Links Between Arsenic and Diabetes/Obesity
Overall, the vast majority of human epidemiological studies have found that people with higher exposures to arsenic have a higher risk of diabetes. This evidence includes long-term, longitudinal studies that follow people over time.
Exposure to arsenic in the womb or during early life-- key periods of susceptibility-- appears to increase the risk of developing diabetes later in life.
Laboratory studies on animals or cells show that arsenic exposures can cause biological effects related to diabetes, and have helped to identify the key periods of susceptibility and the mechanisms involved. A key mechanism involved in arsenic-related diabetes is beta cell dysfunction.
Studies have also found links between arsenic exposure and the risk of diabetes complications.
Reviews of Arsenic and Diabetes/Obesity
A meta-analysis of 38 studies concluded that ingested arsenic is associated with diabetes (there were fewer and mostly older studies on inhaled arsenic, and these did not find associations) (Sung et al. 2015). A meta-analysis of 17 studies with over 2 million participants found that arsenic in drinking water and in urine was associated with diabetes, with a 13% increased risk for every 100 µg arsenic/L in drinking water (Wang et al. 2014).
A review of the evidence by a panel of experts convened by the U.S. National Toxicology Program (NTP) concluded that, "Existing human data provide limited to sufficient support for an association between arsenic and diabetes in populations with relatively high exposure levels (≥ 150 µg arsenic/L in drinking water)." (In science-speak, that is actually pretty strong evidence). The review concluded that, "The evidence is insufficient to conclude that arsenic is associated with diabetes in lower exposure (< 150 µg arsenic/L drinking water), although recent studies with better measures of outcome and exposure support an association," and that, "The animal literature as a whole was inconclusive; however, studies using better measures of diabetes-relevant end points support a link between arsenic and diabetes" (Maull et al. 2012).
As for mechanisms, one review describes four mechanisms by which arsenic exposure could contribute to the development of diabetes: "inhibition of insulin-dependent glucose uptake, pancreatic β-cell damage, pancreatic β-cell dysfunction and stimulation of liver gluconeogenesis," also noting that genetic and epigenetic factors play a role (Martin et al. 2017). A review of laboratory studies on arsenic and diabetes finds that while several mechanisms may be involved, arsenic can affect glucose levels, glucose uptake by cells, insulin secretion, glucose metabolism in the liver, and both fat cell and pancreatic beta cell dysfunction. They note that many studies utilize high exposure levels, and that we need more studies on low levels-- although existing low level studies do show effects (Castriota et al. 2020). For an article about this review, see Arsenic Exposure and Glucose Metabolism: Experimental Studies Suggest Implications for Type 2 Diabetes, published in Environmental Health Perspectives (Konkel 2020). Another review describes the mechanisms by which arsenic acts on beta cells specifically (Carmean and Seino, 2019).
A review of early-life exposure to arsenic and the later development of diabetes finds that while there are no human studies on the topic, rodent studies show that this exposure could lead to an increased risk (Navas-Acien et al. 2019).
A review of arsenic and obesity finds that "Experimental studies provide some evidence that arsenic could play a role in obesity pathogenesis. To date, however, these associations have not been confirmed in human studies. In contrast, several epidemiologic studies have shown that the risks of arsenic-caused disease are markedly higher in obese individuals, highlighting obesity as an important susceptibility factor." (Eick and Steinmaus 2020).
A review and meta-analysis of 5 studies on cholesterol/triglyceride levels and arsenic found that arsenic exposure was associated with lower HDL cholesterol levels and higher LDL cholesterol levels (Zhao et al. 2021). Another review finds that arsenic exposure could contribute to metabolic syndrome (Pánico et al. 2022).
There are other reviews on arsenic and diabetes/obesity as well (e.g., Ro et al. 2022).
Groundwater Arsenic Levels, U.S.
Top: location and arsenic concentration of 31,350 USGS groundwater samples. Bottom: state-level requirements for private well testing, at what occasion, and whether arsenic is included.
Source: Zheng and Flannagan, 2017, EHP.
High Levels of Exposure: Human Studies
Numerous studies of people exposed to arsenic from Taiwan, Bangladesh, Mexico, Sweden, and other areas have shown that high levels of arsenic are associated with diabetes (Navas-Acien et al. 2006; Coronado-González et al. 2007; Del Razo et al. 2011; Currier et al. 2014; Idrees and Batool 2018; Rahman et al. 2019), including one long-term prospective study (Tseng et al. 2000). Arsenic levels are also associated with higher blood glucose levels, and sometimes with insulin resistance or lower beta cell function as well (Mondal et al. 2020). In a coal-burning area of China, residents with high levels of arsenic exposure had higher fasting blood glucose, risk of hyperglycemia, insulin resistance, and inflammation, and lower beta cell function than people who lived in areas with lower arsenic exposure levels (Liu et al. 2022).
Arsenic may interact with other environmental factors to influence the risk of diabetes. In Chile, in an an area of high exposure levels, the risk of arsenic-related diabetes is higher in people with lower socioeconomic status (Eick et al. 2019). Smoking also increases the risk of arsenic-related diabetes (Dai et al. 2020). Arsenic may interact with uranium to promote type 2 diabetes risk (Sanchez et al. 2021). See this article from NIEHS for more about that study: Arsenic, uranium mix may increase diabetes risk in American Indians.
Low Levels of Exposure: Human studies
The question scientists are now trying to answer is, do lower levels of arsenic exposure also play a role in diabetes? A number of recent studies have found that lower levels of arsenic exposure, including those found in certain parts of the U.S. and Canada, are also associated with diabetes (Navas-Acien et al. 2008; Kim and Lee 2011; Grau-Perez et al. 2018; Gribble et al. 2012; Islam et al. 2012; Lampron-Goulet et al. 2017; Mahram et al. 2013; Pan et al. 2013; Paul et al. 2019; Rhee et al. 2013, Jovanovic et al. 2013; Feseke et al. 2015; Fan et al. 2022; Arab YarMohammadi et al. 2021), including five long-term prospective studies (Grau-Perez et al. 2017; Kim et al. 2013; James et al. 2013; Bräuner et al. 2014; Wang et al. 2020).
