Heavy metals include compounds such as mercury, lead, or cadmium.
Mercury is a pollutant ubiquitous in the environment. 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. 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).
Cadmium exposure in the general population occurs most often via smoking.
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). Another study by the same authors, also in Sardinia, found that zinc, iron, and selenium were associated with cholesterol levels in people with type 1 diabetes, and copper and chromium were associated with average blood sugar levels (HbA1c) (Peruzzu et al. 2015).
A meta-analysis and systemic review of studies that measured copper in people with diabetes (both type 1 and type 2) found that copper levels were higher in those with both types of diabetes (Qui et al. 2016).
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). A review finds that inorganic mercury perpetuates autoimmunity more than organic mercury in animals, while in humans, the clinical effects are still unclear (Crowe et al. 2016).
The mercury levels in 7-year old children from the Faroe Islands (which tend to be high level) were associated with levels of various autoantibodies (no antibodies related to type 1 diabetes were measured) (Osuna et al. 2014). 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 inflammation of a type associated with autoimmune disease than less exposed people (Gardner et al. 2010). For these gold miners, exposure to both high levels of mercury and malaria together are associated with an increased risk of autoimmune disease. It may be that mercury plus other factors (e.g., virus, genetics, etc.) could increase the risk of autoimmune disease together (Silbergeld et al. 2005).
At lower levels of exposure found in the general population, a U.S. study found that mercury levels were associated with autoimmune antibodies in women of reproductive age, perhaps relevant for future risk of autoimmune disease (Somers et al. 2015).
Increased mercury levels have been found in Italian people with celiac disease who are following a gluten-free diet (Elli et al. 2015). Why this would be I do not know, but it may be important since many people with type 1 diabetes also have celiac disease.
Mercury was found to activate part of the immune system of NOD (non-obese diabetic) mice, an animal model of type 1 diabetes. By activating this part of the immune system, it also suppressed another part of the immune system, which delayed the development of diabetes in these mice (Brenden et al. 2001). This complicated effect may or may not be relevant for humans; for further discussion, see the Of mice, dogs, and men page.
Many heavy metals can affect the development of the immune system or exacerbate autoimmunity in animals (Holladay 1999; Dietert et al. 2010). Mercury, for example, can induce and exacerbate autoimmunity in genetically-susceptible strains of mice (Hemdan et al. 2007), as well as induce autoimmunity even in mice that are not genetically susceptible (Abedi-Valugerdi 2009). Mercury also triggers the main features of autoimmunity in mice at low doses (Arefieva et al. 2015).
Cadmium exposure has also been found to trigger autoimmunity in animals Bigazzi 1994). Cadmium also appears to cause gut inflammation and affect gut bacteria (Ninkov et al. 2015); both of these effects in turn are linked to type 1 diabetes (see the diet and the gut page). Lead also alters gut microbiota composition in animals (Wu et al. 2016).
DHA, the fatty acid present in fish, appears to protect cells for the immune system-damaging effects of mercury. DHA might lower the risk of autoimmune disease after low-level mercury exposure (Gill et al. 2014).
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. They also had lower functioning beta cells, the cells that produce insulin in the pancreas (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 (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 second Swedish study did not find an association between cadmium and type 2 diabetes either, although it did find that cadmium levels were associated with a higher HbA1c in former and current smokers (Borné et al. 2014). Another Swedish study found that lead levels were associated with higher blood pressure, a component of metabolic syndrome (Gambelunghe et al. 2016).
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).
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 long-term Spanish study of 27 different endocrine disrupting chemicals found thatin utero levels of various persistent organic pollutants were associated with overweight/higher BMI at age 7, while other chemical levels ( lead, cadmium, flame retardants, arsenic, BPA, phthalates) were not associated (Agay-Shay et al. 2015.
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).
A Canadian study found that higher prenatal cadmium and lead levels were associated with higher levels of leptin-- a pro-inflammatory hormone made by fat cells that controls fat storage-- in umbilical cord blood (Ashley-Martin et al. 2014).
