Links Between Heavy Metals and Diabetes/Obesity
Over 400 peer-reviewed studies published since 2006 in scientific journals have examined the relationship between various heavy metals and diabetes or obesity.
Some human epidemiological studies have found that people with higher exposures to some heavy metals have a higher risk of diabetes. This evidence includes long-term, longitudinal studies that follow people over time. The evidence is not overwhelming, however.
Laboratory studies on animals or cells show that exposure to some heavy metals can cause biological effects related to diabetes/obesity, and have helped to identify the mechanisms involved.
Some studies have also found some links between heavy metal exposure and the risk of diabetes complications.
About Heavy Metals
You may have known that you can use your glucose meter to test if diet soda is really diet or not, but did you know you can use your meter to test for the toxicity of sewage sludge?! Apparently heavy metals can affect the glucose consumption of E coli in sewage, enough to show up on a personal glucose meter (Mi et al. 2019); glucose meters can even be used to test for cadmium in particular (Zeng et al. 2019).
These 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). Note that it is possible to continue to eat fish but lower mercury levels in your body, depending on what fish you eat (Kirk et al. 2017).
Cadmium exposure in the general population occurs most often via smoking.
Metal levels are usually measured in blood, but they accumulate in fatty tissue in the body (and in fish and other animals) and can be measured in fat as well (Freire et al. 2020).
Reviews of Heavy Metals and Diabetes/Obesity
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).
A review of the role of metals in metabolic syndrome concludes, "Epidemiological and model system studies support a possible association between heavy metal exposure and metabolic syndrome or comorbid conditions; however, results remain conflicting." (Planchart et al. 2018). A more recent review and meta-analysis, however, found that those with higher metal levels (arsenic, cadmium, lead, and mercury) had a higher risk of metabolic syndrome (Xu et al. 2021).
A review of the effects of mercury, cadmium, and lead on fat tissue functioning finds that these effects are dose-dependent, with increased fat tissue development at low-doses and inhibition of fat tissue differentiation at higher doses. Both of these effects, however, can contribute to metabolic disruption (Tinkov et al. 2021). Another review looks at the mechanisms and enzymes involved in the relationship between heavy metal exposure and diabetes (Javaid et al. 2021).
An older review of the human epidemiological evidence (3 studies) found that there does not seem to be a relationship between diabetes and cadmium exposure. Current evidence is insufficient for diabetes and mercury exposure (2 studies) (Kuo et al. 2013).
Heavy metals are affected by the gut microbiome, and vice versa. A review notes that "There is continuous interaction between heavy metals and the microbiome. Heavy metal exposure retards the growth and changes the structure of the phyla involved in the gut microbiome. Meanwhile, the gut microbiome tries to detoxify the heavy metals by altering the physiological conditions, intestinal permeability, enhancing enzymes for metabolizing heavy metals." (Arun et al. 2021). The gut microbiome is related to the development of diabetes (see the Diet and the gut page).
A review and meta-analysis of 42 human studies concludes that there is "moderate-certainty evidence" for a link between cadmium exposure and an increased risk of both diabetes and prediabetes (Filippini et al. 2021).
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 2016). Another review and meta-analysis also finds cadmium to be associated with diabetes, but the studies on cadmium and obesity are much less consistent and even conflicting (Tinkov et al. 2017). A different meta-analysis found that exposure to cadmium above a certain level was associated with an increased risk of type 2 diabetes (Guo et al. 2019). Meanwhile, another review and meta-analysis found that cadmium was not associated with diabetes (Wu et al. 2017). Interesting conflicting data there, I'm not sure why. Another review of human, animal, and cell data show that cadmium may affect normal insulin function through multiple pathways, and may also alter insulin production in beta cells (Buha et al. 2020). Another review on cadmium and metabolic disease finds that "Both in vitro and in vivo experiments have demonstrated that the Cd-exposure is related to metabolic diseases such as obesity, diabetes and osteoporosis even if human studies are still controversial." (Bimonte et al. 2021). A meta-analysis of 9 studies did find an association between diabetes and cadmium exposure (Li et al. 2017). A meta-analysis found that cadmium exposure is associated with an increased risk of metabolic syndrome among Asian populations (Lu et al. 2022).
A systematic review and meta-analysis of cadmium and gestational diabetes found no association overall, although prospective studies showed a borderline increased risk (Lin et al. 2022). Another found a potential risk but it depended how you look at the data (Zhou et al. 2022).
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, 2017). Another review of mercury concludes that, "Increased total mercury exposure may augment the risk of diabetes mellitus and metabolic syndrome, but the lack of consistency of the epidemiological evidence prevents inference of a causal relationship." (Roy et al. 2017).
A review of both human and animal studies concludes that mercury exposure likely contributes to the development of autoimmunity (Pollard et al. 2019).
A review of lead finds, "Although our understanding of the metabolic health effects of lead exposure is incomplete, there are studies in model systems and a small amount of epidemiological data that together suggest a deleterious effect of environmental lead exposure on metabolic health." (Leff et al. 2018).
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. 2017).
Type 1 Diabetes and Autoimmunity
Type 1 Diabetes in Humans
One study compared the levels of toxic metals (arsenic, cadmium, and lead) in mothers with "insulin-dependent diabetes" and their infants, to Pakistani 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).
Interestingly, the island of Sardinia has high heavy metal levels, as well as very high type 1 diabetes incidence. Who knows if these are linked; the metals may interact with other environmental factors in Sardinia to increase risk (Songini et al. 2017). However, a study from Sardinia 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 variously associated with higher cholesterol levels in people with type 1 diabetes, and copper and chromium were associated with higher average blood sugar levels (HbA1c) (Peruzzu et al. 2015).
In Canada, at the community level, higher levels of fluoride and arsenic in drinking water were associated with a higher incidence of type 1 diabetes. At the regional level, barium and nickel were associated with a lower incidence of type 1 diabetes (Chafe et al. 2018).
In Florida, people with long-standing type 1 diabetes had higher copper levels than those without diabetes. While copper is an essential trace element, too much can be harmful. The essential elements manganese, zinc, and selenium were lower in those with type 1. Of the potentially harmful heavy metals measured, beryllium was lower and molybdenum was higher in those with type 1, while lead, arsenic, nickel, aluminum, and chromium did not statistically differ (Squitti et al. 2019). As this study was cross-sectional, and the people had type 1 for an average of 24 years, it does not really say much about diabetes development. It would be interesting to know, however, if having type 1 affects levels of these metals, or vice versa, or if higher or lower levels of these metals could contribute to disease progression or complications.
