endocrine system of the body is made up of glands that secrete hormones. The pancreas, for example, is an endocrine organ that secretes the hormone insulin. The hormone/endocrine system is one system of communication within the body. Certain cells release hormones as a result of some signal (e.g., the beta cells in the pancreas release insulin when they sense that glucose levels in the blood are rising), and the hormone (in this case, insulin) travels through the blood to bind with hormone receptors (e.g., insulin receptors) on various cells. That triggers some effect, in this example, when insulin binds to a receptor, glucose can enter the cell. Almost all (or perhaps all) cells would have receptors for insulin, but only certain cells would have receptors for other hormones (e.g., estrogen or testosterone, etc.). The numbers and types of hormone receptors on cells change over time, and change depending on the concentration of the hormone in the blood, and on the stage of development of the organism.
Endocrine organs include, among others, the pancreas, thymus, thyroid gland, and adrenal gland. Endocrinologists treat diseases of the endocrine system, such as diabetes and thyroid disease. There are many hormones in humans, estradiol, estrogen, testosterone, androgen, insulin, glucagon, glucocorticoid, thyroid hormones, and more. Vitamin D is also considered to be a secosteroid, a type of steroid hormone.
Substances that can interfere with the endocrine (hormone) system are called "endocrine disruptors." These substances may act like hormones, binding with their receptors, or block the receptors, preventing hormones from binding with them, affecting the ability of cells to produce or secrete hormones hormones, and more (Hotchkiss et al. 2008). For example, an estrogenic chemical is one that acts like estrogen, and binds to estrogen receptors on cells, triggering a response that normally estrogen would trigger. An anti-androgen is a chemicals that can block androgen hormones from binding with their receptors, preventing the cells from responding to an androgen hormone. Some chemicals can affect the ability of beta cells to either produce or secrete the hormone insulin, sometime increasing and sometimes decreasing these processes.
A number of environmental chemicals (as well as other substances, such as some pharmaceutical drugs) are endocrine disruptors (Hotchkiss et al. 2008). Gore et al. (2006) list some common characteristics of how endocrine disruptors can act:
A number of the chemicals considered here, including arsenic, some persistent organic pollutants (POPs) such as PCBs and dioxin, bisphenol A, phthalates, some pesticides, and possibly nitrate, are considered endocrine disruptors. Please visit those pages for studies on these chemicals.
Most research on endocrine disruptors thus far has focused on the reproductive system, but the effects of these chemicals on other body systems are now under investigation. The immune system, the digestive system, the cardiovascular system, the central nervous system, metabolism, and fat (adipose) tissue are also targets of endocrine disrupting compounds (Hotchkiss et al. 2008).
Endocrine disruption is important especially during a fetus/infant/child's development, because hormones play a critical role in controlling how the body develops. Endocrine disrupting chemicals are linked to changes in metabolic processes even in umbilical cord blood, which could contribute to metabolic disorders like diabetes or obesity later in life (Remy et al. 2016).
If you give animals hormones during development, it can affect their later risk of diabetes-related health effects. For example, researchers exposed pregnant ewes to androgen (testosterone), estrogen, and glucocorticoid hormones. The offspring of ewes exposed to androgens had altered development of their pancreas, leading to excess insulin secretion in adolescence (Ramaswamy et al. 2016).
It is becoming clear that numerous endocrine disruptors are linked to the development of type 2 diabetes. The strongest evidence exists for persistent organic pollutants (see Lee et al. 2014; Taylor et al. 2013) and arsenic (Wang et al. 2014; Maull et al. 2012). There is growing evidence for many other endocrine disrupting chemicals as well (see pages on individual chemicals for details) (Reviewed by Chevalier and Fénichel, 2014; Firmin et al. 2016). A systematic review and meta-analysis of 49 studies from diverse populations found that both persistent (PCBs, dioxin, chlorinated pesticides) and non-persistent (BPA, phthalates) endocrine disruptors were associated with type 2 diabetes, impaired fasting glucose, and insulin resistance (Song et al. 2015). Endocrine disruptors are also implicated in complications and diseases that relate to type 2 diabetes, including atherosclerosis and cardiovascular disease (Reviewed by Kirkley and Sargis, 2014).