In Mexico, mothers' lead levels were associated with epigenetic changes in growth-related genes in their infants, which may be a mechanism through which lead exposure in early life could affect growth (Goodrich et al. 2015). Maternal cadmium levels are also associated with epigenetic changes in infants, as well as low birth weight (Vidal et al. 2015).
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. A number of studies of Korean adults have found that mercury levels were associated with various combinations of higher fasting glucose levels, obesity, body mass index (BMI), waist circumference, higher blood pressure, insulin resistance, or higher total cholesterol or triglyceride levels-- in sum, mercury was associated with metabolic syndrome (Bae et al. 2016; Chung et al. 2015; Eom et al. 2014; Kim et al. 2015; Park and Seo 2016; Seo et al. 2014; You et al. 2011). One also found mercury associated with higher HDL cholesterol (the "good" kind) in Korean men with metabolic syndrome (Mortazavi et al. 2016; Park et al. 2016). Another study of Korean adults found that lead levels were associated with metabolic syndrome, but not cadmium or mercury (Rhee et al. 2013). Koreans with metabolic syndrome had higher levels of lead (and arsenic) in their hair than those without metabolic syndrome (Choi et al. 2014). And 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 also found an association between cadmium and metabolic syndrome and inflammation in men (Han et al. 2015). And another found that cadmium and lead were associated with higher blood pressure, with cadmium having the strongest association (Lee et al. 2016). Yet 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). 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. And why are there so many studies from Korea on this topic anyhow?
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). U.S. adults also show an increased risk of pre-diabetes with higher levels of cadmium (Wallia et al. 2014). 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 ; Swaddiwudhipong et al. 2012). However, a study of residents of cadmium-contaminated mining areas in Korea found that cadmium was associated with diabetes in men (Son et al. 2015).
Another U.S. study found that levels of molybdenum, antimony, tungsten, and uranium were associated with diabetes, even at the low levels seen in the general U.S. population (Menke et al. 2015).
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). In Russia, hair levels of various metals were sometimes correlated with body mass index (Skalnaya et al. 2014). And in Spain, iron levels were associated with metabolic syndrome (especially obesity and high triglycerides) (Ledesma et al. 2015).
A study of young black adults from 5 regions (U.S., Jamaica, Ghana, South Africa, and the Seychelles found that higher lead levels were associated with higher fasting blood glucose levels (cadmium and mercury were also, but not statistically significant) (Ettinger et al. 2014).
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).
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).
A study of coke-oven workers from China found that levels of copper, zinc, arsenic, selenium, molybdenum, and cadmium were higher in people with diabetes or high blood sugar. Those with higher levels of manganese, barium, and lead also had a higher risk of high blood sugar (Liu et al. 2015). Another study of occupationally-exposed Chinese workers found that levels of arsenic, nickel, zinc, and cobalt (not copper or cadmium) were associated with higher blood glucose levels (Yang et al. 2016). A study of Chinese adults found that cadmium levels were associated with prediabetes, but negatively related to being overweight (Nie et al. 2016).
A meta-analysis and systemic review of studies that measured copper in people with diabetes (both type 1 and type 2) found that copper levels were higher in those with both types of diabetes (Qui et al. 2016).
A study of the Inuit people found that blood mercury levels were associated with higher fasting glucose levels, higher 2-hour glucose levels, and type 2 diabetes (Jeppesen et al. 2015).