Exposure During Development
A small Scandinavian study found that children who later developed type 1 diabetes had more often increased concentrations of aluminium in umbilical cord blood than the non-diabetic controls, and also more often mercury and arsenic (Ludvigsson et al. 2019).
In Norway, iron supplementation during pregnancy was associated with a higher risk of type 1 diabetes in the offspring (Størdal et al. 2018).
Autoimmunity in Humans
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. 2017). Interestingly, a case study describes two siblings with overlapping features of distinct autoimmune syndromes following accidental exposure to elemental mercury (detected antibodies included GAD autoantibodies, which are linked to type 1 diabetes) (Pérez et al. 2020). Metals are linked to autoimmunity in humans in general (Bjørklund et al. 2020a).
In people who are susceptible (for whatever reason), chronic, low level exposure to mercury could trigger inflammation and exacerbate autoimmunity (Bjørklund et al. 2020b).
In the Seychelles Islands (east of Africa), mercury levels in young adults were associated with an increased risk of autoimmunity markers, after adjusting for fish consumption (McSorley et al. 2020).
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).
Autoantibodies and Mercury Exposure
The blue bars show the amount of mercury in hair (left) and blood (right) in U.S. women of reproductive age. The black lines show the risk of testing positive for antinuclear antibodies (ANA), a sign of autoimmunity. At low levels, considered "safe," there was an increasing dose-response relationship between mercury exposure and ANA positivity. At higher levels of exposure, the line flattened out or decreased. The dotted lines are the 95% confidence intervals.
A case study of a man who experienced severe mercury poisoning found that it led to autoimmunity (although that was the least of his problems) (Kleffner et al. 2017).
At lower levels of exposure found in the general population, in U.S. women of reproductive age, mercury levels were associated with autoimmune antibodies, perhaps relevant for future risk of autoimmune disease (Somers et al. 2015). However, a study from Long Island, New York, found that mercury levels were not associated with signs of autoimmunity (Monastero et al. 2017).
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. However, in U.S. children, mercury and lead levels were lower in those with celiac disease (there was no association in adults). These authors suggest it may be because people with celiac disease absorb lower levels of nutrients, including metals (Kamycheva et al. 2017).
Exposure During Development
In Sweden, eating fish more than once a week during pregnancy and in offspring in early childhood was associated with higher levels of heavy metals, autoantibody positivity, and the autoimmune disease juvenile idiopathic arthritis in children (Kindgren et al. 2019).
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, while prenatal exposures to some chemicals were associated with lower levels (Osuna et al. 2014).
Laboratory Studies: Type 1 and Autoimmunity
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. Also in NOD mice, prenatal exposure to cadmium did not affect the severity or risk of diabetes development (McCall et al. 2021).
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. 2016). The mechanisms by which mercury contributes to autoimmunity is a subject of current research (Carruthers et al. 2018; Gill et al. 2017). 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. 2015). Mice exposed to a combination of both mercury and the solvent trichloroethylene (TCE) developed signs of autoimmune disease before mice exposed to either chemical alone (Gilbert et al. 2011).
In animals, cadmium exposure has also been found to trigger autoimmunity (Bigazzi 1994) and increase inflammation (Hossein-Khannazer et al. 2019; Turley et al. 2019) and to be generally toxic to the immune system (Mirkov et al. 2021). Lead is also linked to toxic effects on the immune system (Fenga et al. 2017), as is nickel (Guo et al. 2020).
Low-level fluoride seems to reduce insulin resistance in mice with chemically-induced type 1 diabetes (Lobo et al. 2015).
Mercury and Autoimmunity
Listen to Dr. Nyland discuss her research on mercury and autoimmunity on this webinar, Environmental Contributors to Autoimmune Disease: Mechanisms, Impacts, and Chemicals of Concern, sponsored by the Collaborative on Health and the Environment (2019).
Heavy Metals and the Gut
Exposure to metals is linked to changes in gut microbiota in humans (Shao and Zhu, 2020), and specifically in infants (Laue et al. 2020). A review discusses how heavy metal exposure alters the composition of the gut microbiota, and in turn, the gut microbiota alter the uptake and metabolism of heavy metals. It also discusses how probiotics have been shown to reduce the absorption of heavy metals in the intestinal tract (Duan et al. 2020). Additional reviews also discuss heavy metals and gut microbiota (Assefa and Köhler, 2020; Bist and Choudhary, 2022). In Canadian children, there were associations between both long- and short-term heavy metal exposure and the gut microbiome, with stronger associations from more recent exposure (Shen et al. 2022).
Numerous heavy metals affect gut microbiota in animals (Richardson et al. 2018), including mercury (Lin et al. 2020; Zhao et al. 2020), manganese (Tinkov et al. 2021), copper (Yang et al. 2020), cadmium, lead and arsenic (Bolan et al. 2022). In rats, cadmium causes gut inflammation and affects gut bacteria (Ninkov et al. 2015), as well as increases intestinal permeability (Luo et al. 2019); it does the same thing in mice (He et al. 2019; Liu et al. 2020). In crayfish, cadmium affects gut microbiota and damages the intestine (Zhang et al. 2019). Lead alters gut microbiota composition in animals (Kou et al. 2019; Wu et al. 2016), causes gut inflammation and increases gut permeability (Liu et al. 2021), and is linked to gut microbiota differences in humans (Eggers et al. 2019). In rats, mercury affects gut microbiota, damages the intestinal lining, and causes gut inflammation (Lin et al. 2021). Aluminum causes inflammation and oxidative stress in intestinal cells and in mice, leading to gut barrier dysfunction (Jeong et al. 2020). All of these effects are linked to type 1 diabetes (see the Diet and the Gut page).
Type 2 Diabetes, Insulin Resistance, Metabolic Syndrome, 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. 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).
Another longitudinal study analyzed concentrations of 20 metals and their mixtures in conjunction with diabetes incidence in the Study of Women's Health Across the Nation, a multi-site, multi-ethnic cohort study of midlife women from around the US. It found that higher concentrations of lead (and arsenic), increased excretion of zinc, as well as higher overall exposure to metal mixtures were associated with an increased risk of diabetes (Wang et al. 2020a). This study also found that molybdenum was associated with better "adipokine profiles" (which includes levels of adiponectin, leptin, and soluble leptin receptor), while exposures to cadmium, cesium, and lead were associated with worse adipokine profiles (Wang et al. 2020b). And they also found that arsenic, cobalt, zinc, as well as metal mixtures, were linked to an increased risk of metabolic syndrome (Wang et al. 2022).