In the U.S., arsenic is also associated with higher fasting glucose levels and higher insulin resistance in people without diabetes (Park et al. 2016; Zhou et al. 2022), and arsenic metabolism is associated with higher insulin resistance as well (Grau-Perez et al. 2017). For an article about the latter study, see Arsenic and Diabetes: Assessing Risk at Low-to-Moderate Exposures, published in Environmental Health Perspectives (Seltenrich 2018).
A study of young adults from the U.S., Ghana, South Africa, Jamaica, and the Seychelles also found higher fasting blood glucose levels in those with higher arsenic levels (Ettinger et al. 2014). A large study from Italy found that arsenic was associated with diabetes mortality in women (as well as other diseases) (D'Ippoliti et al. 2015). In Chile, the association between lifetime arsenic exposure and diabetes was strongest in those with a higher BMI (Castroita et al. 2018). In Mexican adults, higher arsenic levels were associated with a higher BMI and fasting glucose levels (Hernández-Mendoza et al. 2022).
In rural India, farmers did not have an increased risk of diabetes due to traditional risk factors such as body mass index, blood pressure and total cholesterol, but did have an increased risk of diabetes from exposure to heavy metals and arsenic. Arsenic was also associated with an increased risk of pre-diabetes and atherosclerosis (Velmurugan et al. 2018). These authors also found that arsenic and pesticides in combination might separately and synergistically together increase the risk of diabetes and atherosclerosis (Velmurugan et al. 2020). In Mexican-Americans in Texas, arsenic (and other metals) were associated with lower beta cell function, lower insulin resistance, lower insulin levels, and higher insulin sensitivity (Weiss et al. 2022).
While the clear majority of human studies studies have found associations between diabetes and lower level arsenic exposure, there are a few that have not (Chang et al. 2019; Chen et al. 2010; Li et al. 2013; Sripaoraya et al. 2017; Yang et al. 2019). One study of a U.S. Hispanic community who are exposed to arsenic via eating a lot of rice, but not through drinking water, did not find an association between arsenic and diabetes (although arsenic was linked to higher blood pressure) (Scannell Bryan et al. 2019).
Apparently a more efficient arsenic metabolism profile has been associated with reduced risk for some arsenic-related health outcomes, but an increased risk for diabetes-related outcomes. The mechanism behind these conflicting associations is unclear, but researchers are trying to figure out the explanation (Spratlen et al. 2018a; Spratlen 2018b). In New York City, while there was no evidence of an association of total urinary arsenic with prediabetes, diabetes, or HbA1c, the data suggest that a lower arsenic methylation capacity is associated with worse glycemic control and diabetes (Wu et al. 2021), which means that how a person's body processes (metabolizes) arsenic may be critical to the results of these studies. In any case, arsenic metabolism is linked to diabetes (Rangel-Morino et al. 2022) and insulin resistance (Li et al. 2021; Sarker et al. 2021).
Exposure During Development
There is growing evidence that exposure to arsenic during prenatal/early life can increase the risk of developing diseases like diabetes (as well as cancer, cardiovascular disease, and non-alcoholic fatty liver disease (NAFLD)) (Young et al. 2018). There are very few studies specifically looking at the long-term effects of arsenic exposure during development (although many of the people exposed in the studies described above were exposed in early as well as later life). One U.S. study found that maternal arsenic exposure levels were associated with the later development of diabetes in the offspring, 15-20 years later (Tinkelman et al. 2020).
A study examined arsenic exposure in pregnant Taiwanese women and found that it was associated with epigenetic changes in umbilical cord blood. The genetic sites that were affected were related to diabetes, LDL cholesterol levels, and cardiovascular disease. Whether these changes will lead to any of these health effects is unknown, but these changes may serve as markers of arsenic exposure in newborns (Kaushal et al. 2017).
Diabetes and Arsenic Podcasts
The Link Between Arsenic Exposure and Diabetes: A Review of the Current Research featuring presentations by Dr. Navas-Acien and Dr. Styblo, sponsored by The Collaborative on Health and the Environment (2014).
Exploring Links between Arsenic and Diabetes, an interview with Dr. Navas-Acien, via Environmental Health Perspectives (2012).
Arsenic and Obesity: A Compound Risk Factor for Diabetes? with Mirek Stýblo, via Environmental Health Perspectives (2019).
When you give a rat arsenic, they get high blood sugar. Specifically, adult rats exposed to low and high levels of arsenic for 4 weeks developed higher fasting blood glucose levels, impaired glucose tolerance, and higher HbA1c levels (a measurement of long-term blood glucose control), as compared to unexposed control rats (Patel and Kalia, 2013).
Numerous other laboratory studies also show that low level arsenic exposure produces effects in lab animals that are consistent with diabetes. For example, in mice, arsenic inhibits insulin secretion and disrupts beta cell function (Carmean et al. 2021; Kirkley et al. 2018). A study of the insulin-producing pancreatic beta cells of mice showed that arsenic inhibited insulin secretion. Arsenic, then, appears to target beta cells, and impair their ability to respond to glucose in the blood (Douillet et al. 2013). Arsenic can just impair insulin secretion from beta cells in general (Ahangarpour et al. 2017). When rats consumed drinking water from Antofagasta City, Chile, which contained both arsenic and lead, the males showed higher blood glucose levels after a glucose tolerance test than the rats who consumed purified water (Palacios et al. 2012). Interestingly, one study found that the glucose intolerance caused by arsenic appeared only after acute exposure, but not from chronic exposure (Rezaei et al. 2017). Arsenic causes not only high glucose levels in mice, but also reduces energy expenditure (He et al. 2022).
An interesting study of adult male mice found that a low-dose exposure caused glucose intolerance, by disrupting insulin secretion but without affecting insulin sensitivity. However, a higher-dose exposure had fewer effects on glucose tolerance despite disrupted insulin secretion, because the higher arsenic dose actually improved insulin sensitivity. These findings suggest that arsenic has opposite glycemic effects at different doses (Gong et al. 2019). In the rat liver, arsenic can cause insulin resistance (Wu et al. 2022).
