Links Between Dioxin and Diabetes/Obesity
Overall, the vast majority of human epidemiological studies have found that people with higher exposures to dioxin have a higher risk of type 2 diabetes. This evidence includes long-term, longitudinal studies that follow people over time, including Vietnam veterans exposed to Agent Orange.
Laboratory studies on animals or cells show that dioxin exposures can cause biological effects related to diabetes/obesity, and have helped to identify the mechanisms involved.
A review of the role of dioxin in diabetes concludes that: "In the last few decades, a considerable body of epidemiological evidence has been accumulated, whose conclusions strongly suggest that exposure to dioxin and other POPs can be considered as a new risk factor for diabetes in humans in addition to the traditional lifestyle-related factors, such as excess of energy intake and a lack of exercise... an increasing number of experimental evidence clearly indicates that pancreatic beta cells can be considered a relevant and sensitive target of dioxin cytotoxicity, throwing some light on the underlying biological mechanisms." (De Tata 2014).
A meta-analysis of dioxin and dioxin-like PCBs and diabetes found that both sex and the type of exposure make a difference. When all 18 studies were considered in the meta-analysis, there was an increased diabetes incidence for both sexes, and the overall risk was higher in males than in females. However, when looking only at disaster-exposed populations, the risk was higher in females than males. In contrast, in non-disaster exposed populations, the risk for females was lower than males (Gang et al. 2022).
There are many types of polychlorinated dibenzodioxins (PCDDs), or dioxins. This page focuses on 2,3,7,8 tetrachlorodibenzo-p-dioxin (known as TCDD or dioxin) in particular. Polychlorinated dibenzofurans (PCDFs) are related chemicals. Dioxins are a type of persistent organic pollutants (POPs). Some other persistent organic pollutants act like dioxin, and are called "dioxin-like compounds." For information on studies relating to other persistent organic pollutants, or combinations of POPs, see the POPs page.
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).
Type 2 Diabetes
Higher-Level Dixon Exposure
Studies of people exposed to high levels of dioxin (TCDD) have sometimes found increased rates of type 2 diabetes. For example:
Agent Orange, an herbicide used during the Vietnam War, contains dioxin (TCDD) as a contaminant. The unit known as Operation Ranch Hand carried out spraying from 1962 to 1971, and significant amounts of dioxin have been found in their bodies, many years after the war. The U.S. Air Force has a long-term prospective study that followed people over time compared the health effects of members of Operation Ranch Hand to other Air Force veterans who were not involved in the spraying. A study has found that diabetes and glucose abnormalities are more prevalent in members of Operation Ranch Hand as compared to the others. In addition, insulin abnormalities increased with dioxin exposure in exposed veterans without diabetes (Henriksen et al. 1997). Other studies have also found that diabetes is associated with dioxin exposure in Vietnam (e.g., Michalek and Pavuk 2008; Kang et al. 2006), as well as in Korean Vietnam veterans exposed to Agent Orange (Yi et al. 2014). Based on the Institute of Medicine's evaluation of the evidence (IOM 2000), since 2001, the U.S. Department of Veterans Affairs (VA) has recognized veterans' type 2 diabetes as associated with exposure to Agent Orange and other herbicides during military service. What about type 1? I have received emails from a number of people who developed type 1 after dioxin exposure, and who are not able to get diabetes supplies covered from the VA. Please email me if you think dioxin or other chemical exposures could have contributed to your type 1 diabetes: email@example.com. Also, veterans exposed to dioxin have some epigenetic changes in their fat tissue and blood (Rytel et al. 2021); what this means for their health we do not know.
