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Heavy Metals

New Articles on Diabetes and Chemicals

Heavy metals include compounds such as mercury, lead, or cadmium. 

Mercury is a pollutant ubiquitous in the environment (Selin et al. 2010). Each year, perhaps 300,000 U.S. children are born who were exposed in utero to blood levels of methylmercury that are above levels thought to be unsafe (Mahaffey et al. 2004).
 
Mercury is emitted from waste incinerators and coal-fired power plants. This inorganic mercury can be converted to methylmercury in the environment, which bioaccumulates in the food chain (Selin et al. 2010). Fish is the main source of human exposure to methylmercury. Exposure to inorganic mercury may be from dental fillings, cosmetics, or accidental spills (Mahaffey et al. 2004). Methylmercury can cause health effects such as immune suppression and neurodevelopmental delays (Selin et al. 2010).

Cadmium exposure in the general population occurs most often via smoking. Lead is found in old paints, soil, toys, and leaded gasoline. Blood lead levels in children have been declining in the U.S. since it was removed from paint and gasoline.
 
Type 1 diabetes and autoimmunity

Insulin-dependent diabetes in humans

One interesting study compared the levels of toxic metals (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. 2011).

A study from Sardinia, Italy, where there are very high rates of type 1 diabetes, did not find any difference in blood levels of mercury, copper, iron, or selenium in people with long-standing type 1 diabetes as compared to controls without diabetes. Those with type 1 did have lower levels of certain metals than controls, including chromium, manganese, nickel, zinc, and lead. Aside from lead, most of these minerals are beneficial in trace amounts (Forte et al. 2013).

Autoimmunity in humans

In Brazil, a study found elevated autoantibody levels in gold miners (exposed to high levels of inorganic mercury), as well as in people who ate fish containing methylmercury, as compared to less exposed people (Silva et al. 2004). A further study from Brazil has found that gold miners not only had higher levels of autoantibodies, but also higher levels of certain inflammatory cytokines that are associated with autoimmune disease than less exposed people (see the inflammation page for more on cytokines) (Gardner et al. 2010).

In studies of humans, mercury has been linked to autoimmunity, in both people with high exposures, and people with lower exposure levels. (Nyland et al. 2011). However, evidence linking high levels of mercury exposure to autoimmunity is much stronger than evidence linking low levels of exposure to autoimmunity (Karagas et al. 2012). Some researchers propose that while mercury can induce autoimmune disease in susceptible lab animals, this only occurs at high levels of exposure. It may be that mercury does not cause autoimmune disease directly, but interacts with other factors such as infections, antigens, or genetic predisposition to promote autoimmune disease. Animal research backs up this hypothesis, showing that low-dose mercury exposure exacerbates autoimmune disease in genetically-prone mice. In humans, exposure to both mercury and malaria together are associated with an increased risk of autoimmune disease (Silbergeld et al. 2005).

Laboratory studies: autoimmunity

Many heavy metals, including lead, cadmium, and methylmercury, can affect the development of the immune system (Holladay 1999). Some additional metals, including lead and gold, have also been found to exacerbate autoimmunity in animals. Perhaps these contaminants contribute to a dysfunctional immune system, leading to an improper response to an infection, and resulting in autoimmune disease (Dietert et al. 2010). 

Mercury was found to activate the immune system and delay diabetes in NOD (non-obese diabetic) mice (Brenden et al. 2001), which are one of the lab animals used to model autoimmune diabetes. However, most interventions-- 195 of them so far-- delay or prevent disease in NOD mice, including some that have not shown the same effect in humans. This is one reason many researchers question the usefulness of NOD mice (Roep and Atkinson 2004) (discussed further on the of mice, dogs, and men page).

Exposure to mercury can induce autoimmunity as well as worsen ongoing cases in some strains of mice genetically susceptible to autoimmunity (Hemdan et al. 2007). Mercury has also been shown to induce autoimmunity even in mice that are not genetically susceptible to autoimmunity (Abedi-Valugerdi 2009). The effects of mercury in part depend on the type of mercury. Inorganic mercury, for example, can induce autoimmunity in genetically susceptible mice, similar to the effect of the vaccine preservative thimerosal. Organic mercury leads first to immunosuppression and then to autoimmunity in these mice (Havarinasab and Hultman 2005). McCabe et al. (2003) describe a mechanism by which inorganic mercury affects the immune system and thereby could contribute to autoimmune disease, by interfering with apoptosis (programmed cell death) processes.

