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Arsenic

Arsenic and diabetes/obesity
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There is very good evidence that high levels of arsenic can contribute to the development of diabetes in humans. 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).

Diabetes

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-González et al. 2007; Del Razo et al. 2011; Currier et al. 2014), 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. and Canada, are also associated with diabetes (Navas-Acien et al. 2008; Kim and Lee 2011; Gribble et al. 2012; Islam et al. 2012Lampron-Goulet et al. 2017Mahram et al. 2013; Pan et al. 2013; Rhee et al. 2013, Jovanovic et al. 2013; Feseke et al. 2015), including three long-term prospective studies (Kim 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. 2015). 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).

Dr. Navas-Acien

Dr. Ana Navas-Acien of Johns Hopkins has found that low levels of arsenic exposure, as you might find in the U.S., could contribute to diabetes development.

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).

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).

Exposure During Development

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).

Laboratory Studies: Arsenic Can Affect Beta Cells

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, 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). 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. 2014; Yao et al. 2015Zhu et al. 2014), affects insulin secretion (Dover et al. 2017), and what makes beta cells susceptible to arsenic (Cui et al. 2017). 

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; Liu et al. 2014). 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).

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. 2016). 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). 

What Type of Diabetes Is It?

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 for testing data.

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).
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).

Type 1 Diabetes and Arsenic?

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. 2016). For a good article describing this study, see Could arsenic exposure contribute to type 1 diabetes in youths? published in Medscape.

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).

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). 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?

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 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).

Diabetes and Arsenic Podcasts

The Link Between Arsenic Exposure and Diabetes: A Review of the Current Research
Teleconference call featuring presentations by Dr. Navas-Acien and Dr. Styblo from March 2014. 

Courtesy of The Collaborative on Health and the Environment

Exploring Links between Arsenic and Diabetes
An interview with Dr. Navas-Acien from Nov. 2012. 

Courtesy of Environmental Health Perspectives
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 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).

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

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).

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).

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).

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).

Laboratory Studies

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). 

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. 2016). 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. 2016).

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. 2017). Arsenic  can impair the development (differentiation) of fat cells and thereby affect metabolism (Beezhold et al. 2017).

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).

Exposure During Development: Animals

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. 2015) 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. 2015).
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

Gestational Diabetes

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 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).

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).

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. 2016).

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). 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); 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).

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. 2016Jiang et al. 2015) studies. (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. 2015). The link between cardiovascular disease and arsenic is also related to genetic background (Wu et al. 2015)-- some populations do not seem to be susceptible (Ameer et al. 2015). 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 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).

In animals, mice with diabetes are more susceptible to the effects of arsenic than those without diabetes (Yin et al. 2017).

Reviews

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). 

References

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