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), and a study of American Indians found that those with higher levels of cadmium at the beginning of the study had a higher increase in blood pressure over time (Oliver-Williams et al. 2018).
A long-term study of male steel workers in Italy who are exposed to high levels of metals (and other pollutants) had an increased risk of diabetes (along with other health problems) (Cappelletti et al. 2016). A multi-year study of people in Taiwan living in an area polluted by heavy metals found higher rates of diabetes, hypertension, stroke, and end-stage renal disease in those exposed to higher levels of metals (Tsai et al. 2018). Chinese seniors with higher levels of titanium (and selenium), but not other metals, had a higher risk of diabetes (Yuan et al. 2018).
In Norway, before bariatric weight-loss surgery, higher lead levels were associated with a lower BMI, and higher mercury levels with high blood pressure. In the year after surgery, lead levels in their bodies increased while mercury and cadmium levels decreased (Mikalsen et al. 2019).
In Spain, cadmium exposure, particularly from tobacco smoking, may be a risk factor for type 2 diabetes (Salcedo-Bellido et al. 2021).
In Australia, women aged 45-50 had a higher risk of type 2 diabetes after 20 years, in association with exposure to heavy metals via air and water industrial emissions (Hendryx et al. 2019).
A longitudinal study in China found that higher cadmium levels were associated with higher fasting glucose levels and an increased prevalence of type 2 diabetes (Xiao et al. 2020). Another Chinese study found that a mixture of seventeen metals was linked to a reduced risk of obesity (Zhong et al. 2021). Also in China, higher levels of aluminum, arsenic, strontium, and vanadium were associated with a higher incidence of poor cholesterol levels (Jiang et al. 2021). In Chinese adults, higher lead levels were associated with higher blood glucose levels and lower beta cell function after 5 years, only in women (Wang et al. 2022).
Longitudinal Studies in Children
In Mexican adolescents and young adults with obesity compared to normal BMI, as lead exposure increased, subcutaneous and visceral fat accumulation increased. And, mercury was associated with subcutaneous and abdominal fat deposition among adolescents with obesity (Betanzos-Robledo et al. 2022).
In Kuwaiti children, a possible marker of uranium exposure (due to military activity) was associated with the development of obesity and metabolic syndrome (Goodson et al. 2019).
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.
In Europe, moderate fish intake consistent with current health recommendations (1-3 times per week) during pregnancy was associated with improvements in metabolic syndrome in children as compared to no fish intake, while high maternal mercury exposure was associated with unfavorable metabolic effects in children (Stratakis et al. 2020).
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).
In pregnant Inuit women from Arctic Quebec, mercury levels were associated with reduced fetal growth, due to their association with shorter duration of pregnancy (Dallaire et al. 2013). In Mexico City, prenatal lead exposure was linked to lower weight in female children age 0-5 (Afeiche et al. 2011).
In the Boston Birth Cohort, a multi-ethnic, urban population living in Boston, Massachusetts, maternal blood lead levels were associated with an increased risk of overweight/obesity in children, in a dose-response fashion. Child overweight/obesity was highest among children of overweight/obese or diabetic mothers with high lead levels, but the increased risk was reduced if the mothers had adequate folate levels (Wang et al. 2019a; Wang et al. 2019b). In addition, exposure to metals was widespread. Maternal levels of mercury and lead were individually and in mixture with cadmium associated with an increased risk of offspring overweight and obesity during childhood. Adequate maternal selenium and folate mitigated the risk (Huang et al. 2022).
In U.S. children, prenatal cadmium levels were associated with higher risk of obesity (an animal study of similar levels of exposure supported these results) (Green et al. 2018). However, a study from Mexico found that prenatal cadmium levels were associated with lower weight-related measures in girls (Moynihan et al. 2019). In Canada, 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. 2015). Cadmium was associated with numerous differently methylated regions (an epigentic change) in both newborn cord blood and maternal blood. The function of genes that overlapped these differently methylated regions in maternal blood included BMI, blood pressure, and body weight (Cowley et al. 2018). A U.S. study found that higher concentrations of low levels of lead during childhood were associated with lower height, BMI, waist circumference, and percent body fat in girls (Deierlein et al. 2018).
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). Also in Mexico, maternal lead levels during pregnancy was associated with growth during childhood-- in this case, lower height and weight at age 4-6 (Renzetti et al. 2017) and lower BMI in children around puberty (Liu et al. 2019a). Prenatal lead levels were also associated with lower total, HDL, and LDL cholesterol levels in boys in this study, but not in girls, and not with measures of insulin resistance, glucose, or insulin levels (Liu et al. 2019b). Another study from Mexico found that higher early life lead exposure was associated with various markers related to metabolic syndrome, such as higher BMI, total cholesterol, and triglyceride levels (Muciño-Sandoval et al. 2021).
In the U.S., maternal cadmium levels are also associated with epigenetic changes in infants, as well as low birth weight (Vidal et al. 2015), and placental cadmium levels with low birth weight as well in Spain (Freire et al. 2019). (Combinations of metals are also associated with low birth weight, e.g., in China (Hou et al. 2019).) Another study from Mexico found that the use of personal care products predicts metal levels in children, and that BMI was associated with lower molybdenum levels (Lewis et al. 2018). And in Mexico, higher total metals during pregnancy were associated with lower HbA1c, leptin, and systolic blood pressure, and with higher adiponectin and non-HDL cholesterol in children. However, the associations found for non-essential metals (things like lead) were weaker than those found for essential metals (things like iron); low levels of essential metals during pregnancy were associated with increased cardio-metabolic risk in childhood (Kupsco et al. 2019). In Canada, mixtures of metals were associated with lower birth weight, with lead from the metal mixture having the greatest impact (Hu et al. 2021).
In Russian boys, lead (and persistent organic pollutants) at age 8-9 negatively affected growth during puberty (and that lead may delay puberty timing, while other chemicals might advance it) (Sergeyev et al. 2017), and lead levels were associated with leaner weight and shorter height through age 18 (Burns et al. 2017).
In Greece, prenatal cadmium exposure was associated with delayed growth in early childhood (Chatzi et al. 2018).
A large European study found higher levels of copper and cesium during childhood were associated with higher BMI in children, although prenatal metal levels were not associated (Vrijheid et al. 2020).