In 1976, an accident at a chemical plant caused a large release of dioxin (TCDD) into an area of Seveso, Italy. Follow-up studies have found increased rates of death from diabetes among people who were living in the contaminated area during the time of the accident (Pesatori et al. 1998). A review of the long term effects of dioxin exposure in Seveso found an excess of diabetes cases. Deaths from diabetes were slightly elevated in men and significantly elevated in women in the moderately contaminated zone, while in the highly contaminated zone, there was a small but not significant increase of deaths from diabetes in women (Bertazzi et al. 1998). However, another study-- of women in Seveso-- did not find an association between dioxin exposure and diabetes or obesity in these women. Dioxin exposure was associated with metabolic syndrome in these women, but only in women who were 12 years of age or younger during the explosion (Warner et al. 2013). These researchers are now investigating the possible effects of these exposures in the next generation. In sons, in utero TCDD exposure is associated with increased risk for metabolic syndrome later in life, while in daughters, exposure was associated with lower BMI (Warner et al. 2019a). In adult daughters (but not sons), higher levels of TCDD at pregnancy was associated with lower insulin levels, lower insulin resistance, and lower beta cell function, and BMI probably played a role in these trends (Warner et al. 2019b).
In the 1960s, a number of workers in the former Czechoslovakia were exposed to very high levels of dioxin (TCDD). Forty years later, their body levels of dioxin are still much higher than the general public. In a health analysis of 11 exposed workers, 55% have type 2 diabetes, and many have other health issues also associated with diabetes (see the "Diabetes complications" section below) (Pelclova et al. 2009). A further study of these workers (the 8 remaining alive), 50 years out, finds a 3.5 times higher rate of diabetes, as compared to other people of the same age (Pelcl et al. 2018).
A long-term study from U.S. chemical plant workers exposed to dioxin (TCDD) many years ago found that the prevalence of diabetes was not significantly different between the workers and controls. However, it also found that 60% of the people with the highest current levels of dioxin had diabetes (Calvert et al. 1999). And, there was an association between dioxin levels and fasting blood glucose levels (Sweeney et al. 1997-8).
Dioxin was associated with diabetes in people living near a factory that released dioxin in Taiwan, in both men and women (Huang et al. 2015). These authors also found an increased risk of metabolic syndrome in men, but not women. It did not matter at what age the exposure started (Huang et al. 2017).
In New Zealand, pesticide workers exposed to high levels of dioxin had an increased risk of diabetes, as well as higher glucose levels, triglycerides, and low HDL ("good") cholesterol, several decades after the last exposure ('t Mannetje et al. 2018).
Lower-Level Dioxin Exposure
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). Pretty much the same thing was found in Japan, where levels of dioxin in incinerator workers were associated with diabetes, but the diabetes rates and dioxin levels were similar to those in the general population (Yamamoto et al. 2015).
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).
A meta-analysis of studies on dioxin and diabetes finds that among people with low level dioxin exposures, there is an association between dioxin and diabetes. Among people with high level exposures, the association is not clear (Goodman et al. 2015). Thus the effects of dioxin may be more critical at low levels of exposure.
In a study that compared people with type 2 diabetes, impaired glucose tolerance, and normal glucose tolerance, those with type 2 had the higher levels of dioxin ("dioxin equivalents"), and the highest AhR activity. (AhR activity is associated with exposure to certain persistent organic pollutants, especially dioxin and dioxin-like compounds). In those without diabetes, AhR activity was associated with fasting glucose and insulin levels, as well as higher insulin resistance (Roh et al. 2015). In people without diabetes, higher AhR levels are linked to lower beta cell function (Wang et al. 2018).
Insulin Resistance and Body Weight
People without diabetes living near a Superfund site in Arkansas 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). In Taiwan, 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. 2010). A subsequent study by the same authors found that men with the highest dioxin levels as well as abdominal obesity had 5-fold increased insulin resistance levels than those with the lowest levels (both were individually associated with higher insulin resistance as well, but the effect was greatest when combined) (Chang et al. 2016).
In Chinese workers, dioxin exposure was linked to changes in triglyceride levels, among other things (Liang et al. 2021).