Arsenic may influence diabetes development by a variety of mechanisms, including oxidative stress, inflammation, endocrine disruption, epigenetics, and beta cell dysfunction and apoptosis (Beck et al. 2018; Fu et al. 2010; Gribble et al. 2014; Liu et al. 2014; Navas-Acien et al. 2006; Tseng 2004), and more (Jochem et al. 2019). For more on the epigenetic effects of arsenic, see the article, Inner workings of arsenic: DNA methylation targets offer clues to mechanisms of toxicity, published in Environmental Health Perspectives (Konkel 2015; Argos et al. 2015). More recent publications have looked at the role of epigenetics in arsenic and diabetes in particular (Beck et al. 2017, Khan et al. 2017). Arsenic can also affect mitochondria, which can have implications for diabetes development (Kalo and Rezaei, 2022).
Arsenic's effects may also depend on the hormonal levels of the individual. Adult female mice exposed to arsenic developed high blood sugar and other signs of diabetes, especially when they had lower estrogen levels. Thus estrogen levels play an important role in arsenic-induced diabetes, with post-menopausal women likely at higher risk (Huang et al. 2015). There are also gene-arsenic interactions that may influence diabetes development (Balakrishnan et al. 2018). In mice, the effects of inorganic arsenic exposure on diabetes-related health effects, while overall relatively minor, depended on genetic background and dose (Douillet et al. 2021).
How Are We Exposed to Arsenic?
In the U.S., the main sources are arsenic exposure are food and water (Mantha et al. 2017). About 13 million Americans live where arsenic levels in public drinking water supplies exceed the EPA's standard (Navas-Acien et al. 2008). The main sources of arsenic in food are rice and chicken (Nachman et al. 2013).
Arsenic consumption can be a concern for people with celiac disease who eat a lot of rice-based products (Munera-Picazo et al. 2014). See How much arsenic is in your rice? by Consumer Reports (2014) for testing results. It is also a concern for people who live in areas of the world with naturally high arsenic levels and who have a rice-based diet, such as parts of South Asia (Hassan et al. 2017). Washing rice before cooking can reduce arsenic levels (Liu et al. 2018). Eating a variety of gluten-free grains might also help (Punshon and Jackson 2018).
Arsenic Can Affect Beta Cells
Rat pancreatic beta cells treated with arsenic showed impaired insulin synthesis and secretion (Díaz-Villaseñor et al. 2006), and suffer from increased apoptosis, that is, programmed cell death (Lu et al. 2011). Scientists are now trying to figure out how exactly arsenic kills beta cells (Pan et al. 2016; Yao et al. 2015; Zhu et al. 2014), affects insulin synthesis and secretion (Dover et al. 2018; Sun et al. 2018; Wu et al. 2018), causes beta cell dysfunction (Carmean et al. 2018; Khan et al. 2020; Wei et al. 2019), and what makes beta cells susceptible to arsenic (Cui et al. 2017). It appears, for example, that arsenic and its metabolites can both affect insulin secretion from beta cells (Huang et al. 2019; Li et al. 2020). Arsenic also affects gene expression in beta cells (Todero et al. 2022).
Zinc deficiency and arsenic, both alone and in combination, adversely affect pancreatic beta cells (Cao et al. 2019).
Researchers are also looking into substances that can protect beta cells from arsenic; taurine is one example (Pei et al. 2019). Taurine can also protect mice from arsenic-induced impaired glucose tolerance and insulin resistance (Yang et al. 2019).
Exposure During Development
Low level exposure to arsenic beginning in the womb and through adulthood causes high blood sugar, insulin resistance, and beta cell damage in rats (Dávila-Esqueda et al. 2011). In rats, developmental exposure to arsenic messed up their metabolism (Rivas-Santiago et al. 2019). Arsenic exposure in the womb and early life not only causes glucose intolerance in female rat pups, but also gestational diabetes in the mothers (see the Gestational Diabetes section below) (Bonaventura et al. 2017).
Arsenic exposure in the womb affected glucose tolerance and increased insulin resistance in offspring mice (Xu et al. 2022). In two different strains of mice, combined in utero and pre-conception exposure to arsenic caused insulin resistance in offspring (Fry et al. 2019). A follow-up study looked at pre-conception exposure alone, and found that in male offspring, insulin levels were higher (although blood glucose remained OK). Female offspring had more fat but lower blood glucose and insulin resistance than controls (Venkatratnam et al. 2020).
As seen in beta cells, zinc deficiency worsens the effects of arsenic exposure in developing embryos, effects that are related to the development of diabetes (Beaver et al. 2017). Another shows that folate/vitamin B12 supplementation during pregnancy may improve the impaired glucose metabolism caused by prenatal exposure to arsenic (Huang et al. 2018). (But note that folate can also worsen health effects of arsenic (Tseng et al. 2012).)
The exposure of male mice to inorganic arsenic causes glucose intolerance and insulin resistance in their female offspring, but not males, without affecting body weight. The offspring from grand-paternal arsenic exposure show temporary growth retardation at an early age, which diminishes in adults. However, reduced adiposity persists into middle age and is associated with altered gut microbiome and effects on brown fat tissue. In their (the fourth generation) offspring of the male-lineage, arsenic exposure caused increased fat, especially on a high-calorie diet (Gong et al. 2021). So interestingly, arsenic exposure to fathers has metabolic effects in multiple generations, and the effects are different in each generation.
If you expose roundworms to arsenic, they have higher glucose content in their bodies (and lower glucose metabolites), as do their offspring-- for the following six generations! (Gu et al. 2020). Who knows what this means for humans, but other chemicals show effects that can be transmitted down to following generations.
What Type of Diabetes Is It?
The most fascinating aspect of arsenic-induced diabetes is that it seems to be somewhat different than standard type 1 (autoimmune) or type 2 (insulin resistant) diabetes. Many of the human studies have found that arsenic exposure is indeed associated with diabetes, but surprisingly, not necessarily with insulin resistance (Del Razo et al. 2011; Gribble et al. 2012; Peng et al. 2015). Instead, it seems that arsenic exposure is instead linked to lower insulin secretion, not only in animals but also in humans (Rhee et al. 2013).