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. 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; Jeon et al. 2020; Kang et al. 2021; Kim et al. 2015; Lee 2018; Park et al. 2017; Park and Oh, 2020; Park and Seo 2016; Seo et al. 2014; Sohn et al. 2020; 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; Lee and Kim 2016); 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). Another found that levels of lead, mercury, and cadmium were significantly higher in people with metabolic syndrome, and this risk was reduced when curry and vitamin B1 and C intakes were higher (Duc et al. 2021a). Mixtures of heavy metals were associated with various measures of obesity in Korean adults aged 50 and over, with mercury playing the largest role (Duc et al. 2021b). Also in Korea, both lead and mercury exposures were associated with an increased risk of obesity, and mercury and cadmium exposures were associated with increased odds of non-alcoholic fatty liver disease (NAFLD). These metals, however, were not associated with an increased risk of diabetes (Moon et al. 2021). In Korean adults, of 26 chemicals, mercury, lead and 3PBA were the most important associated with obesity (Nguyen et al. 2021). 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 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). In U.S. adults, being overweight/obesity may substantially increase the adverse effects of long-term cadmium exposure on diabetes risk, especially in men (Jiang et al. 2018). U.S. adults with higher cadmium levels had a higher risk of type 2 diabetes, and it seems that cadmium could be problematic at a lower dose for type 2 diabetes than for kidney or bone disease (Shi et al. 2021). Another U.S. study found that higher levels of cadmium were not associated with an increased risk of metabolic syndrome, but were associated with altered components of metabolic syndrome. Current smokers were the most vulnerable group, with higher long-term cadmium exposure being associated with increased risk of metabolic syndrome, low HDL cholesterol levels, and high blood pressure (Noor et al. 2018). Also in the U.S., cumulative exposure to heavy metals as mixtures was associated with obesity, hypertension, and type 2 diabetes (Wang et al. 2018). Another U.S. study found that co-exposures to various metals were also associated with metabolic syndrome, including arsenic/elemental mercury, and selenium/zinc, while cadmium/lead were associated with a lower risk (Bulka et al. 2018). Another found non-linear associations, and those with higher levels of most metals having a decreased risk of metabolic syndrome, although it varied by subgroup (Zhou et al. 2021). Also in the U.S., higher blood lead, mercury, and cadmium levels were associated with a higher risk of having high total cholesterol (Buhari et al. 2019).
In U.S. adults, manganese levels were associated with glucose levels, insulin resistance and kidney function, with variations by sex and by interactions with other metals (Yang et al. 2020). In Dallas, Texas, chronic environmental cadmium exposure was associated with type 2 diabetes (onset before age 50) in Blacks who lived near a lead smelter (Little et al. 2020). In Arkansas, higher cadmium levels were linked to an increased risk of obesity in post-menopausal (not pre-menopausal) women (Stahr et al. 2021).
In Mexican-Americans in Texas, arsenic, molybdenum, and a mixture of 8 metals were associated with lower beta cell function, lower insulin resistance, lower insulin levels, and higher insulin sensitivity. Higher urinary copper levels were associated with reduced beta cell function (Weiss et al. 2022).
In U.S. adults, a study using NHANES data evaluated ten metals: antimony, barium, cesium, uranium, molybdenum, thallium, tungsten, cobalt, cadmium and lead. Blood lead had a negative linear association with obesity, and in those with obesity, high blood lead was associated with lower risk of dyslipidemia. There was a curvilinear relationship between urinary antimony and obesity with the moderate group having the highest odds of obesity. The relationship between urinary antimony and hypertension and dyslipidemia was linear, positive, and independent of obesity. High urinary uranium was associated with 30% higher odds for type 2 diabetes but not with obesity (Swayze et al. 2021). Also using NHANES data, cobalt and tin were linked to a higher diabetes risk, and strontium with a lower risk (Yang et al. 2022).
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 Thai study found that those with higher exposure cadmium and lead had an increased risk of diabetes and kidney dysfunction (Yimthiang et al. 2022).
In the U.S., 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. 2016). Another U.S. study found that methyl mercury levels were associated with higher total cholesterol levels in adolescent girls (Zhang et al. 2018). And, tin is associated with diabetes in U.S. adults as well (Liu et al. 2018). Yet mercury was linked to a lower risk of diabetes in U.S. adults with higher selenium intake (Zhang et al. 2021).
In adults from urban areas of Ireland and Pakistan, 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). In Turkey, 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). In Lebanon, higher cadmium levels were linked to worse cholesterol levels, but not diabetes or obesity (Ayoub et al. 2021).
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).
In a contaminated area in Taiwan, 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). Also in Taiwan, higher levels of mercury in blood were associated with higher risk of type 2 diabetes (Tsai et al. 2019), and some metals were associated with metabolic syndrome (Wen et al. 2020). In Taiwanese adults without diabetes, blood lead levels were associated with higher long-term blood glucose levels (HbA1c), while urinary levels of other metals were not (nickel, chromium, manganese, arsenic, copper, and cadmium) (Chang et al. 2021). Taiwanese adults residing in close proximity to a petrochemical complex had high arsenic and mercury exposure that was associated with high cholesterol levels (Shun et al. 2021).
In Sardinia, Italy (where there are very high rates of type 1 diabetes), there was no statistically significant 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). Indeed, in China, the risk of type 2 diabetes was highest in people with either low or high levels of manganese in their blood (Shan et al. 2016).
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. 2016). 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. 2017a). A third found that multiple metals, especially nickel, zinc and cobalt, were associated with blood glucose among Chinese metal exposed workers (Yang et al. 2017b). A fourth, larger study, found that both exposures to heavy metals and high alcohol intake were associated with the risk of diabetes, with a strong interaction between the two exposures (Yang et al. 2019). A Korean study of smelter workers found that cadmium levels were associated with high blood pressure, but not lead (An et al. 2017). Polish smelter workers with diabetes had higher levels of arsenic, cadmium, and lead, and smoking further exacerbated the metal levels (Bizoń et al. 2016). In Chinese workers, levels of various metals were associated with fasting glucose levels, and the associations varied by sex (Ge et al. 2020).