We do not have much evidence regarding type 1 diabetes and endocrine disruptors; it is a largely unexplored field.
First, we might ask whether natural hormones can influence the development of type 1 diabetes. There is some evidence that they can. Gender differences are present in type 1 (and type 2) diabetes, and it is possible that sex hormones may influence the risk of developing type 1 diabetes in some way (Gale and Gillespie 2001). The incidence of type 1 diabetes in children peaks at puberty, a time of hormonal changes (see the puberty page). Pregnancy, another time of hormonal change, can lead to gestational diabetes, later followed by type 1 or 2 diabetes. Psychological stress may be a risk factor for type 1 diabetes (see the stress page), and while the mechanism is unknown, perhaps hormones released during stress could play a role. In addition, the hormone vitamin D appears to be protective against type 1 diabetes development (see the vitamin D page). The role of taller height and excess weight as risk factors for type 1 diabetes may also involve hormones (see the height and weight page).
It is clear to me, as someone with type 1 diabetes, that hormone levels can also influence blood glucose levels and blood glucose control day-to-day. Again, times of natural hormonal changes like puberty and pregnancy make it hard to control type 1 diabetes. Even the hormonal fluctuations during the menstrual cycle can affect insulin sensitivity in women with type 1 diabetes (see Brown et al. 2015).
We do not know, however, if chemicals that interfere with the endocrine (hormone) system contribute to the development of type 1 diabetes, or affect blood sugar management. The following sections provide some evidence that this possibility exists, although this hypothesis has not yet been tested.
The ability of many endocrine disruptors to interfere with the body's endocrine system may be important for the immune system, since the immune and endocrine systems interact. Evidence is growing that endocrine disruptors can affect the immune system, although exactly how is still under investigation (Clayton et al. 2011).
The effects of endocrine disruptors on the immune system may be particularly important for type 1 diabetes, since it is an autoimmune disease.
Because females are more susceptible than males to many autoimmune diseases, some researchers hypothesize that environmental estrogens could promote autoimmune disease (e.g., see Walker et al. 1996; Ahmed et al. 1999). Gender does influence the behavior of the immune system, since sex hormones interact directly with immune system cells, although how these hormones might affect the development of type 1 diabetes is not known. Type 1 diabetes, unlike other autoimmune diseases, is not more common in females (Gale and Gillespie 2001).
In animals, some estrogenic endocrine disruptors have been found to promote autoimmunity. For example, Yurino et al. (2004) found that bisphenol A enhances autoantibody production in mice. Bisphenol A is an estrogenic compound. These researchers also found that the estrogenic pharmaceutical diethylstilbestrol (DES) had the same effects. The weakly estrogenic organochlorine pesticide chlordecone accelerates the development of autoimmune disease in mice. Its effects were similar to estradiol, but not identical (Wang et al. 2007) (described further on the persistent organic pollutants page). In animals, estrogen can cause the thymus to shrink, affect thymocytes, and promote autoimmunity; estrogenic chemicals may act similarly (Ahmed et al. 1999).
DES was given to pregnant women decades ago to prevent miscarriage (it didn't work, but instead led to various health problems in these women's offspring). There is some limited evidence linking autoimmunity and DES in humans: women exposed to DES in utero seem to have a higher incidence of autoimmune disease, but only when various autoimmune diseases are grouped together (Ahmed et al. 1999). Yet a more recent study that followed these women over 25 years found that there was not an overall increase in autoimmune diseases in DES exposed daughters, although type 1 diabetes was not included in this study (only four autoimmune diseases were included). However, there was an increased risk of the autoimmune disease rheumatoid arthritis in women under 45, and a lower risk in those over 45 (Strohsnitter et al. 2010).
Yet other chemicals that act via different, non-estrogenic pathways also have been shown to promote autoimmunity in animals. Thus estrogenic compounds are not the only compounds of concern. Phthalates, for example, can induce autoantibodies in mice, although the resulting health effects depend on the strain of mouse (Lim and Ghosh 2005). And, dioxin exposure during immune system development has been shown to result in changes suggestive of autoimmune disease in mice (Mustafa et al. 2008). Several phthalates are anti-androgens, and dioxin acts on multiple components of the endocrine system, via the aryl hydrocarbon receptor (AhR) (Hotchkiss et al. 2008). And, some chemicals can affect a number of receptors. Bisphenol A, for example, affects the activation of not only estrogen receptors, but also androgen and AhR receptors (Kruger et al. 2008).
