Coordinator, CHE’s Diabetes – Obesity Spectrum Working Group
This essay is reprinted with the author’s permission from her website: Diabetes and the Environment. See also CHE’s March 11th Partnership call: The Link Between Arsenic Exposure and Diabetes: A Review of the Current Research
Arsenic can be found naturally in drinking water. Millions of people worldwide rely on drinking water sources containing arsenic; in the U.S., about 13 million people live where arsenic levels in public drinking water supplies exceed the U.S. Environmental Protection Agency’s standard (Navas-Acien et al. 2008). In 2001, the US EPA lowered the drinking water standard for arsenic from 50 µg/L to 10 µg/L (10 ppb) (EPA). Arsenic has also been found in food, such as rice and conventional chicken (Nachman et al. 2013).
High Levels of Exposure: Human Studies
Numerous studies of people exposed to arsenic from Taiwan, Bangladesh, Mexico, and Sweden have shown that high levels of arsenic are associated with diabetes (Navas-Acien et al. 2006; Coronado-Gonzalez 2007; Del Razo et al. 2011), 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).
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., are also associated with diabetes (Navas-Acien et al. 2008; Kim and Lee 2011; Gribble et al. 2012; Islam et al. 2012; Mahram et al. 2013; Pan et al. 2013; Rhee et al. 2013), including two long-term prospective studies (Kim et al. 2013; James et al. 2013).
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).
Laboratory studies show that low level exposure produces effects in lab animals that are consistent with diabetes. For example, a laboratory study of the insulin-producing pancreatic beta cells of mice showed that arsenic inhibited glucose-stimulated insulin secretion (GSIS). Arsenic, then, appears to target beta cells, and impair their ability to respond to glucose in the blood (Douillet et al. 2013). 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).
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).
Low level exposure to arsenic beginning in the womb and through adulthood causes high blood sugar, insulin resistance, and beta cell damage in rats (Davila-Esqueda et al. 2011). 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.
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 (Tseng 2004; Navas-Acien et al. 2006; Fu et al. 2010; Gribble et al. 2014).
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 with insulin resistance (Del Razo et al. 2011; Gribble et al. 2012). 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).
An 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 and insulin resistance (altered insulin signalling) (Bailey et al. 2013).
Usually arsenic-induced diabetes is assumed to be type 2 diabetes, but scientists are questioning this assumption. That is because arsenic-induced diabetes does not appear to involve insulin resistance, which is typically associated with type 2 diabetes. Arsenic-induced diabetes is usually studied in adults, which is probably why it assumed to be type 2. We do not know if arsenic plays a role in type 1 diabetes. Beta cell destruction and lower insulin secretion, both associated with arsenic exposure, are also involved in type 1 diabetes. I wonder if arsenic exposure might help to explain why some people with diabetes who do not have signs of either insulin resistance or autoimmunity (e.g., see Dabelea et al. 2011). That is, I wonder if arsenic may just cause the beta cells to malfunction, without involving an autoimmune reaction at all.
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 diabetes (Kolachi et al. 2010). I have tried to confirm with the authors that this “insulin-dependent” diabetes was truly type 1 diabetes, but have not heard.
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. 2010). A study of prenatal exposure to arsenic found that exposure was associated with genetic pathways related to diabetes as well as the immune system (Rager et al. 2013).
Who Is Susceptible to Arsenic-induced Diabetes?
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 (Drobna et al. 2012; Diaz-Villasenor et al. 2013, Pan et al. 2013). In some cases, the genetic risk was dependent on arsenic exposure level, age, gender, and BMI, but not in other cases (Diaz-Villasenor et al. 2013).
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. For example, 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.
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).
Body Weight, BMI, and Metabolic Syndrome
Researchers are just beginning to examine whether or not arsenic exposure is linked to weight. One study of US 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. 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 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). (It is not entirely surprising that these studies showed varying results; chemical exposures can have different effects at different levels of exposures).
Arsenic exposure is also associated with metabolic syndrome, a group of conditions associated with type 2 diabetes (Chen et al. 2012).
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 for 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, by Julia Barrett, published in Environmental Health Perspectives.
There is also evidence that arsenic exposure may increase the risk of gestational diabetes. A 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, and had arsenic levels higher than those in unexposed people, but their exposures were still “relatively low” (Ettinger et al. 2009).
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). In addition, arsenic exposure was also associated with albuminuria (protein in the urine), a sign of kidney disease and common complication of diabetes (Zheng et al. 2013).
The Bottom Line
There is good evidence that high levels of arsenic can contribute to the development of diabetes. The effects of lower levels of arsenic exposure are not clear, although newer studies suggest that lower exposures could be involved in diabetes as well. Arsenic may also affect the progression of diabetes and complications associated with it. While arsenic-induced diabetes is usually considered to be type 2 diabetes, it actually seems that it may be different, since arsenic exposure is not usually associated with insulin resistance. Arsenic may act via atypical mechanisms to promote diabetes, and beta cell dysfunction is likely the most important mechanism in arsenic-induced diabetes (as opposed to more typical insulin resistance or autoimmune mechanisms).