In Chinese adults, cadmium levels were associated with prediabetes, but negatively related to being overweight (Nie et al. 2016). A large study of Chinese adults from 16 regions found that lead levels were associated with fasting blood glucose levels, BMI, blood pressure, and cardiovascular disease in women (Chen et al. 2017). A different study of Chinese adults found that cadmium levels were associated with higher BMI as well as type 2 diabetes (Lei et al. 2019). Additional studies of Chinese adults found that many metals, including manganese, copper, zinc, arsenic, selenium, and cadmium, are associated with diabetes risk (Li et al. 2017), and others (vanadium, zinc, mercury, iron, and selenium) are associated with high blood pressure (Wu et al. 2018). Chinese men with metabolic syndrome has significantly higher blood concentrations of lead, cadmium, copper, and selenium than those who were healthy (Guo et al. 2019). Studies from China also found that the links between type 2 diabetes and various metals (including copper, arsenic, selenium, and antimony) were partly explained by oxidative DNA damage (Xiao et al. 2018), the links between type 2 diabetes and cadmium were partially explained by inflammation (Xiao et al. 2019), and links between obesity and lead were dependent on genetic background (Wang et al. 2018). Another Chinese study found that genetic background was involved in the link between higher copper levels and a higher risk of type 2 diabetes (Yin et al. 2019). Metabolic syndrome was associated with lower magnesium and selenium levels, and with higher mercury and barium levels in adults from Beijing (Zhang et al. 2020). In elderly Chinese, combined exposure to cadmium, strontium, and lead was a risk factor of dyslipidemia (Zhu et al. 2020). In China, people with higher blood lead levels had higher fasting glucose levels (Wan et al. 2021). Chinese adults with higher levels of copper had higher blood glucose levels (HbA1c), while those with higher nickel levels had lower Hba1c (Cai et al. 2021). Additional studies from China also find various associations between various metals and blood glucose levels (Mo et al. 2021). Also in China, of 13 metals analyzed, higher levels of plasma magnesium and molybdenum were associated with decreased prevalence of metabolic syndrome (Huang et al. 2022). In a chromium-polluted area of China, chromium levels were associated with a higher BMI (Zhao et al. 2022). And in a cadmium-polluted area, metal exposure was linked to an increased risk of diabetes (Zhang et al. 2022).
In rural farmers from India, there was no association between diabetes and traditional risk factors such as body mass index, blood pressure and total cholesterol, but there was an association between diabetes and metals. Arsenic, chromium, aluminium, and zinc were associated with diabetes, and arsenic and zinc were associated with pre-diabetes and atherosclerosis (Velmurugan et al. 2018). In the general Pakistani population, cadmium exposure was associated with an increased risk of diabetes (Sabir et al. 2020).
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. 2017).
In Inuit people in Greenland, blood mercury levels were associated with higher fasting glucose levels, higher 2-hour glucose levels, and type 2 diabetes (Jeppesen et al. 2015). In Inuit and Cree people from northern Canada, higher mercury levels were also associated with higher fasting glucose levels (Cordier et al. 2020). In the Cree, higher cadmium levels were associated with lower obesity-related measurements (Akbar et al. 2020).
Cadmium levels (but not other metals) were associated with insulin resistance in Brazilians (Pedro et al. 2019). In France, cadmium exposure levels were associated with higher long-term blood sugar levels (HbA1c) people who had never smoked, as well as in former and current smokers (smoking is a major source of cadmium exposure). The effect level was not high. (Trouiller-Gerfaux et al. 2019).
Nigerian workers exposed to electronic waste had higher LDL and total cholesterol levels compared to those unexposed. There were significant positive correlations between cadmium and total/LDL cholesterol levels (Igharo et al. 2020).
In Russia, mercury levels were higher in the hair of women with metabolic syndrome than in those without (Ivanova et al. 2021).
Cross-Sectional Studies in Children
In U.S. children and adolescents, copper levels were associated with obesity and cholesterol, manganese levels were associated with obesity, mercury and selenium levels were positively related to cholesterol, and zinc levels were associated with reduced obesity (Fan et al. 2017). Another study of U.S. children and adolescents found copper levels were associated with total cholesterol and fasting insulin levels as well (Zang et al. 2018).
A third U.S. study of children and adolescents found that levels of barium were associated with an increased risk of obesity, but cadmium, cobalt, and lead were associated with a decreased risk. Other metals, including cesium, molybdenum, antimony, thallium, and tungsten, were not associated (Shao et al. 2017). Another study of U.S. children and a metal mixture found lead linked to lower weight/growth-related measures, and manganese linked to higher measures (Signes-Pastor et al. 2021).
As U.S. children gained weight (between 1976 and 2008), their blood pressure remained stable. The declining levels of lead over that time, however, can largely explain this trend (Zachariah et al. 2018).
In Canada, childhood blood levels of cadmium, mercury, and arsenic were not associated with childhood BMI, weight, or height in boys or girls. But girls with higher lead levels had a lower BMI, and boys had a higher BMI (Ashley-Martin et al. 2019).
Korean children and adolescents with higher blood mercury levels had a higher risk of being overweight (Shin et al. 2018; Cho 2021). Cadmium and lead together (but not individually) were associated with pre-hypertension in Korean adolescents (Ahn et al. 2018). Total and LDL cholesterol levels significantly increased as blood mercury levels increased in Korean adolescent males, but not in females. HDL cholesterol and triglyceride levels were not associated with mercury levels (Cho et al. 2020).
In adolescents from Sicily, Italy, cadmium exposure was associated with higher insulin resistance (Pizzino et al. 2017).
Taiwanese adolescents with higher lead levels had higher diastolic blood pressure, glucose and insulin levels, insulin resistance, β-cell function, BMI, and and increased risk of metabolic syndrome (Lin et al. 2019).
In Mexico, higher levels of fluoride exposure during puberty was associated with increased fasting glucose and insulin levels in girls but not boys (Liu et al. 2019).
In Iran, childhood and adolescent exposure to arsenic, lead, chromium, and zinc were variously associated with obesity or cardiovascular disease markers (Nasab et al. 2022).
Additional Metals Linked to Diabetes or Obesity?
In China, 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). Occupational exposure levels of nickel are also linked to higher HbA1c levels in China (Liu et al. 2020).
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, molybdenum, manganese, lead, tin, antimony, and tungsten (but not mercury) were associated with higher blood pressure, a component of metabolic syndrome (Shiue 2014a; Shiue 2014b). Also in the U.S., higher blood cobalt concentrations were associated with improved cholesterol/triglyceride levels, and not associated with the risk of high blood pressure or diabetes (Wang et al. 2022).
In China, titanium levels were associated with increased risk of metabolic syndrome via increasing waist circumference and triglycerides in people under high metal exposure (Huang et al. 2020). Also in China, mixtures of metals had different associations with fasting blood glucose levels depending on the region in which people lived and depend on levels of other metals. Heavy metals and their effects may depend for example on arsenic and selenium exposures (Li et al. 2019).