A Chinese study found that aluminum, titanium, cobalt, nickel, copper, zinc, selenium, rubidium, strontium, molybdenum, cadmium, antimony, barium, tungsten and lead were all associated with diabetes, fasting glucose levels, or impaired fasting glucose (Feng et al. 2015). Also in Chinese adults, nickel has been associated with type 2 diabetes, higher fasting glucose, higher average glucose (HbA1c), higher insulin levels, and increased insulin resistance (Liu et al. 2015). While nickel may be a new chemical now linked to diabetes, there are also reasons to be cautious in interpreting the results of this study. For example, diabetes affects urine, and the researchers measured nickel in urine, thus the diabetes may affect nickel levels (instead of the other way around). The authors did not address whether arsenic or cadmium could have affected the results. The source of nickel is also an issue-- nickel exposure can result from air pollution, which is also linked to diabetes. In any case, it will be important to look for new chemicals such as nickel and further evaluate them to see if they are really linked to diabetes or not (Kuo and Navas-Acien 2015).
Tungsten is another chemicals that appears to promote the development of fat cells in mice, although it depends on sex and age of the mice (Bolt et al. 2016).
In addition, in U.S. adults, cobalt, cesium, molybden, manganese, lead, tin, antimony, and tungsten (but not mercury) were associated with higher blood pressure, a component of metabolic syndrome (Shiue 2014a; Shiue 2014b).
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). In U.S. adults, those who had a higher BMI had lower levels of mercury in their blood (the opposite of what animal studies have found). The authors suggest that obesity may affect the metabolism, distribution, or excretion of mercury in the body (Rothenberg et al. 2015). In Polish men with metabolic syndrome, various metals were associated with various measurements-- too many to list here-- but in general, magnesium seemed to be protective while manganese, chromium, and selenium may intensify metabolic syndrome (Rotter et al. 2015). And, overweight/obese women were found to have a high prevalence of nickel allergy. Many successfully lost weight on a low-nickel diet (Lusi et al. 2015).
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 dysfunction 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).
Different researchers found that mice exposed to mercury for 4 weeks had higher insulin levels as well as glucose intolerance, insulin resistance, and high blood sugar (Magbool et al. 2016).
A study of various metals and obese mice found that mercury may accelerate the development of obesity-related diseases (Kawakami et al. 2012).
In rats, cadmium causes high blood sugar, insulin resistance, and beta cell dysfunction. In this study, cadmium also caused increased insulin release, similar to what is found in type 2 diabetes (Treviño et al. 2015).
Other studies show that cadmium can accumulate in pancreatic beta cells and cause beta cell dysfunction, but also that it inhibits insulin secretion (El Muayed et al. 2012). Cellular studies show that cadmium can decrease beta cell viability and even induce beta cell death (Chang et al. 2013). Cadmium also causes glucose intolerance by affecting fat cells (Han et al. 2003). It causes fat cells to develop abnormally and malfunction, perhaps contributing to insulin resistance as a result (Kawakami et al. 2010).
In rats, cadmium can also cause problems associated with the metabolic syndrome, including raising triglycerides, total cholesterol, and LDL ("bad") cholesterol, while reducing HDL ("good") cholesterol levels (Samarghandian et al. 2015).
Cadmium also increased cholesterol levels and altered the gut microbiome in mice (Zhang et al. 2015). Early life exposure to low doses of cadmium leads to later life changes in gut microbiota, fat accumulation, and other metabolic changes in mice (Ba et al. 2016).
Early-life exposure to lead is associated with lower body weight in human infants and later life obesity in rodents. In one rodent study, lead intake during development caused higher food intake, higher body weight and body fat, and higher insulin response, and these effects varied by age and sex (Faulk et al. 2014). Other studies also found that low-level lead exposure during development resulted in later life obesity in adult mice (Leasure et al. 2008; Wu et al. 2016).
When pancreatic beta cells were exposed to lead developed disturbed insulin secretion. Exposed rodents developed glucose intolerance via insulin resistance (Mostafalou et al. 2014).
Developmental exposure to a mixture of cadmium and mercury causes insulin resistance, higher body weight, higher insulin and leptin levels, and impaired glucose metabolism in male mice (Camsari et al. 2016).
Molybdenum causes dysfunction and death in laboratory beta cells (Yang et al. 2016).
A study of American women found that those with gestational diabetes had higher levels of cadmium in their bodies, no matter what their weight (Romano et al. 2015). A study of Chinese women found that the infants of those with gestational diabetes had higher levels of cadmium, chromium, and arsenic 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).