The hormone vitamin D is also involved in the immune system, and may be protective against some autoimmune diseases, including type 1 diabetes (Norris 2001). Some chemicals may be able to affect vitamin D levels in animals. Lilienthal et al. (2000) hypothesized that since PCBs can affect other hormones, it might make sense that they could interfere with vitamin D levels. Their study found that PCBs did reduce vitamin D levels in rats. See the vitamin D page for more studies on vitamin D, type 1 diabetes, and chemical effects on vitamin D levels.
Glucocorticoids are other hormones involved in the immune system. Disturbed glucocorticoid action is associated with a number of conditions, including autoimmune disease, type 2 diabetes, and obesity. Chemicals that can disrupt glucocorticoid action include PCBs, organotins, arsenic, dithiocarbamate chemicals (found in some pesticides and cosmetics), and more (Odermatt et al. 2006).
Some endocrine disruptors have been found to affect the insulin-producing beta cells or insulin secretion from beta cells, including bisphenol A, PCBs, dioxin, and arsenic, potentially leading to beta cell stress. See those pages for information on these studies.
Nadal et al. (2009) review how the beta cell is a target of estrogenic compounds. They discuss how an excess of estrogen or estrogenic compounds such as bisphenol A could produce an excess of insulin signaling and insulin secretion, overstimulating beta cells. This signaling in turn may provoke increased insulin resistance and beta cell exhaustion. The authors argue that these compounds may thus contribute to the development of type 2 diabetes, but we should also consider the possibility that they may contribute to the development of type 1 diabetes as well. Environmental factors that stress or overload beta cells may be a factor in the increased incidence of type 1 diabetes in children (Dahlquist 2006; Ludvigsson 2006), and increased insulin resistance may accelerate the appearance of type 1 diabetes (see the beta cell stress and insulin resistance pages).
Dioxin has also been shown to stimulate insulin secretion from beta cells (Kim et al. 2009). Other researchers, however, found that dioxin impaired insulin secretion (Kurita et al. 2009). Like bisphenol A, dioxin has been associated with type 2 diabetes in humans, and autoimmunity in animals. Other chemicals that interfere with AhR include PCBs and polychlorinated dibenzofurans (PCDFs) (Hotchkiss et al. 2008).
Li et al. (2008) tested the hypothesis that androgen hormones (testosterone is an androgen hormone) and androgen receptors could be involved in the development of type 1 diabetes, perhaps helping to explain why type 1 diabetes is not more common in women than men. To test this idea, they looked for, and found, androgen receptors in beta cells. These receptors help to control the process of beta cell apoptosis (programmed cell death).
Could androgenic or anti-androgenic chemicals then affect beta cells? This question has not yet been researched. In rats, increased androgen levels impair insulin secretion by disrupting pancreatic beta cells (Wang et al. 2015). Some endocrine disrupting chemicals can influence androgen receptor actions and can be androgenic or antiandrogenic at levels found in the environment, although the health effects investigated so far are related to the reproductive system. Masculinized female fish have been found in living in rivers contaminated with effluent from pulp mills around the world, indicating androgenic activity. Yet the responsible androgenic chemicals in this effluent have not yet been identified. Androgenic action has also been found in effluent from cattle feedlot operations in the U.S. (Hotchkiss et al. 2008). Cadmium has also been shown to have androgenic effects (Byrne et al. 2009), and has been associated with type 2 diabetes (see the heavy metals page). Anti-androgens can interfere with androgen signaling and can affect androgen-sensitive organs in animals. Some anti-androgens include the persistent organic pollutant DDE, some fungicides (vinclozolin, procymidone, and prochloraz), the herbicide linuron, several phthalates, PBDE flame retardants (Hotchkiss et al. 2008), and bisphenol A and other components of plastics (Krüger et al. 2008).
Some endocrine disruptors have been found to increase insulin resistance, including bisphenol A, some persistent organic pollutants (including dioxin, and PCBs), some pesticides, and phthalates.