On the other hand, in a few studies, arsenic exposure has been linked to insulin resistance (e.g., Lin et al. 2014). A review finds that arsenic does have effects on fatty tissue and may play a role in obesity and insulin resistance (Renu et al. 2018).
So maybe it's a little bit of both types of diabetes? The effects of arsenic on the immune system aren't really clear (more on that below), so I'm not sure how much autoimmunity would play a role, however. So most authors call arsenic-induced diabetes type 2. Others just call it arsenic-induced diabetes.
Type 1 Diabetes
The SEARCH for Diabetes in Youth study, a U.S. based study found that arsenic metabolism was associated with type 1 diabetes in children. The association depended on folate levels-- those with high folate levels had a higher risk. Note that overall arsenic levels were not associated with type 1 or type 2 diabetes; only arsenic metabolism, and only with type 1 (Grau-Pérez et al. 2017). For a good article describing this study, see Could arsenic exposure contribute to type 1 diabetes in youths? published in Medscape.
In Canada, a study found that at the community level, those who had higher levels of arsenic (and fluoride) in their drinking water had higher rates of type 1 diabetes, although they did not find associations at the regional or provincial levels (Chafe et al. 2018).
Another interesting study of arsenic-exposed people from Mexico found that urinary arsenic metabolite levels were associated with genes that have known associations to diabetes. These genes are involved in both type 1 and type 2 diabetes and are involved in processes such as the destruction of pancreatic beta cells as well as insulin resistance (Bailey et al. 2013).
One study compared the levels of arsenic, cadmium, and lead in mothers with "insulin-dependent" diabetes and their infants, to mothers without diabetes and their infants. The researchers found that levels of all these metals were significantly higher in the women with diabetes and their infants than in the women without diabetes and their infants. The researchers suggest that these metals may play a role in the development of insulin-dependent diabetes (presumably type 1) (Kolachi et al. 2011).
In Floridians with long-standing type 1 diabetes, arsenic levels did not statistically differ from those without diabetes (levels of copper and other metals did differ; see the Heavy Metals page for info) (Squitti et al. 2019). As this study was cross-sectional, and the people had type 1 for an average of 25 years, it does not really say much about diabetes development.
Dr. Ana Navas-Acien of Columbia University has found that low levels of arsenic exposure, as you might find in the U.S., could contribute to diabetes development.
Exposure During Development: Type 1 Diabetes and Arsenic
A small Scandinavian study found that children who later developed type 1 diabetes had more often increased concentrations of arsenic in umbilical cord blood than the non-diabetic controls, as well as other heavy metals (although the association was not statistically significant) (Ludvigsson et al. 2019).
Laboratory Studies: Type 1 Diabetes and Arsenic
One animal study using non-obese diabetic mice (NOD mice) found that arsenic prevents the development of diabetes in these mice. Well, I'm not convinced that this is a meaningful study, since many other environmental factors prevent diabetes in NOD mice, including some that are associated with an increased risk in humans (see the Of Mice, Dogs, and Men page for further discussion on this point). And in contrast, another study shows that arsenic causes β-cell dysfunction in pancreatic tissue from NOD mice (Ramdas et al. 2018).
Arsenic and the Immune System: 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. Arsenic exposure during pregnancy has been found to affect the immune cells in the placenta and umbilical cord blood, via inflammation and oxidative stress. Prenatal exposure to arsenic, then, may affect the function of the immune system of the baby, and have consequences for diseases later in life (Ahmed et al. 2011). A study of prenatal exposure to arsenic from Mexico found that exposure was associated with genetic pathways related to diabetes as well as the immune system (Rager et al. 2014). Some of the same authors also found that childhood arsenic exposure was associated with immune system changes [also note that the arsenic metabolite linked to these changes, monomethylated arsenic, is the same one linked to type 1 diabetes in the study above] (Smeester et al. 2017). A similar study from the U.S. (New Hampshire) found that the mother's arsenic exposure levels were associated with immune system changes, notably an increase in one type of immune cells, CD8+ T-cells in their infants (Koestler et al. 2013) and another study found the same thing in cord blood (Kile et al. 2014). These T-cells are thought to be involved in beta cell destruction in type 1 diabetes. Another New Hampshire study found higher levels of inflammatory cytokines in the placenta of fetuses exposed to arsenic in the womb, implying that the fetal immune system may be altered by arsenic (Nadeau et al. 2014).
A review finds that arsenic can adversely affect the immune system, although its specific effects are still being worked out (Dangleben et al. 2013). A more recent review notes that while arsenic is often assumed to suppress the immune system, it has also been linked to autoimmune diseases, depending on dose and timing (Ferrario et al. 2016). Arsenic can also increase susceptibility to infections (Attreed et al. 2017) and may disrupt the body's ability to correctly respond to infections (Parvez et al. 2019). A review finds that arsenic can affect regulatory T cells, which are cells that help control the immune response. This could lead to increased infection, as well as autoimmune disease (Haque et al. 2017). Arsenic is also linked to changes in other T cells and inflammatory cells, which are also linked to autoimmunity (Lauer et al. 2019), including regulatory T cells, which help control autoimmunity (Ma et al. 2020).
In mice, prenatal arsenic exposure affects the immune system, making them more susceptible to infection (Chakraborty and Bhaumik, 2020).
Who Is Susceptible to Arsenic-Induced Diabetes?
Genetic Background and Arsenic Metabolism
Genetic background may play a role in the susceptibility of individuals to the effects of arsenic. Studies from areas of the world (e.g., Mexico, Bangladesh) with historically high levels of arsenic in drinking water, found that people who had certain genes are more likely to develop diabetes when exposed to arsenic (Drobná et al. 2013; Díaz-Villaseñor et al. 2013, Pan, Kile et al. 2013). In some cases, the genetic risk was dependent on arsenic exposure level, age, gender, and BMI, but not in other cases (Díaz-Villaseñor et al. 2013). In China, arsenic exposure levels were associated with higher blood glucose levels as well as other health effects, including high blood pressure. The blood pressure association also depended on genetic background (Gao et al. 2017). In a study of US adults, arsenic levels were associated with expression of an arsenic metabolism gene, implying that arsenic exposure levels may be involved in controlling the function of this gene (Gribble et al. 2014).
