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Arsenic


Arsenic and diabetes/obesity

Summary

Links Between Arsenic and Diabetes/Obesity

The Details

Reviews of Arsenic and Diabetes/Obesity



Summary

Links Between Arsenic and Diabetes/Obesity

Over 300 peer-reviewed studies published since 2006 in scientific journals have examined the relationship between arsenic and diabetes or 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.


The Details

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).

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). 

Diabetes

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), including one long-term prospective study (Tseng et al. 2000). A meta-analysis of data from 17 published articles 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)" (Maull et al. 2012). (In science-speak, that is actually pretty strong evidence).

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).

Low Levels of Exposure: Human studies

Groundwater Arsenic Levels, U.S.

arsenic in groundwater, USA

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.
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. 2018Gribble et al. 2012; Islam et al. 2012Lampron-Goulet et al. 2017Mahram et al. 2013; Pan et al. 2013; Paul et al. 2019Rhee et al. 2013, Jovanovic et al. 2013; Feseke et al. 2015), including four long-term prospective studies (Grau-Perez et al. 2017Kim et al. 2013; James et al. 2013; Bräuner et al. 2014). 

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), 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).

A study from rural India (mostly of farmers, who can be exposed to metals in fertilizers), found no association between diabetes and traditional risk factors such as body mass index, blood pressure and total cholesterol, but did find associations between diabetes and heavy metals, including arsenic. Arsenic was also associated with pre-diabetes and atherosclerosis (Velmurugan et al. 2018).

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 (Chen et al. 2010; Li et al. 2013Sripaoraya 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).

The National Toxicology Program 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" (Maull et al. 2012).

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).

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 study examined arsenic exposure in pregnant 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).

In U.S. infants, arsenic exposure levels are linked to the gut microbiome composition (Hoen et al. 2018), a factor linked to diabetes development.

Laboratory Studies: Arsenic Can Affect Beta Cells

How Are We Exposed to Arsenic?

rice

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). 

Formula-fed babies have higher levels of arsenic exposure than breastfed babies, due to both arsenic in formula powder and in well water (Schmidt 2015; Carignan et al. 2015).
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 (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).

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. 2018Wu et al. 2018), causes beta cell dysfunction (Carmean et al. 2018), and what makes beta cells susceptible to arsenic (Cui et al. 2017). They 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).

The National Toxicology Program review concluded 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). 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's effects may also depend on the hormonal levels of the individual. In human studies, adult women have higher levels of diabetes in areas with high levels of arsenic in drinking water. 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).

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).

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). Arsenic exposure in the womb and early life causes glucose intolerance in female pups (as well as gestational diabetes in the mothers; see the Gestational Diabetes section below) (Bonaventura et al. 2017). As with other environmental chemical exposures, the timing of exposure may be significant. Most studies of arsenic and diabetes have thus far been on adults, and so the effect of early life arsenic exposure is still relatively unknown.

One laboratory study finds that 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). (Note, however, that folate can also worsen health effects of arsenic (Tseng et al. 2012).

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 and Arsenic?

Dr. Navas-Acien

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.

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).

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

Arsenic Exposure Can Affect Gene Expression

arsenic and gene expression

At very low (A) and higher (B) doses, arsenic exposure can increase (red) or decrease (green) gene expression. Many of these genes are related to the immune system.
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). Another 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). 

Who Is Susceptible to Arsenic-Induced Diabetes?

Arsenic Exposure Affects the Gut Microbiota

arsenic and the gut
 
Arsenic exposure disturbed the gut microbiome in mice, increasing some microbiota metabolites (green) and decreasing others (red).
Sources: Mouse ©The Jackson Laboratory; Scatterplot from Lu et al. 2014, EHP; figure from Potera 2014, EHP.
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).

Folate levels affect arsenic metabolism. For example, a human trial showed that supplementation with folic acid affect arsenic metabolite levels (Bozack et al. 2019).

In addition, the gut microbiome is involved in arsenic metabolism and pathways of arsenic-associated diseases, 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). 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), may affect metabolism (Xue et al. 2019).

Other authors have found that arsenic exposure itself 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). Studies on intestinal cells found that exposure to arsenic alters causes inflammation and loss of microvilli, and reduces the intestinal barrier (Chiocchetti et al. 2018; Chiocchetti et al. 2019). 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). 

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). In addition, vitamin B levels may also be related to arsenic metabolism, in more well-nourished populations exposed to low levels of arsenic, as in the U.S. (Spratlen et al. 2017).

Body Weight and Metabolic Syndrome

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, sponsored by Environmental Health Perspectives (2012).
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). 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 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 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).

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).

As with diabetes, the risk of obesity related to arsenic may be related to genetic background (Martínez-Barquero et al. 2015).

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).

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

More Information on Arsenic

Factsheet on arsenic from the National Institute of Environmental Health Sciences (NIEHS).

Arsenic and You website, with information on how to lower your exposure to arsenic.
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). Another study found that 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). 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). 

Another 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).

An additional 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).

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).

Realgar, an arsenic compound used in traditional Chinese medicine, caused abnormal blood glucose levels in rats (Yi et al. 2018).

Taurine, found in fish and meat, helped ameliorate arsenic-induced insulin resistance in mice (Gao et al. 2018).

Exposure During Development: Animals

Arsenic in the Womb and Later Glucose Intolerance

arsenic in utero

Mice exposed to arsenic in the womb had higher body weight, and higher leptin and insulin levels as adults, compared to unexposed control mice.
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).

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).

Gestational Diabetes

Arsenic is Associated with Impaired Glucose Tolerance in Women

arsenic and gestational diabetes
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.
There is also evidence that arsenic exposure may increase the risk of gestational diabetes. A U.S. study has found that 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).

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). Another study from China found that arsenic levels were associated with gestational diabetes (Xia et al. 2018). However, a study from Chile found women with higher arsenic levels did not have a higher risk of gestational diabetes (Muñoz et al. 2018).

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

The Effects of Developmental Exposure to Arsenic

developmental arsenic exposure

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.
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). A study from rural US communities found that in people with diabetes, arsenic was associated with poorer average blood glucose control (a higher HbA1c) (Gribble et al. 2012). 

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).

Arsenic exposure has been linked to hypertension (high blood pressure) in cross-sectional (Hossain et al. 2017Mahram et al. 2013; Wei et al. 2017) and longitudinal (Farzan et al. 2015; Hall et al. 2017Jiang 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)). 

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 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 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 meta-analysis of 12 studies found a dose-response relationship between low to high arsenic exposure levels and cardiovascular disease (Moon et al. 2017). Developmental exposure may also be a concern; early-life exposure to arsenic may increase cardiovascular risk even by adolescence (Kuo et al. 2018).

A metabolite of arsenic is linked to stroke, in a study from the U.S. (Tsinovoi et al. 2018).

Arsenic exposure is linked to peripheral neuropathy as well (Chatterjee et al. 2018; Mochizuki et al. 2019).

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). 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 as well as berberine both protect against the arsenic-induced diabetes-related oxidative stress in lab studies (Rezaei et al. 2018).

Diabetes Complications: Laboratory Studies

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).

References

To download or see a list of all the references cited on this page, see the collection Arsenic and diabetes/obesity in PubMed.