Exposure During Development
Data from Europe shows that exposure to dioxin and dioxin-like compounds in the womb and early life was associated with increased early infant growth, and increased body mass index (BMI) in 7 year old girls (Iszatt et al. 2016).
Laboratory Studies: Diabetes/Obesity
Dioxin has been shown to stimulate insulin secretion by beta cells (Kim et al. 2009; Lai et al. 2017). Some authors suggest that dioxin may therefore contribute to the risk of developing diabetes by causing continuous insulin release, followed by beta cell dysfunction. Other studies have found that dioxin exposure impaired insulin secretion from beta cells (Hoyeck et al. 2020; Ibrahim et al. 2020; Kurita et al. 2009, Novelli et al. 2005), and, at higher doses, even kill them (Ibrahim et al. 2020; Piaggi et al. 2007). Pancreatic beta cells are a sensitive and a specific target of the toxic action of dioxin. One study found that even the lowest dose of dioxin decreased insulin secretion, and dioxin caused a dose-related increase in beta cell death (Michela et al. 2020).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.
A more recent study confirms that dioxin is highly toxic to pancreatic beta cells, and that a substance in green tea is protective against it (Martino et al. 2013). Another substance in licorice, glabridin, is protective against the effects of dioxin on fat cells (Choi et al. 2018), as are the flavonoids Biochanin A (Choi et al. 2019) and orientin (Choi et al. 2020). Oleuropein, a phenolic compound found in olives, prevents pancreatic beta cell impairment caused by dioxin (Choi et al. 2021).
Low-dose TCDD exposure did not cause any adverse metabolic effects in male or female mice fed regular mouse food, or in males fed a high-fat diet. However, in female mice fed a high-fat diet, TCDD accelerated the onset of hyperglycemia and impaired glucose tolerance. TCDD also caused a small increase in islet area in males but reduced the percent of beta cell area within islets in females (Matteo et al. 2021).
Dioxin Can Cause Inflammation
The top row show mouse fat cells before (left) and after (right) being exposed to TCDD. The arrows show signs of inflammation. This study found both in cells and in animals, fat cells are targets of POPs and that one of the main pathways that these pollutants trigger is inflammation.
Soure: Kim et al. 2012, EHP.
A 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 interfered with the development of fat cells, affected gene expression, and may interfere with insulin signaling (Hsu et al. 2010). Another study found that dioxin increases insulin resistance during active periods but not during rest periods, in mice (Takuma et al. 2015). Rats exposed to dioxin developed insulin resistance, and the researchers tested to see if exercise would counteract that effect. It didn't, but it did help improve insulin secretion to compensate (Wang et al. 2021).
Interestingly dioxin has been seen to counteract high glucose levels in some rodents with diabetes (Fried et al. 2010).
Dioxin can cause weight gain at higher doses, in combination with a high-fat diet (Zhu et al. 2008). It can cause weight gain at lower doses, also in combination with a high-fat diet (Brulport et al. 2017). Excess weight can affect the rate of elimination of dioxin from the body (Emond et al. 2018). At really high levels of exposure, dioxin can cause weight loss and wasting syndrome (Choi et al. 2019; Choi et al. 2018).
At low doses, dioxin can induce insulin resistance in muscle cells (via a mechanism that does not involve AhR-- via mitochondrial oxidative stress) (Im et al. 2022).
In quails, which are sometimes used for lab experiments, dioxin decreased concentrations of HDL (the "good") cholesterol and thyroid hormones, increased total cholesterol levels, and disrupted liver function (Leśków et al. 2020).
Dioxin is an endocrine (hormone) disruptor because it interferes with the endocrine system (Hotchkiss et al. 2008). The mechanisms may involve the AhR receptor; animal studies show that the AhR affects glucose tolerance and insulin resistance (Wang et al. 2011). Animal studies also show that the AhR is involved in numerous effects on glucose and fats in mice-- and that these effects did not occur in mice without the AhR (Zhang et al. 2015). A similar finding is shown for mice with and without AhR and exposed to a high-fat diet in that AhR deficient mice were protected from the harmful effects of the diet (Xu et al. 2015). AhR is linked to a variety of biological processes, and exactly how it works is still being worked out (Girer et al. 2020).