Mice exposed to both mercury and the solvent trichloroethylene (TCE) developed signs of autoimmune disease before mice exposed to either chemical alone (Gilbert et al. 2011).

Cadmium exposure has also been found to result in autoimmunity in animals (Bigazzi 1994).

Type 2 diabetes, insulin resistance, and body weight

Longitudinal studies in humans

The strongest evidence for the ability for environmental exposures to contribute to the development of diabetes comes from longitudinal studies. These are studies that take place over a period of time, where the exposure is measured before the disease develops.

A large, longitudinal study of U.S. adults found that those with the highest levels of mercury exposure had a higher risk of diabetes, as well as lower beta cell function (He et al. 2013). However, data from two other longitudinal studies of U.S. adults found that there was no relationship between diabetes and mercury levels (measured in toenail clippings) (Mozaffarian et al. 2013).

A longitudinal study of Swedish women found that neither blood nor urinary cadmium levels were associated with diabetes, impaired glucose tolerance, blood glucose levels, insulin production, insulin resistance, or hemoglobin A1c (HbA1c) (a measure of long-term glucose control) (Barregard et al. 2013).

A review of the human epidemiological evidence found that there does not seem to be a relationship between diabetes and cadmium exposure. Current evidence is insufficient for diabetes and mercury exposure (Kuo et al. 2013).

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. A study of pregnant Inuit women from Arctic Quebec found that mercury levels were associated with reduced fetal growth, due to their association with shorter duration of pregnancy (Dallaire et al. 2013). A study from Mexico City found that prenatal lead exposure was linked to lower weight in female children age 0-5 (Afeiche et al. 2011).

Cross-sectional studies in humans

Cross-sectional studies are studies that measure exposure and disease at one point in time. These provide weaker evidence than longitudinal studies, since the disease may potentially affect the exposure, and not vice versa.

There have been a number of studies of Korean adults relating to lead, cadmium, and mercury. Levels of mercury tend to be higher in Koreans than in the U.S./Europe, and similar to other Asian countries. One study of Korean adults found that blood mercury levels were associated with higher fasting glucose levels, obesity, body mass index (BMI), waist circumference, higher blood pressure, and higher total cholesterol and triglyceride levels-- in sum, mercury was associated with metabolic syndrome (Eom et al. 2013). Another study of Korean adults found that lead levels were associated with metabolic syndrome, but not cadmium or mercury (Rhee et al. 2013). And yet a different study of Korean adults found that cadmium levels were associated with metabolic syndrome in men (not women), but not lead or mercury (Lee and Kim, 2013). Another found that there while levels of lead, cadmium, and mercury were slightly higher in Korean adults with diabetes, there was no statistically significant association between levels of these metals and diabetes, beta cell function, or insulin resistance (Moon 2013). Another study, this time of elderly Koreans, found that blood mercury levels were associated with higher waist circumference and waist-to-hip ratio (a measure of obesity) as well as other cardiovascular risk factors (You et al. 2011). Yet another study found that blood levels of lead and mercury were associated with lower body fat in men (Park and Lee, 2013). So... in sum, I'd say these are not exactly consistent results. 

In a study of U.S. adults, urinary cadmium levels were associated with impaired fasting glucose levels and type 2 diabetes (Schwartz et al. 2003)A study from cadmium-contaminated villages in Thailand did not find a significant association between cadmium exposure and diabetes in adults (Swaddiwudhipong et al. 2010), but comparing exposed villagers in 2005 with 2010, there was a significant increase in diabetes (Swaddiwudhipong et al. 2012).

A study of adults from urban areas of Ireland and Pakistan found that hair levels of cadmium and lead were higher in people with diabetes than those without diabetes, whereas levels of essential minerals were lower (Afridi et al. 2013). A study from Turkey found that the levels of lead, nickel, aluminium, copper, and chromium were higher in people with diabetes and impaired fasting glucose than controls without diabetes (Serdar et al. 2009).

A study from a contaminated area in Taiwan found that people with the highest levels of exposure to both mercury and PCDD/Fs (persistent organic pollutants) had 11 times the risk of insulin resistance than those with the lowest exposures. Insulin resistance increased with both mercury and PCDD/F exposure, but simultaneous exposure to both compounds may increase the risk of insulin resistance more than exposure to one or the other alone. This study also found that each component of metabolic syndrome that they studied was associated with both mercury and PCDD/F exposure levels, including an increased waist circumference (Chang et al. 2011). Koreans with metabolic syndrome had higher levels of lead (and arsenic) in their hair than those without metabolic syndrome (Choi et al. 2014).