While genes (and patterns of gene expression) likely influence an individual's capacity to metabolize arsenic, other factors may also play a role. Individual differences in susceptibility to the effects of arsenic are often associated with different patterns of arsenic metabolism. Of a population in Mexico exposed to arsenic, those with diabetes have different metabolites in response to arsenic than those without diabetes (Martin et al. 2015). In the U.S., arsenic metabolism is also related to diabetes, and lower exposure levels (Kuo et al. 2015). A systematic review of the literature found that arsenic metabolism was associated with an increased risk of diabetes and metabolic syndrome (Kuo et al. 2017).
In China, more efficient arsenic metabolism (higher urinary DMA%) is associated with a higher risk of diabetes, especially in women, older people, and those with a lower BMI (Zhang et al. 2020).
Arsenic and the Gut
In U.S. infants, arsenic exposure levels are linked to the gut microbiome composition (Hoen et al. 2018), a factor linked to diabetes development.
The gut microbiome is involved in arsenic metabolism and pathways of arsenic-associated diseases (reviewed by Yang et al. 2021), including diabetes. By changing the composition of the gut microbiome in mice, researchers found that arsenic metabolite levels in urine also changed (Lu et al. 2013). The same laboratory found that arsenic exposure itself significantly disturbed the gut microbiome composition in mice. Whether or not this plays a role in diabetes remains to be seen, but this mechanism may help to explain some of the individual differences in susceptibility to the effects of arsenic (Lu et al. 2014). This new area of research, the evaluation of arsenic's ability to affect the gut and the gut's microbiome, will be interesting to follow. For an article about this lab's research, see Clues to arsenic's toxicity: Microbiome alterations in the mouse gut, published by Environmental Health Perspectives (Potera 2014).
Other authors have also found that arsenic exposure affects the gut microbiome of mice-- after a single or repeated exposure, and in both adult and juvenile animals-- as well as the immune system response (Gokulan et al. 2018). After 2 weeks of arsenic exposure at levels found in the environment, mice showed significant changes to the gut microbiome in ways associated with metabolism (Li et al. 2019). Long-term exposure also affects the gut microbiome in mice (Chen et al. 2021; Li et al. 2021). Studies on intestinal cells found that exposure to arsenic alters causes inflammation, oxidative stress, loss of microvilli, and reduces levels of proteins that help maintain intestinal barrier, leading to the loss of the gut barrier function (Chiocchetti et al. 2018;Chiocchetti et al. 2019a; Chiocchetti et al. 2019b). These authors also found that in mice, exposure to arsenic in drinking water led to changes in intestinal microbiota, gut inflammation, oxidative stress, and changes linked to increased gut permeability (Chiocchetti et al. 2019c). In zebrafish larvae, arsenic alters the microbiome as well (Dahan et al. 2018). Zinc deficiency also increases the effects of arsenic on gut microbial diversity (Gaulke et al. 2018), and interacts with arsenic to promote inflammation and oxidative stress (Wong et al. 2019).
Exposure to arsenic during development affects the gut microbiota and increases gut permeability as well (Chakraborty et al. 2022).
Further research shows that changes to the gut microbiome, in addition to increasing the toxicity of arsenic (Chi et al. 2019; Coryell et al. 2018; Coryell et al. 2019), may affect metabolism (Xue et al. 2019). Gut microbiota (as affected by antibiotics) play a role in the toxic effects of arsenic. Specifically, arsenic exposure exerted opposite effects on cholesterol levels in mice treated with antibiotics vs not treated, i.e., arsenic led to higher cholesterol levels in untreated mice but lower levels in antibiotic-treated mice, as compared to respective unexposed controls. Triglyceride levels were higher in untreated mice exposed to arsenic, while arsenic exposure did not significantly affect triglyceride levels in antibiotic-treated mice (Chi et al. 2019).
The gut microbiome variability among individuals could play a significant role in determining the fate, mobility and toxicity of arsenic in the body (McDermott et al. 2019). In human studies, high arsenic levels in drinking water are associated with changes to the gut microbiome in individuals (Brabec et al. 2020). Exposure to arsenic and other chemicals interact with nutrients as well as with antibiotics to influence the gut microbiome in infants as well (Laue et al. 2020).
Arsenic also has other effects on the gut, including on certain intestinal cells (Kellett et al. 2022). Inorganic arsenic and hexavalent chromium exposure reduced beneficial gut bacteria and increased harmful gut bacteria, impaired gut barrier structure, enhanced adipogenesis and reduced thermogenesis in brown adipose tissue, and caused inflammation (Singh et al. 2022). There are other studies on arsenic and the gut as well (Calatayud et al. 2022).
Another factor that may affect an individual's susceptibility to the diabetogenic effects of arsenic is vitamin D levels. In a study of the general Korean adult population, people with the lowest vitamin D levels and the highest arsenic arsenic levels had about a 300% increased risk of diabetes, as compared to people with the highest vitamin D and lowest arsenic levels (Lee and Kim 2013).
Folate levels affect arsenic metabolism. For example, a human trial showed that supplementation with folic acid affect arsenic metabolite levels (Bozack et al. 2019).
Body Weight and Metabolic Syndrome
Researchers are just beginning to examine whether or not arsenic exposure is linked to weight. One study of U.S. adults found that higher levels of urinary arsenic metabolites were associated with a higher body mass index (BMI) (Gribble et al. 2013). The authors suggest that future studies of arsenic should consider BMI as a potential modifier of arsenic-related health effects. Another US study, however, found that BMI was not associated with arsenic (Bulka et al. 2017). An another found generally that those with higher arsenic exposure levels had a lower BMI (Warwick et al. 2021). A Mexican study found that BMI was associated with lower levels of inorganic arsenic and monomethylated arsenic (MMA), and positively associated with dimethylated arsenic (DMA). Unlike previous studies, this association was not affected by the intake of certain micronutrients like folate (Bommarito et al. 2018). In U.S. middle-aged women, arsenic was associated with an increased risk of metabolic syndrome (Wang et al. 2022). In the U.S., those with higher arsenic and arsenic metabolite exposure levels had higher LDL cholesterol levels (Qu and Huang 2022).