Exposure During Development
Evidence is growing that exposure to pollution during critical developmental periods, such as in utero or during childhood, may have effects later in life.
Mice exposed to dioxin in the womb and while nursing were then given either a high-fat or low-fat diet and compared to unexposed controls. The control mice who ate a high fat diet developed obesity and some other signs of metabolic syndrome. The dioxin-exposed mice, however, did not develop these or other symptoms, but instead reduced the risk of metabolic problems (Sugai et al. 2014).
Another study that looked at what happened to the offspring when pregnant/lactating mice were exposed to low levels of dioxin (levels generally encountered by humans). The effects differed by gender, but there were effects on the immune system and body weight (van Esterik et al. 2015).
A cell study showed that early embryonic exposure to low levels of TCDD can alter the development of the pancreas and beta cell function (Kubi et al. 2019).
In rats, TCDD exposure can promote the transgenerational inheritance of disease susceptibility in subsequent generations. In other words, if a pregnant mother rat is exposed to dioxin, the health effects from that exposure can appear in numerous subsequent generations of offspring. These changes are passed down via epigenetic mechanisms, and the diseases include obesity (Ben Maamar et al. 2020).
Type 1 Diabetes and Autoimmunity
Dioxin can mess with the immune system, we know that. We just don't quite know what it does, or how it does it. It is likely, however, that dioxin's effects on the immune system are related to its AhR activity. The AhR controls or influences many aspects of the immune system (Quintana and Sherr 2013), and can be modulated by environmental chemicals such as dioxin, diet, gut microbiota, and metabolism (Wheeler et al. 2017). Immune cells have AhR receptors, through which they are activated for physiological (immunity) or non-physiological (allergy and autoimmunity) processes. They can be activated by regular hormones or by endocrine disrupting chemicals, which could provoke pathological alterations for life (Csaba, 2019).
Dioxin can suppress the immune system of animals and possibly humans (Baccarelli et al. 2002). Dioxin exposure can also expand the population of regulatory T cells that are protective against autoimmunity, and animal studies indeed show that arrests the development of various autoimmune conditions (Quintana and Sherr 2013), including type 1 diabetes in mice (Kerkvliet et al. 2009). Some are looking at the role of AhR in type 1 diabetes, and find that AhR activators may be protective (Yue et al. 2020).
But Can Dioxin Also Promote Autoimmunity?
Since the AhR has so much influence on the immune system, it might. For example, dioxin can also expand the populations of inflammatory cells that promote autoimmunity. Dioxin could, under various conditions, either promote or ameliorate autoimmunity (Quintana and Sherr 2013). Timing of exposure may be important; adult exposure is generally found to suppress the immune system, while prenatal exposure may promote autoimmunity. The effects also depend on the dose, genetic background, and route of exposure (pers. comm., Dr. Boule, 2014). There may be other explanations as well-- some chemicals that bind to AhR activate inflammatory T cells that are linked to autoimmune diseases, and some chemicals that bind to AhR activate immunosuppressive T cells, and we don't know why (Prasad Singh et al. 2020; Suzuki et al 2020).
The dose may be a key factor here. Some animal studies show that low doses of dioxin can promote autoimmunity, and high doses can suppress it (Kakutani et al. 2021).
Exposure During Development
In a review, Gogal and Holladay (2008) find that current evidence supports the hypothesis that exposure to dioxin in utero may 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). Other authors also find that low dose exposure to TCDD in the womb causes autoimmunity, and that an infant's thymus is more susceptible to these effects than an adult's thymus (Ishimaru et al. 2009).