A study from Sardinia, Italy, where there are very high rates of type 1 diabetes, did not find any difference in blood levels of lead, zinc, mercury, copper, iron, or selenium in people with long-standing type 2 diabetes as compared to controls without diabetes. Those with type 2 did have lower levels of certain metals than controls, including chromium, manganese, and nickel. Most of these minerals are beneficial in trace amounts (Forte et al. 2013).

Since deficiencies of essential metals are known to affect weight, it is possible that toxic metals could contribute to weight gain or loss as well. Some researchers have found associations between various metals and body mass index (BMI) / waist circumference (WC) in a study of U.S. residents. Higher levels of barium and thallium were associated with higher BMI/WC, while cadmium, lead, cobalt and cesium were associated with lower BMI/WC (Padilla et al. 2010). 

Laboratory studies

Many metals, including cadmium, chromium, mercury, and nickel, have been found to affect gene expression in animals (Baccarelli and Bollati 2009). 

Mercury

A number of studies have examined the effects of mercury on beta cells in laboratory experiments. One found that inorganic mercury has been found to cause beta cell death, and decrease insulin secretion from beta cells in laboratory experiments (Chen et al. 2010) (see the beta cell stress page). Another found that methylmercury, at concentrations similar to those found in fish (under the recommended limits), can damage beta cells and lead to beta cell dysfunction (Chen et al. 2006a). A third experiment involved exposing mice to low doses of methylmercury or inorganic mercury. It found that decreased insulin secretion and increased blood glucose levels. Interestingly, insulin and glucose levels gradually returned to normal after mercury exposure ended. The authors conclude, "these observations give further evidence to confirm the possibility that mercury is an environmental risk factor for diabetes" (Chen et al. 2006b). A later experiment by some of the same authors found that mice treated with mercury had increased blood glucose levels and lower insulin secretion, and that mercury can cause beta cell dysfunction and beta cell death via mechanisms involving oxidative stress (Chen et al. 2012).

A study of various metals and obese mice found that mercury may accelerate the development of obesity-related diseases (Kawakami et al. 2012).

Cadmium

Animal studies show that cadmium can cause high blood glucose, damage beta cells, and cause diabetes in rodents (Schwartz et al. 2003). Edwards and Prozialeck (2009) review the literature (both human and animal studies) concerning cadmium exposure, blood glucose levels, and diabetes. They conclude that cadmium can have direct toxic effects on the pancreas, and may be a factor in the development of diabetes.

Cellular studies show that cadmium can accumulate in pancreatic beta cells and that it results in a inhibition of insulin secretion and impaired beta cell function (El Muayed et al. 2012). Other cellular studies show that cadmium can decrease beta cell viability and induce beta cell death via mechanisms involving oxidative stress (Chang et al. 2013).

Gestational diabetes

A study of pregnant women from across Canada found that a those with higher levels of mercury, manganese, cadmium and arsenic had a higher risk of gestational diabetes, but that the association was statistically significant only for arsenic (Shapiro et al. 2013).

Diabetes complications

If someone has diabetes already, can heavy metal exposure increase their risk of diabetes complications? Perhaps. Human studies have found that cadmium levels were higher in people with diabetes who had albuminuria (a marker of nephropathy, or kidney disease) as compared to people with diabetes who did not (Haswell-Elkins et al. 2008). A review of the human and animal evidence finds that cadmium exacerbates nephropathy and may interact with high blood glucose to damage the kidney (Edwards and Prozialeck, 2009). A study of smelter workers found that pancreatic dysfunction appears to result at a lower cadmium exposure level than kidney dysfunction does (Lei et al. 2007).

A longitudinal study of Swedes exposed to low levels of lead, mercury, and cadmium found that only higher levels of lead were associated with an increased risk of end-stage kidney disease, especially in men. Cadmium was not associated, and mercury was associated with a decreased risk (Sommar et al. 2013).

Various metals have also been associated with atherosclerosis (hardening and narrowing of the arteries), another diabetes complication (Lind et al. 2012).

The bottom line

Based on the above findings, which are somewhat inconsistent, the possibility that heavy metals can contribute to the development of diabetes should be studied further.

References

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

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