In a study of Taiwanese adolescents, the higher the BMI, the lower the urinary arsenic, in individuals with no obvious sources of arsenic exposure. The authors conclude that obese children may retain higher levels of arsenic in the body, as compared to normal weight children (Su et al. 2012). Lin et al. (2014), on the other hand, found higher BMI with higher arsenic levels in Taiwanese adolescents; how well the liver detoxified arsenic seemed to be critical.
In Bangladeshi adults and adolescents, various arsenic methylation levels were variously associated with BMI, depending on sex and choline levels (Abuawad et al. 2021).
In a study of Bangladeshi infants/children, exposed to high levels of arsenic, postnatal arsenic exposure was associated with lower body weight and length among girls at age 2 (Saha et al. 2012). In New Hampshire, maternal arsenic levels were associated with higher levels of the hormone leptin in umbilical cord blood-- leptin can influence body weight and metabolism in adults, and this could be a way that arsenic may influence childhood growth (Gossai et al. 2015). In young Canadian children, with low exposure levels, arsenic was not associated with body weight measures (Ashley-Martin et al. 2019).
Arsenic exposure is also associated with metabolic syndrome, a group of conditions associated with type 2 diabetes (Chen et al. 2012). Koreans with metabolic syndrome had higher levels of arsenic (and lead) in their hair than those without metabolic syndrome (Choi et al. 2014). Young adults with higher arsenic levels have lower HDL cholesterol levels (the "good" cholesterol). (Ettinger et al. 2014). A U.S. study found no association between arsenic methylation and metabolic syndrome, except possibly in women of normal weight (Pace et al. 2018). In a long-term study of American Indians, arsenic levels were associated with higher fasting glucose levels, but not other components of the metabolic syndrome. Arsenic metabolism, however, was associated with higher waist circumference and higher risk of metabolic syndrome overall (Spratlen et al. 2018). In Iran, arsenic metabolism was also associated with metabolic syndrome (Kazemifar et al. 2020).
In people with moderate levels of arsenic exposure, arsenic is associated with diabetes as well as high triglycerides and high total cholesterol (however, HDL, the "good" cholesterol, was also higher in those with higher arsenic exposures) (Mendez et al. 2016). In China, adults with higher arsenic levels had a higher risk of dyslipidemia (i.e., poor cholesterol/triglyceride levels) (Luo et al. 2022).
In Arkansas, higher arsenic levels were linked to an increased risk of obesity in post-menopausal (not pre-menopausal) women (Stahr et al. 2021).
As with diabetes, the risk of obesity related to arsenic may be related to genetic background (Martínez-Barquero et al. 2015).
In Serbian women, higher levels of arsenic were associated with higher insulin levels (Đukić-Ćosić et al. 2022).
Exposure During Development: Humans
A long-term Spanish study of 27 different endocrine disrupting chemicals found that in utero levels of various persistent organic pollutants were associated with overweight/higher BMI at age 7, while other chemical levels (arsenic, BPA, phthalates, flame retardants, lead, and cadmium) were not associated (Agay-Shay et al. 2015).
A study from New Hampshire found that arsenic levels are linked to height (length) in infancy, although not body weight (Muse et al. 2019).
A large European study found no association between prenatal or childhood arsenic exposure levels and childhood BMI (Vrijheid et al. 2020).
According to a systematic review and meta-analysis of 12 studies, arsenic levels during pregnancy are associated with lower birth weight babies, especially in the Americas (Zhong et al. 2019). Prenatal arsenic exposure is also associated with lower birth weight at levels that Americans are commonly exposed to (Claus Henn et al. 2016). (Low birth weight is associated with later type 2 diabetes). Third trimester arsenic exposure levels appear to be more important than first or second trimester levels in this association (Liu et al. 2018).
Laboratory Studies: Body Weight
Paul et al. (2011) fed rats a high or low fat diet, in combination with low levels of arsenic. The mice that were only fed a high fat diet (and no arsenic) were fatter, more insulin resistant, and had a higher fasting blood glucose than those fed a low fat diet (and no arsenic). But, those fed a high fat diet plus arsenic showed worse glucose intolerance after a glucose tolerance test than those fed no arsenic. It seems that arsenic acts in tandem with a high fat diet and obesity to promote glucose intolerance, but that the mechanisms of arsenic may differ from diabetes induced by obesity alone. In other words, arsenic may promote diabetes in ways that are not typically associated with type 2 diabetes. For an article describing this study, see A different diabetes: Arsenic plus high-fat diet yields an unusual diabetes phenotype in mice, published in Environmental Health Perspectives. (Barrett 2011). A high-fat diet may worsen the effects of arsenic on the liver, and just increase sensitivity to arsenic in general (Hou et al. 2017). Arsenic can also have other effects on the liver, by depleting glycogen stores (Zhang et al. 2017), or by causing liver insulin resistance (Jia et al. 2020). Additional animal studies have also found interactions between arsenic and a high-fat diet. For example, in mice, exposure to arsenic plus a high fat diet impaired glucose tolerance and insulin secretion (Ahangarpour et al. 2018).
A study of mice found that arsenic exposure leads to insulin resistance and higher body mass, and that the level of impairment depends on sex and the level of exposure to inorganic arsenic (Douillet et al. 2017). Rats exposed to arsenic in drinking water for 3 months developed lower "good" HDL cholesterol levels, and higher "bad" LDL cholesterol and triglycerides (Waghe et al. 2017).
A mouse study found that arsenic exposure led to lower levels of adiponectin (a hormone involved in glucose and metabolism), triglycerides, and HDL cholesterol, although not insulin or glucose levels (Song et al. 2017). However, a different mouse study found that arsenic (plus a high fat diet) increased adiponectin levels and decreased lipid levels, and increased leptin levels (another hormone involved in metabolism) (Ahangarpour et al. 2018). Arsenic can impair the development (differentiation) of fat cells and thereby affect metabolism (Beezhold et al. 2017). In mice, arsenic exposure induced cold intolerance and impaired the expression of genes related to fat cell differentiation in brown adipose tissue (Zuo et al. 2019).
