribute to diabetes development. They identified certain markers that were correlated to both dioxin levels and fasting glucose levels. Interestingly, the same change and correlation was also seen in the tissues of vets who were not exposed to Agent Orange. This finding implies that dioxin may be hazardous at current levels of exposure to the general public (Fujiyoshi et al. 2006). For information on the overlap between type 2 diabetes and type 1, see the types of diabetes page.
Beta cellsDioxin has been shown to stimulate insulin secretion by rat beta cells (Kim et al. 2009). The authors suggest that dioxin may therefore contribute to the risk of developing diabetes by causing continuous insulin release, followed by beta cell exhaustion. Another study has found that dioxin exposure impaired some processes of insulin secretion from mouse beta cells (Kurita et al. 2009). Hectors et al. (2011) review the effects of chemicals on beta cells, and find that other chemicals have also been found to increase as well as decrease insulin secretion. The effect may depend on dose, the animal or cells used in the experiment, or other factors. Dioxin's ability to affect beta cells may have importance for diabetes development.
Insulin resistanceA study of people without diabetes living near a Superfund site in Arkansas found that people with higher levels of dioxin (TCDD) in their bodies had higher levels of insulin after a glucose tolerance test. This study suggests that high levels of dioxin may increase insulin resistance (Cranmer et al. 2000). Another study of the Operation Ranch Hand Vietnam vets found that high dioxin (TCDD) levels may promote insulin resistance, but that the effect was small (Kern et al. 2004). A Taiwanese study found that people with higher levels of dioxin (PCDD/F) had higher levels of insulin resistance. The people in this study lived near a contaminated site (Chang et al. 2010b). Yet in animals, dioxin has been found to decrease insulin resistance, and even lower blood glucose levels in rats with diabetes (Fried et al. 2010). How dioxin affects insulin resistance is not clear, and may depend on dosage, timing, species, and other factors.
For information on the role of increased insulin resistance in type 1 diabetes, visit the insulin resistance page.
Potential mechanismsDioxin can affect the developing immune system (Dietert 2009). Mustafa et al. (2008) (discussed in the autoimmunity section above) found changes in numerous immune system cells in mice after developmental dioxin exposure, and that many of these were dependent on gender. This latter finding suggests possible interactions with hormones, and that the health effects may not appear until times of hormonal shifts such as puberty. Dioxin is an endocrine (hormone) disruptor because it interferes with the endocrine system (Hotchkiss et al. 2008). Type 1 diabetes incidence in children peaks at puberty (see the gender and age page).
Remillard and Bunce (2002) suggest that dioxin may promote diabetes by mechanisms that involve the aryl hydrocarbon receptor (AhR). TCDD was found to affect insulin secretion from mouse beta cells via a mechanism involving AhR (Kurita et al. 2009). Kerkvliet et al. (2009) found that dioxin affected NOD mice via this receptor. They also found that dioxin induces regulatory T cells, immune system cells thought to be protective against autoimmune disease (discussed further on the autoimmunity page). Dioxin can affect beta cells, another mechanism that could play a role in diabetes development (Hectors et al. 2011).
A different study found that dioxin interferes with the ability of mouse fat cells to take up glucose, perhaps a mechanism that can explain how dioxin exposure could lead to insulin resistance in humans. The study aimed to determine how dioxin might cause dysfunction of the metabolism. Dioxin interefered with the development of fat cells, affected gene expression, and may interfere with insulin signaling. Thus exposure during sensitive periods of fat cell development, such as during early childhood or in the womb, may contribute to the later development of high blood glucose levels (Hsu et al. 2010).
Dioxin may also be able to interact with other factors relevant to type 1 diabetes, such as the gut and viruses. It is present in cow's milk and breastmilk.
The bottom lineExposure to high levels of dioxin appears to increase the risk of developing type 2 diabetes, and possibly exposure to low levels as well. There is contradictory evidence of how dioxin affects beta cells and autoimmunity. Perhaps these contradictions depend on the timing of exposure, with developmental exposures increasing the risk of autoimmunity, and later life exposures decreasing it. It is not clear how dioxin would affect the development of type 1 diabetes, but its role should be studied. |