High iron (ferritin) levels have also been associated with gestational diabetes (Bowers et al. 2016; Rawal et al. 2016).
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 (Barregard et al. 2014, 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). Hypertension is also associated with cadmium exposure as well (Van Larebeke et al. 2014). And, for people undergoing dialysis, high cadmium levels increased the risk of death (Hsu et al. 2015). A study of Nigerian adults found that those with higher blood glucose levels had higher cadmium levels than those with better control (Anetor et al. 2016).
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). A similar study of Koreans found that neither lead, mercury, nor cadmium were associated with kidney disease-- but that in people with diabetes or hypertension, cadmium was associated with kidney disease (Kim et al. 2015).
Various metals have also been associated with atherosclerosis (hardening and narrowing of the arteries), another diabetes complication (Lind et al. 2012). The evidence is strongest for lead and cadmium as cardiovascular risk factors. For other metals, including antimony, barium, chromium, nickel, tungsten, uranium, and vanadium, a review concludes that "the current evidence is not sufficient to inform on the cardiovascular role of these metals because of the small number of studies. Few experimental studies have also evaluated the role of these metals in cardiovascular outcomes." (Nigra et al. 2016).
In Poland, the concentration of various metals in rainwater-- as a marker of dust in the air and thus exposure-- was associated with more frequent hospitalizations for people with diabetes (Bunio et al. 2010).
In rodent studies, metals are some of the multiple chemicals associated with fatty liver-- non-alcoholic fatty liver disease (NAFLD) is a complication of diabetes as well (Al-Eryani et al. 2014). Lead causes more harmful effects on the kidneys of rats with diabetes than those without (Baş and Kalender, 2015). Lead also causes weight loss, thyroid problems, kidney damage, and oxidative stress in rats with diabetes (Zadjali et al. 2015). Rats with diabetes are more susceptible to toxic effects of lead than rats without diabetes (Kalender et al. 2015).
Perhaps! Chelation therapy is used to treat lead poisoning by binding with metals and removing them from the body. Chelation has successfully reduced the risk of cardiovascular problems in people with diabetes who had had prior heart attacks (Avila et al. 2014; Escolar et al. 2014; Lamas et al. 2016; Ouyang et al. 2015).
According to a review of cadmium and diabetes, both human and laboratory studies show that cadmium is associated with high blood sugar, low insulin levels, and type 2 diabetes. Cadmium can cause beta cell dysfunction and impaired insulin release (which may have implications for type 1 diabetes as well as type 2). The authors find that it is likely that multiple mechanisms work simultaneously to contribute to these effects (Edwards and Ackerman 2015).
A review of mercury and diabetes states, "Quite recently, methyl mercury has been shown to have adverse effects on pancreatic beta (β) cell development and function, resulting in insulin resistance and hyperglycemia and may even lead to the development of diabetes... While additional information is needed regarding associations between mercury exposure and specific mechanisms of the pathogenesis of diabetes in the human population, methyl mercury's adverse effects on the body's natural sources of antioxidants suggest that one possible therapeutic strategy could involve supplementation with antioxidants (Schumacher and Abbott, 2016).
A review of the role of metals on glycemic control finds, "Metals have been implicated as causes of chronic inflammation and oxidative stress and are associated to obesity, hyperglycemia and even diabetes. Arsenic, iron, mercury, lead, cadmium and nickel have been studied as a risk factor for hyperglycemia and diabetes. There is another group of metals that causes hypoglycemia such as vanadium, chromium, zinc and magnesium by different mechanisms. Zinc, magnesium and chromium deficiency is associated with increased risk of diabetes" (González-Villalva et al. 2016).
Based on the above findings, the possibility that heavy metals can contribute to the development of diabetes should be studied further.
To download or see a list of all the references cited on this page, see the collection Heavy metals and diabetes/obesity in PubMed.