A mouse study found that arsenic exposure altered lipid metabolism, carbohydrate metabolism, and energy metabolism, but had higher influence on metabolic profiles of mice with diabetes than mice without diabetes (Yin et al. 2017).
A review of the effects of arsenic on white fat tissue and fat cells suggests that arsenic could be a potential obesogen (Ceja-Galicia et al. 2017). Arsenic can also affect the function of brown fat tissue (Bae et al. 2019). Other studies, however, found that arsenic can lead to lower weight (Carmean et al. 2020). The specific effects may depend on dosage.
In mice, arsenic exposure affects the generation of body heat in cold temperatures. These mice also had increased total fat mass and white fat tissue (Castriota et al. 2020).
In wild-type mice, exposure to inorganic arsenic in drinking water resulted in insulin resistance in mice only when combined with a high-fat diet and low folate intake (Huang et al. 2018). For an article describing this study, see A Complex Relationship: Dietary Folate, Arsenic Metabolism, and Insulin Resistance in Mice, published in Environmental Health Perspectives (Schmidt 2019).
Laboratory Studies: Body Weight and Exposure During Development
Mice exposed to arsenic during development (in the womb and after weaning), and fed a Western diet, grew up with exacerbated fatty liver disease, increased body weight, insulin resistance, high blood sugar, and high triglycerides, as compared to those only fed a Western diet. Developmental exposure to arsenic in combination with a high fat diet may increase the risk of metabolic disease later in life (Ditzel et al. 2016) The study attempted to determine which time period the mice were most susceptible to the exposure-- pre-natal exposure only, pre- and post-natal, or post-natal. The mice with both pre- and post- natal arsenic exposure suffered the most severe effects, and those in the pre-natal exposure group had more severe effects than the post-natal exposure group. The effects of arsenic exposure included impaired glucose control, increased insulin resistance, increased obesity, and increased triglycerides. For an article on this study, see Arsenic exposure and the Western diet: a recipe for metabolic disorders? published in Environmental Health Perspectives (Barrett 2016).
Mice exposed to low levels of arsenic during the time that organs develop in the womb had higher body weight gain, higher body fat, and glucose intolerance in adulthood (Rodriguez et al. 2016). Male offspring mice exposed to arsenic in utero had increased body weight from birth through 5 months of age, as well as glucose intolerance (Rodriguez et al. 2020).
Developmental exposure to arsenic, BPA, or their combination, induced metabolic disruption in male mice offspring, and the combined exposure exacerbated the metabolic changes induced by either BPA or arsenic alone. The combined exposure influenced both glucose tolerance and insulin tolerance, and affected the expression of genes involved in lipid and glucose metabolism (Wang et al. 2018).
Arsenic in the Womb and Later Glucose Intolerance
Mice exposed to arsenic in the womb had higher body weight, and higher leptin and insulin levels as adults, compared to unexposed control mice.
There is also evidence that arsenic exposure may increase the risk of gestational diabetes. A meta-analysis of 9 studies on this topic found an overall increased risk of gestational diabetes with higher arsenic levels, although there were variations among studies (Salmeri et al. 2020).
U.S. pregnant women who had higher arsenic levels also had higher blood glucose levels after a glucose tolerance test. This finding implies that arsenic may impair glucose tolerance, and may be associated with an increased risk of gestational diabetes. The women in this study lived near a hazardous waste site (the Tar Creek Superfund Site in Oklahoma), and had arsenic levels higher than those in unexposed people, but their exposures were still "relatively low" (Ettinger et al. 2009). For an article on this study, see Mother load: arsenic may contribute to gestational diabetes, published in Environmental Health Perspectives (Barrett 2009).
A study from New Hampshire (which has relatively high arsenic levels in well water) found that arsenic exposure was associated with the development of gestational diabetes, especially in obese women (Farzan et al. 2016). A study from France showed similar findings in that higher arsenic levels in drinking water was associated with an increased risk of gestational diabetes in overweight and obese women (Marie et al. 2018).
A study from Canada found that of women in the general population, those with higher levels of arsenic in their bodies in the first trimester had a higher risk of gestational diabetes (BPA, phthalates, lead, cadmium, and mercury were not associated with gestational diabetes) (Shapiro et al. 2015). Canadian women with higher levels of an arsenic metabolite were more likely to have gestational diabetes, especially women carrying male fetuses (Ashley-Martin et al. 2018).
Arsenic is Associated with Impaired Glucose Tolerance in Women
Increased arsenic exposure is associated with higher blood glucose levels and impaired glucose tolerance in pregnant women. The solid line shows the risk, and the dashed lines are 95% confidence intervals.
A study of Chinese women found that the infants of those with gestational diabetes had higher levels of arsenic, cadmium, and chromium in their meconium than those whose mothers did not have gestational diabetes. These metals were associated with gestational diabetes in a dose-dependent manner, with arsenic most strongly associated (Peng et al. 2015). Additional studies from China found that arsenic levels were associated with gestational diabetes (Wang X et al. 2020; Wang Y et al. 2019; Xia et al. 2018). One study from China found that the relationship depends on the type of arsenic, as well as vitamin levels. Pregnant women with higher urinary arsenite (As3+) (inorganic) and total arsenic with lower serum vitamin B12 were more likely to have a higher risk of gestational diabetes. There was also a positive relationship between urinary arsenite and gestational diabetes, but a negative relationship between arsenate (As5+) (also inorganic) and gestational diabetes (i.e., a lower risk with arsenate-- in general arsenite is considered more toxic than arsenate) (Zhang et al. 2021).
A study from Chile found women with higher inorganic arsenic levels did not have a higher risk of gestational diabetes (Muñoz et al. 2018). But, other studies also found this but then found that women with gestational diabetes may have less ability to detoxify arsenic, so the total arsenic level may not be the key thing to measure, but instead methylated arsenic (Chen et al. 2021).