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).
Laboratory Studies: Diabetes and Obesity
Lead, mercury, cadmium, and molybdenum all inhibited glucose-stimulated insulin secretion in beta cells (Elmorsy et al. 2020) and were toxic to beta cells via mechanisms of oxidative stress, apoptosis, and inflammation (Al Doghaither et al. 2021). For more studies on these and other metals:
A number of studies have examined the effects of mercury on beta cells in laboratory experiments. In beta cells themselves, inorganic mercury can cause beta cell death, and decrease insulin secretion (Chen et al. 2010), as can methylmercury (Yang et al. 2022), including at levels similar to those found in fish (under the recommended limits) (Chen et al. 2006a). Exposing mice to low doses of methylmercury or inorganic mercury led to 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). Similarly and also in mice, methylmercury exposure caused high fasting glucose and insulin resistance (Faheem et al. 2019). Others also found that in rats, low level mercury exposure reduced white fatty tissue weight, fat cell size, insulin levels, glucose tolerance, and antioxidant defenses, and increased glucose and triglyceride levels (Rizzetti et al. 2019).
Fish fat cells exposed to low levels of mercury show metabolic effects, implying that mercury in water could affect fish (Tinant et al. 2021).
A study of various metals and obese mice found that mercury may accelerate the development of obesity-related diseases (Kawakami et al. 2012). Mercury does affect the function of fat cells, and a substance in black tea is protective against these inflammatory effects (Chauhan et al. 2019).
The effects of methylmercury on cardiovascular disease risk factors like high blood pressure resemble those caused by a high-fat diet in mice (Lacerda Leocádio et al. 2020).
Diabetes may also affect the absorption and elimination of mercury. Methylmercury was more rapidly absorbed by, and eliminated from, the blood cells, brain, liver, kidney, and pancreas of mice with diabetes than those without diabetes (Yamamoto et al. 2020).
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). Female rats are more sensitive to some of the diabetes-promoting effects of cadmium than male rats (Jacquet et al. 2018a), although even male rats exposed to low levels of cadmium developed glucose intolerance, high insulin levels, inflammation, and insulin resistance in the liver and fat tissue (Sarmiento-Ortega et al. 2021). Exposure to cadmium during development has long-lasting effects on rats' response to glucose (Rocca et al. 2020). An levels found in the environment, cadmium can cause not only higher blood glucose levels but also weight gain in rats (Nguyen et al. 2022). Cadmium can also lower insulin levels; a rat study found that cadmium led to lower insulin and higher total cholesterol/triglyceride levels (Oluranti et al. 2021),
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; Fitzgerald et al. 2020; Hong et al, 2021). Cellular studies show that cadmium can decrease beta cell viability, inhibit insulin secretion, and even cause beta cell death (Chang et al. 2013; Huang et al. 2019; Xu et al. 2021). Cadmium has complex effects on gene expression in islets related to glucose levels, at levels found in the environment (Wong et al. 2021). Researchers are figuring out exactly how beta cells are affected by and adapt to cadmium exposure (Jacquet et al. 2018b; Qu et al. 2021). Cadmium reduces viability of the islets, while estradiol (estrogen) was able to alleviate this disturbance to some extent (Mohammadi et al. 2019). In mice, cadmium exposure reduced fasting insulin levels, and caused islet atrophy and decreased islet area, but did not affect beta cell function, insulin resistance, fasting blood glucose, or glucose tolerance (Li et al. 2019). Note that cadmium (and manganese) appear to be less potent than arsenic in inhibiting insulin secretion from beta cells (Beck et al. 2019). It appears that low-level cadmium do not affect insulin secretion until the beta cells are about to die (Moulis et al. 2021).
In mice, cadmium exposure increased blood glucose levels, decreased insulin levels, led to glucose intolerance and suppressed insulin expression in the pancreas. In beta cells, cadmium exposure inhibited cell viability and suppressed insulin secretion in vitro, targeting the mitochondria (Hong et al. 2022a; Hong et al. 2022b). Accumulation of cadmium in islets causes changes in glucose clearance and beta cell function (Wong et al. 2022).
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). Cadmium induces inflammation and affects the function of fat cells (Gasser et al. 2022).
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).
In fish, cadmium caused high glucose levels (Atli et al. 2015) and increases triglyceride accumulation (Pan et al. 2018). Also in fish, low doses of cadmium increased food intake, as well as weight and length gains, whereas high doses appear to have the opposite effect (Cai et al. 2019). It appears no one is safe; cadmium affects glucose metabolism even in chickens (Tian et al. 2018) and marine worms (Liu et al. 2018).
Cadmium also increased cholesterol levels and altered the gut microbiome in mice (Zhang et al. 2015). After 2 weeks of cadmium and 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). In mice, cadmium exposure disturbed energy metabolism, as well as both the liver and gut microbiome (He et al. 2019).
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. 2017). Maternal exposure to low levels of cadmium may also cause insulin resistance in rat pups (Jacquet et al. 2018). In offspring female mice as adults, cadmium exposure during gestation causes insulin insensitivity, obesity, and metabolic syndrome (Jackson et al. 2020). Following maternal cadmium exposure during gestation, offspring mice developed hyperglycemia in puberty and impaired glucose tolerance in adulthood. The mechanism involved enhancing glucose production via oxidative stress in the liver (Yi et al. 2021).
In rats, cadmium exposure during adolescence disturbed the gut microbiota and increased triglyceride levels (Yang et al. 2021).
Interestingly, in rats with cadmium-induced metabolic problems, the diabetes drug metformin was found to be only partially effective (Sarmiento-Ortega et al. 2018). This implies that diabetes treatments should probably depend on the cause of the diabetes... which hardly ever happens now.
In lab animals, lead exposure reduced insulin secretion, pancreatic beta cell mass, and beta cell proliferation (Daniel et al. 2022).
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). Lead exposure during development causes epigenetic changes that may be involved in metabolic conditions later in life (Montrose et al. 2017).
In mice, lead caused low blood sugar, increased cholesterol levels, lowered triglyceride levels, and affected the pancreas (Das et al. 2020). A different mouse study shows that low lead exposure can affect liver glucose production, increasing glucose levels (Wan et al. 2021).
When pancreatic beta cells were exposed to lead developed disturbed insulin secretion. Exposed rodents developed glucose intolerance via insulin resistance (Mostafalou et al. 2015).