Estradiol helps to maintain normal insulin sensitivity and beta cell function. Estrogen levels that are either too high or too low may promote insulin resistance and type 2 diabetes (Nadal et al. 2009). In fact, men with higher levels of natural estrogens are of at higher risk of type 2 diabetes, according to a large, long-term study (Jasuja et al. 2013). In obese women, levels of chemicals that act like estrogen are pervasive, and associated with inflammation, metabolic abnormalities, and cardiovascular risk (Teixeira et al. 2015).
Other hormone receptors involved in obesity and insulin resistance are PPAR receptors. These receptors control metabolism, and some chemicals can interfere with them (Casals-Casas et al. 2008) (see the organotins and phthalates pages, for example). More and more chemicals are being screened for their ability to interact with PPAR receptors, and thereby be labeled as potential obesogens. For example, components of the crude oil dispersant used in the Deepwater Horizon oil spill was found to activate these receptors (Temkin et al. 2015). Sex hormones also play a role in the function of the PPAR receptors (Sato et al. 2014). Exposure to excess testosterone during development can also lead to adult metabolic disorders in animals (Abi Salloum et al. 2015; Lu et al. 2016). In sheep, those exposed to testosterone in the womb show metabolic effects later in life that could predispose them to metabolic diseases (Padmanabhan and Veiga-Lopez, 2014).
Some endocrine disruptors have been shown to increase the formation of fat cells. For example, both nonylphenol and DES promote the formation of fat cells in laboratory studies, and increase body weight in mice (Hao et al. 2012a, Hao et al. 2012b). Certain parabens, chemicals found in cosmetics and other consumer products, increase fat cell development and are potential obesogens (Hu et al. 2016; Pereira-Fernandes et al. 2013). Wastewater discharged from water treatment plants also contains endocrine disrupting compounds, and mice who drank this water gained more fat (Biasiotto et al. 2016). For studies on other endocrine disrupting compounds linked to obesity, see the individual chemical pages.
The effects of endocrine disruptors are important during development. For example, a study found that higher levels of environmental estrogens in the placenta were associated with higher birth weight in boys (Vilahur et al. 2013). Other studies have found exposure to endocrine disrupting chemicals to be associated with low birth weight (Birks et al. 2016).
The May 25, 2009 issue of the journal Molecular and Cellular Endocrinology published a special issue on the role of environmental endocrine disrupting chemicals in the development of obesity and diabetes. For example, Heindel and vom Saal (2009) propose that the recent increase in obesity is due to both nutrition and environmental chemical exposures in early life. Grün and Blumberg (2009) review the evidence that a variety of endocrine disrupting chemicals can influence fat formation and obesity. Newbold et al. (2009) review the mechanisms involved in endocrine disruption and obesity.
More recent reviews also find that early-life exposure to endocrine disrupting compounds may play a role in the development of obesity (Braun 2016; Giulivo et al. 2016; Heindel et al. 2016; Heindel et al. 2015; Holmes 2016; Janesick and Blumberg 2016; Lind et al. 2016; Nappi et al. 2016; Russ and Howard 2016; Wang et al. 2016).
The OBELIX Project is a pan-European effort to evaluate the role of endocrine disrupting chemicals in obesity, using both long-term human studies (focusing on exposure during development) and laboratory studies (Legler, 2013). OBELIX is an abbreviation for “OBesogenic Endocrine disrupting chemicals: LInking prenatal eXposure to the development of obesity later in life.”
A review of the evidence on endocrine disrupting chemicals and obesity notes that:
There is a dearth of research on endocrine disrupting compounds and gestational diabetes, although research has linked a few endocrine disrupting chemicals to gestational diabetes (search this website for gestational diabetes to see where links have been found, and for a review of the topic, see Ehrlich et al. 2016).
Endocrine disruptors are also a likely environmental factor contributing to the earlier appearance of puberty, a possible accelerator of type 1 diabetes (see the puberty page for information).
Up to 25% of patients with type 1 diabetes have evidence of thyroid disease, the most common autoimmune disease associated with type 1 diabetes (Umpierrez et al. 2003). The effect of endocrine disruptors on the thyroid hormone is another area that is beginning to be researched. For a review of the main thyroid-disrupting chemicals (PCBs, perchlorates, brominated flame retardants, and phthalates), see Jugan et al. (2010). Since thyroid levels during pregnancy are critical to proper fetal development, these thyroid disrupting chemicals are also important during development. Thyroid hormones are also important for glucose levels and metabolism. Thus prenatal exposure to thyroid disruptors are also linked to changes in glucose and metabolism in the offspring (Molehin et al. 2016).