In Bangladesh, although arsenic exposure during pregnancy has been consistently associated with gestational diabetes, a study found no clear evidence for an adverse effect on postpartum insulin resistance or beta cell function (Fleisch et al. 2022).
Laboratory Studies: Gestational Diabetes
In laboratory animals, arsenic exposure during pregnancy alters beta cell function and blood glucose levels, increasing the risk of gestational diabetes (as well as causing glucose intolerance in the female pups) (Bonaventura et al. 2017).
Diabetes Management and Complications
What if you have diabetes, and you are exposed to arsenic? Can arsenic affect the progression of the disease, and the eventual development of diabetes complications? Perhaps. One systematic review of this topic found that yes, markers of diabetes complications were indeed associated with arsenic exposure levels (Andra et al. 2013).
Blood Glucose Control
Arsenic exposure is also associated with albuminuria (protein in the urine), a sign of kidney disease and common complication of diabetes (Zheng et al. 2013); a systematic review found that there is some evidence linking arsenic exposure to kidney disease (Zheng et al. 2014). In a group of American Indians, arsenic levels were associated with kidney disease (Zheng et al. 2015). A nation-wide study from Taiwan also found arsenic exposure associated with kidney failure (ESRD, end stage renal disease) (Cheng et al. 2018). Arsenic levels are also high in people undergoing kidney dialysis (Xiang et al. 2019). However, a study from Croatia found that albuminuria levels were lower in people with higher levels of arsenic (although HbA1c levels were higher) (Lucio et al. 2020).
In Chinese older adults with diabetes, arsenic (and vanadium) were associated with an increased risk of chronic kidney disease, separately and in a mixture. The metals mixture showed a linear dose-response association with the odds of kidney disease (Zhou et al. 2021).
The Effects of Developmental Exposure to Arsenic
Developmental exposure to arsenic followed by a Western diet leads to all sorts of problems in mice, including higher glucose levels and insulin resistance, liver damage and fatty liver disease, and more.
High Blood Pressure
Arsenic exposure has been linked to hypertension (high blood pressure) in cross-sectional (Hossain et al. 2017; Mahram et al. 2013; Wei et al. 2017) and longitudinal (Farzan et al. 2015; Hall et al. 2017; Jiang et al. 2015; Zhong et al. 2018) studies (the mechanisms involved are reviewed by da Cunha Martins et al. 2018). (For an article on the Jiang longitudinal study, see Arsenic and Blood Pressure: A Long-Term Relationship, published in Environmental Health Perspectives (Seltenrich 2015)). Exposure to higher levels of arsenic in early life and in adolescence was associated with higher blood pressure in Bangladeshi teens (Chen et al. 2019).
A meta-analysis of 12 studies found a dose-response relationship between low to high arsenic exposure levels and cardiovascular disease (Moon et al. 2017). A review finds that low to moderate arsenic exposure levels are linked to cardiovascular disease, in addition to high levels (Kononenko and Frishman, 2020). Developmental exposure may also be a concern; early-life exposure to arsenic may increase cardiovascular risk even by adolescence (Kuo et al. 2018).
And, in a longitudinal study, low-to-moderate levels of arsenic exposure were associated with cardiovascular disease (Moon et al. 2013) and cartoid intima media thickness (CIMT), a measure of vascular disease (Mateen et al. 2017). A follow up study looked specifically at those with diabetes, to help figure out the mechanisms involved (Moon et al. 2017). In New Hampshire adults, arsenic levels were associated with biomarkers of cardiovascular disease and inflammation (Farzan et al. 2017). The link between cardiovascular disease and arsenic is also related to genetic background (Hsieh et al. 2011; Wu et al. 2015)-- some populations do not seem to be susceptible (Ameer et al. 2015). Other studies have also found links between arsenic and cholesterol or other cardiovascular complications (Harmon et al. 2018). It appears that high blood sugar levels may increase the cardiovascular effects of arsenic, giving people exposed to both a double whammy (Newman et al. 2017).
Arsenic is linked to coronary heart disease specifically as well (Yuan et al. 2017). For an article about this study, see "Assessing a Medley of Metals: Combined Exposures and Incident Coronary Heart Disease, published in Environmental Health Perspectives (Konkel 2018).
A metabolite of arsenic is linked to stroke, in a study from the U.S. (Tsinovoi et al. 2018).
Arsenic is also linked to cancer, and people who had higher levels of obesity in early adulthood and later life had a higher risk of arsenic-related cancer (Steinmaus et al. 2015).
Arsenic exposure is associated with increased non-alcoholic fatty liver disease (NAFLD) in US teens and adults, especially those who are obese, and especially in Mexican-Americans (Frediani et al. 2018).
Arsenic causes glucose intolerance and liver damage in mice, and betaine prevents these effects (Esfahani et al. 2022).
Metformin May be Protective
Interestingly, the diabetes drug metformin protects liver cells from the toxic effects of the chemotherapy drug arsenic trioxide (Trisenox) (Ling et al. 2017), as well as from the effects of regular arsenic on both liver and beta cells (Ahangarpour et al. 2017). Metformin also protects against the cardiovascular effects of arsenic in rats (Wang et al. 2019). Metformin and berberine both protect against the arsenic-induced diabetes-related oxidative stress in lab studies (Javadipour et al. 2019; Rezaei et al. 2018).
Laboratory Studies: Diabetes Complications
In animals, mice with diabetes are more susceptible to the effects of arsenic than those without diabetes (Yin et al. 2017). In rats with diabetes, arsenic aggravates liver damage (Souza et al. 2018). In zebrafish, arsenic exposure during development causes fatty liver disease and can also interact with alcohol to cause liver disease (Bambino et al. 2018). And, having type 1 diabetes increases the uptake of arsenic in certain tissues in mice (Wei et al. 2018).
While either arsenic exposure or diabetes can impact kidney function, their combined impact is unclear. Using a rat model of type 1 diabetes, a study found that aside from intensifying glycogen nephrosis, the kidney could handle arsenic toxicity (Sertorio et al. 2019).
In male rats with diabetes, arsenic exposure lowered testosterone levels, lowered sperm production, and caused additional damage to the reproductive system (Souza et al. 2019).