Lead exposure in zebrafish led to changes in the richness and diversity of gut microbiota, in metabolites associated with the pathways of glucose and lipid metabolism, and in the transcription of genes related to glucose breakdown and to lipid metabolism (Xia et al. 2018). Prebiotics, meanwhile, may reduce the absorption of lead into the body by affecting the gut microbiota (Zhai et al. 2019).
Alarmingly, the effects of exposure to some chemicals can be passed from one generation to the next, and the next, and the next, and so on. For example, in mice, exposure to cadmium and mercury during development caused persistent transgenerational effects in adult offspring through the fourth generation -- even though the exposure ended. These effects included impaired glucose tolerance, increased body weight, and higher abdominal fat (Camsari et al. 2019).
Other Metals and Metal Mixtures
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. 2017).
Low-dose exposure to a mixture of cadmium, lead, and manganese affected various cholesterol markers in rats (Oladipo et al. 2017), as did a low-dose mixture of lead, cadmium, and mercury, while Costus afer aqueous leaf extract reversed these effects (Anyanwu et al. 2020).
Cadmium, manganese, and arsenic impair insulin secretion from beta cells in the laboratory, but not zinc. In combination, the effects of these metals did not change (Dover et al. 2018). Molybdenum also causes beta cell dysfunction-- plus even beta cell death (Yang et al. 2016).
Particulate air pollution binds to heavy metals and arsenic in the air, giving these metals a pathway to enter the body. Mice exposed to particulate-bound metals from a coal-burning area developed high triglyceride and cholesterol levels, especially if exposure occurred during young or old ages. The metals reached and gathered in tissues besides the lung, including the heart, liver, and brain (Ku et al. 2017).
Water from a lagoon contaminated with heavy metals interferes with the carbohydrate metabolism of two fish species (Petersen et al. 2019).
A review found that copper concentrations were higher in women with gestational diabetes than in pregnant women with normal glucose tolerance, particularly among Asians and during the third trimester (Lian et al. 2021).
In France, higher cadmium levels were associated with a higher risk of gestational diabetes and impaired glucose tolerance, while lead levels were almost but not quite statistically significant (Soomro et al. 2019).
A number of studies from China have looked at gestational diabetes and various metals. One found that the infants of those with gestational diabetes had higher levels of cadmium, chromium, and arsenic in the 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). A further study by some of the same authors found that eight elements were associated with gestational diabetes, some increasing the risk (Al, As, Ba, Cd, Hg, and Sn), and others decreasing it (Ca and V) (Wu et al. 2018). Others found that levels of cadmium in pregnant women were associated with gestational diabetes (Li et al. 2020), especially in overweight or obese women (Xing et al. 2018). First trimester levels of cadmium were associated with gestational diabetes, especially in women carrying male fetuses (Liu et al. 2018). Chinese women with higher copper levels also had an increased risk of gestational diabetes (Li et al. 2019). Comparing exposure levels to various different metals, a study found that overall high heavy metal levels were associated with an increased risk of gestational diabetes, and that the increased risk is mainly driven by mercury and, to a lesser extent, by nickel, lead, and arsenic (Wang Y et al. 2019). A different Chinese study found that multiple metals (Ni, As, Sb, Co, and V) were individually and in combination linked to a higher risk of gestational diabetes, especially nickel and antimony (Wang X et al. 2020). Another study also found that antimony exposure was associated with increased gestational diabetes risk, as well as impaired blood glucose homeostasis in pregnant women (Zhang et al. 2020). Aluminum levels in the first trimester were also associated with a higher risk of gestational diabetes (Huang et al. 2020). Higher thallium exposure in pregnant women was associated with an increased risk of gestational diabetes in China as well (Zhang et al. 2020). Another study also found higher maternal thallium levels in early pregnancy were associated with an increased risk of gestational diabetes, and that the relationship depended on BMI, and was strongest in women over 30 (Zhu et al. 2019). A long-term study from China found that higher manganese and zinc but lower lead, calcium, and magnesium concentrations before 24 weeks' gestation might impair fasting plasma glucose during pregnancy (Zhou et al. 2021). Also in China, a study found that while no individual trace elements were found significantly associated with gestational diabetes, trace element exposure was associated with specific gut microbiome features that may contribute to gestational diabetes development (Zhang et al. 2021). In China, pregnant women with gestational diabetes had higher levels of mercury and tin in their hair than those without diabetes (Jia et al. 2021). Early pregnancy exposure to higher levels of a mixture of rare earth elements was associated with a lower risk of gestational diabetes, and neodymium, praseodymium, and lanthanum exhibited the strongest (protective) effects in the mixture. No associations were found for individual elements (Xu et al. 2021).
A large, nationwide study from Japan found that higher mercury exposure levels were associated with an increased risk of gestational diabetes. Other elements (lead, cadmium, manganese, and selenium) were not associated (Tatsuta et al. 2022). Also in Japan, cadmium and lead levels were slightly higher among women with gestational diabetes than those without, however, these differences were not statistically significant (Oguri et al. 2018). In Japanese women, the benefits of optimal gestational weight gain were lower in women exposed to high concentrations of mercury, lead, and cadmium. These heavy metals affected the associations between gestational weight gain and various health outcomes, particularly for underweight and overweight women (Jung et al. 2020).
Higher iron levels during pregnancy are linked to glucose intolerance in the mother (Zein et al. 2015) and gestational diabetes (Bowers et al. 2016; Fernández-Cao et al. 2017; Khambalia et al. 2016; McElduff 2017; Rawal et al. 2017).
Pregnant women with higher methyl mercury (but not inorganic mercury) levels had higher systolic blood pressure (Wells et al. 2017).
In the U.S., higher copper and lower molybdenum concentrations were associated with an increased risk of higher blood glucose levels during pregnancy, with women at higher risk of gestational diabetes potentially affected to a greater extent (Zheng et al. 2019a). These authors also found consistent evidence of higher second trimester glucose levels associated with higher early pregnancy copper levels, and potential synergism between zinc and copper on glucose levels (Zheng et al. 2019b). In a different group of US women (Project Viva), they found that early pregnancy barium and mercury concentrations were associated with altered post-meal glucose concentrations in later pregnancy (barium with higher glucose and mercury with lower), with potential interactions between barium and lead (Zheng et al. 2021).
In Turkey, women with gestational diabetes had higher levels of cadmium, lead, antimony, and copper and lower levels of chromium-III, zinc, and selenium as compared to pregnant women without diabetes. Levels of copper, mercury, and arsenic were statistically similar (Onat et al. 2020). In Iran, concentrations of arsenic, cadmium, and mercury were significantly higher in women with gestational diabetes (Rezaei et al. 2021).