Interestingly, since endocrine disruptors can affect the development (differentiation) of cells, they affect the activity of stem cells. Some authors argue that this has importance for the therapeutic uses of stem cells to treat diseases (Bateman et al. 2017).
There are a variety of methods to identify endocrine disrupting chemicals. The Endocrine Disruption Exchange hosts an online searchable list of potential endocrine disrupting chemicals. As of June 2015, there were almost 1000 chemicals on that list.
The U.S. Environmental Protection Agency (EPA) is supposed to be identifying endocrine disruptors using its Endocrine Disruption Screening Program, but they are way behind and have barely made a dent in screening chemicals.
The EPA wants to use more modern techniques than animal studies to screen chemicals. The advantage of these approaches is that they can screen hundreds of chemicals in a very short time. The disadvantage, so far, is that they may not be accurate. The debate continues.
While we wait for them to figure this out, we are experimenting on ourselves (but without an unexposed control group). For example, some scientists analyzed 65 compounds that migrate from polycarbonate plastic baby bottles (into milk), and found that 53 of them showed some endocrine activity (Simon et al. 2016). Exposing babies to these chemicals is just not ethical.
While this webpage focuses on chemicals individually, we are all exposed to hundreds of endocrine disrupting compounds at the same time. What are the effects? We have no idea. One study studied exposure to low doses of 27 chemicals, similar to those found in humans. They found a variety of effects, including effects on weight and metabolism (Hadrup et al. 2016). We need more studies that address chemical mixtures or new methods to address this problem, and some are beginning to show up (e.g., see Lee and Jacobs 2015; Watt et al. 2016).
Some researchers have tried to estimate the economic costs of exposure to endocrine disrupting chemicals. For example, an expert panel of scientists has determined that exposure to 3 types of endocrine disrupting chemicals (BPA, DDE, and phthalates) in the European Union leads to economic costs of at least €18 billion per year -- for obesity and diabetes alone (not including other diseases) (Legler et al. 2015). Another study calculated that a reduction of chemical exposures (to phthalates, DDE, PCBs, and PFCs) could lead to a 13% reduction in diabetes. Extrapolating to Europe, they estimate that reducing chemical exposures could prevent 152,481 cases of diabetes in Europe and €4.51 billion/year in associated costs, compared with 469,172 cases prevented by reducing BMI (Trasande et al. 2016).
The effects of endocrine disruptors on all endocrine glands, including the pancreas, and all relevant systems, including the immune system, are important areas to research. Suvorov and Takser (2008) point out that "the role of environmental contaminants in increasingly prevalent endocrine disorders such as childhood obesity and diabetes mellitus is an important research avenue."
The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals (EDCs) devotes a section to diabetes and obesity. Their summary points (Gore et al. 2015):
The Endocrine Society's Statement concludes, "...there is sufficient evidence to conclude that some EDCs act as obesogens and others act as diabetogens." Also, "...animal studies indicate that some EDCs directly target beta and alpha cells in the pancreas, adipocytes, and liver cells and provoke insulin resistance together with hyperinsulinemia."
They also call for more research on EDCs and type 1 diabetes: "Studies relating EDCs and other contaminants to T1D are beginning to emerge, although they are still very preliminary... this is an important area that deserves further research and more studies in humans" (Gore et al. 2015).
We do not know if endocrine disruptors contribute to the development of type 1 diabetes or the increased incidence of the disease in children, but judging from their effects on animals, the potential certainly exists, and should be investigated. It is critical to keep in mind that the health effects discussed on this page were almost all seen at very low doses, such as we encounter in the environment.
An expert panel estimated that exposure to endocrine disrupting chemicals has a median annual economic cost of €163 billion in the European Union. This estimate includes costs related to childhood obesity, adult obesity, and adult diabetes (Trasande et al. 2016).
To see these and many additional articles on endocrine disruption and diabetes/obesity, see my PubMed collection, Endocrine Disruption.