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 (Mustafa et al. 2008). The same authors have found that prenatal TCDD exposure worsens autoimmune disease progression in genetically prone mice as well (Mustafa et al. 2011a). These authors found changes in numerous immune system cells in mice after developmental dioxin exposure, many dependent on sex. This latter finding suggests possible interactions with hormones; the health effects of dioxins may not appear until times of hormonal shifts such as puberty. They also found that prenatal dioxin exposure leads to more autoimmune symptoms later in life (Mustafa et al. 2011b).
Col. James Walter Shugart III was diagnosed with type 1 diabetes after exposure to Agent Orange during the Vietnam War. He encouraged Vietnam veterans who developed diabetes to apply to the VA for disability compensation, since the VA recognized Agent Orange as associated with type 2 diabetes since 2001.
However, all the 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, not type 1.
Prenatal exposure to dioxin has also been shown to affect T cell response to infection, and since type 1 diabetes (and other autoimmune diseases) are influenced by T cells, its development may be altered by early dioxin exposure (Boule et al. 2014; Winans et al. 2015). For an article describing the Boule et al. study, see Focusing on the AhR: A Potential Mechanism for Immune Effects of Prenatal Exposures, published in Environmental Health Perspectives (Konkel 2014). Further research by the same authors found that developmental exposure of autoimmune-prone mice to AhR activation accelerated disease, accompanied by increased T cell populations (Boule et al. 2015). In test tubes, dioxin does affect immune cells, including T cells, with the specific effects differing by dose (Pang et al. 2019). The effects of dioxin on T cell response to infection can also be passed down to subsequent generations, via either parental line (Post et al. 2019).
Other authors propose that the AhR receptor can be both friend and foe, depending on conditions of exposure. Pollutants that bind the AhR for long periods of time, for example, may promote autoimmunity (Julliard et al. 2014).
Dioxin also may affect other things related to type 1 diabetes. In mice treated with a chemical to give them a type 1-like diabetes, TCDD affects the gut microbiome and liver in detrimental ways (Lefever et al. 2016; Massey et al. 2022). The AhR receptor is also involved in intestinal barrier function and the intestinal immune system (Lamas et al. 2018), both of which may be important in type 1 (see the Diet and the Gut page). Dioxin can also lead to an increased susceptibility to viruses (Fiorito et al. 2017). The relationship between infections, AhR, and the effect on the immune systems is pretty complicated, and scientists are still trying to figure it out (Ambrosio et al. 2019). Mice exposed to dioxin in early life and then viruses in later life had different T cell reactions and different epigenetic changes due to the virus than mice unexposed to dioxin. These changes are linked to autoimmune diseases (Burke et al. 2021). For an explanation of this study, see, Developmental Origins of Delayed Adult Immune Response: The AhR Connection, published in Environmental Health Perspectives (Pascual et al. 2021).
Diabetes Management and Complications
A review finds that dioxin is linked to cardiovascular disease (Lind and Lind 2020).
Veterans exposed to dioxin via Agent Orange have higher rates of neuropathy-- nerve damage often associated with diabetes-- than those who were less exposed (Michalek et al. 2001). The VA recognizes peripheral neuropathy as related to Agent Orange exposure, if the disease appeared within one year of exposure. Exposed veterans also have higher rates of high blood pressure (Cypel et al. 2016).
People with type 2 diabetes who have nephropathy -- kidney disease often associated with diabetes-- have higher levels of AhR activity in their blood than people with type 2 who do not have kidney abnormalities (Kim et al. 2013).
In a group of workers exposed to high levels of dioxin in the former Czechoslovakia, 40 years after the exposure, many suffer from high levels of cholesterol and triglycerides, hardening of the arteries, high blood pressure, and heart disease, in addition to neurological damage of the brain (Pelclová et al. 2002, Pelclová et al. 2009). Fifty years later, they still have higher rates of high blood pressure, heart disease, and other problems (Pelcl et al. 2018).
In animals, dioxin promotes liver problems in combination with a high-fat diet (Duval et al. 2017).