Note that an study previously described on this page was since retracted; the description had said, "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)." It turns out that there were "inadvertent errors in the statistical code that resulted in the exclusion of 12 gestational diabetes mellitus cases with urinary cadmium below the limit of detection" with the result that some of the associations were not statistically significant after all (Romano et al. 2017). A later study of women from New Hampshire found a slight but not statistically significant association between cadmium levels and high blood glucose levels in normal weight pregnant women, and in women with no exposure to smoking during pregnancy and those who had never smoked (Romano et al. 2019).
Diabetes Management and Complications
In animals, just having diabetes may increase susceptibility to the effects of heavy metals. Rats with diabetes, for example, are more susceptible to toxic effects of lead than rats without diabetes (Kalender et al. 2015). Lead also causes weight loss, thyroid problems, kidney damage, and oxidative stress in rats with diabetes (Zadjali et al. 2015). Numerous metals, both in combination and alone, can cause problems for rats with diabetes. Rats with diabetes are more prone to heavy metal-induced organ damage (in the heart, kidney, liver, pancreas, and spleen) as compared to rats without diabetes (Riaz et al. 2020).
Note that one source of lead can be traditional medicine, sometimes used to treat type 1 diabetes. In fact, lead poisoning has been found in a child with type 1 who was treated with Indian traditional medicine (Sony and Dayal, 2019).
If someone has diabetes already, can heavy metal exposure increase their risk of diabetes complications? Perhaps. See the sections below.
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). Cadmium is also associated with kidney dysfunction in people both with and without diabetes (Grau-Perez et al. 2017; Jain 2019; Madrigal et al. 2019). In U.S. adults, kidney dysfunction is associated with exposure to various metals in combination with perfluoroalkyl substances (Jain 2019). In U.S. children, levels of various metals and metal mixtures are associated with markers of kidney problems (Sanders et al. 2019).
In Chinese older adults with diabetes, arsenic and vanadium were associated with an increased risk of chronic kidney disease, separately and in a mixture. The metals mixture showed a linear dose-response association with the odds of kidney disease (Zhou et al. 2021).
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). 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.
Chromium is also associated with lower kidney function in adults, especially combined with lead and cadmium exposure (Tsai et al. 2017). The heavy metals lead, arsenic, cadmium, and mercury are all linked to kidney problems in fact (Chávez-Gómez et al. 2017), as are molybdenum, and copper as well (Yang et al. 2019).
Lead, even at low levels of exposure, is linked to kidney dysfunction in Saudi Arabians with and without diabetes (Aziz et al. 2019). Lead and mercury are linked to markers of kidney problems in elderly Koreans (Lim and Yoon, 2019). In Chinese people with type 2 diabetes, higher lead levels were linked to kidney injury (Chen et al. 2021).
In the Netherlands, higher cadmium and lead levels were associated with a higher risk of diabetic kidney disease (Hagedoorn et al. 2020).
In animals, lead causes more harmful effects on the kidneys of rats with diabetes than those without (Baş and Kalender, 2016). Cadmium damages the kidney (Liu et al. 2019) and can induce diabetic nephropathy in lab animals (Gong et al. 2021), while caffeic acid phenethyl ester (CAPE) (from honeybee hives) can prevent it (Gong et al. 2017). In rats, exposure to multiple heavy metals (lead, cadmium, manganese, and arsenic) induced more kidney toxicity as compared to each metal alone. Rats with diabetes were more prone to kidney damage from these metals compared to rats without diabetes (Riaz et al. 2019). In mice, proanthocyanidins from grapes were protective against diabetic kidney disease caused by cadmium (Gong et al. 2022).
High Blood Pressure
Hypertension (high blood pressure) is also associated with cadmium exposure (Garner and Levallois, 2017; Van Larebeke et al. 2015). A review discusses the synergism between kidney cadmium toxicity, diabetes, and high blood pressure (Satarug et al. 2017). The mechanisms involved linking cadmium and mercury to high blood pressure are reviewed by da Cunha Martins et al. 2018. The associations between cadmium and blood pressure may also depend on kidney function (Gao et al. 2018), as well as on sex, ethnicity, and body weight (Wang and Wei, 2018). A review of mercury and blood pressure in children and adolescents finds that four (of eight) articles found a positive significant association between chronic mercury exposure and blood pressure in children or adolescents; three of these evaluated prenatal exposures (Gallego-Viñas et al. 2018).
In New Hampshire, maternal prenatal lead levels were associated with statistically significant increases in child systolic blood pressure (Farzan et al. 2018). In European children, childhood levels of copper are associated with higher diastolic blood pressure (Warembourg et al. 2019). In Korea, higher mercury levels were associated with high blood pressure in people living near abandoned metal mines (Kim et al. 2019).
In animals, rats exposed to low levels of mercury developed high blood pressure, which then disappeared after the exposure was removed (Rizzetti et al. 2017).
Exposure to lead and cadmium alone or in combination was associated with higher risk of cardiovascular disease mortality (as well as mortality from any cause) among U.S. adults with diabetes (Zhu et al. 2022).
Various metals have also been associated with atherosclerosis (hardening and narrowing of the arteries), another diabetes complication (Lind et al. 2012; Obeng-Gyasi 2020; Riffo-Campos et al. 2018). 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). Another review finds that, "Exposure to arsenic, lead, cadmium, and copper is associated with an increased risk of cardiovascular disease and coronary heart disease. Mercury is not associated with cardiovascular risk." (Chowdhury et al. 2018).
Eating fish high in arsenic and mercury is associated with higher cholesterol levels in Spain (Aranda et al. 2017). Children exposed to electronic waste in China with higher blood lead levels have cardiovascular abnormalities, more inflammation, and higher cholesterol levels (Lu et al. 2018). U.S. studies have found tungsten associated with cardiovascular disease, an association that may depend on levels of molybdenum (Nigra et al. 2018).
In the U.S., levels of some metals have declined in recent decades. Some authors argue that this decline in lead and/or cadmium levels may help explain the reduction in deaths from cardiovascular disease since the 1980s and saved tens of thousands of lives (Brown et al. 2020; Ruiz-Hernandez et al. 2017).
In Chinese adults with type 2 diabetes, of 23 metals measured, and over 6 years of follow up, zinc and selenium levels were associated with a lower risk of developing cardiovascular disease, and strontium with a higher risk (Long et al. 2019). In China, certain metals are associated with stroke as well (Wen et al. 2019; Xiao et al. 2019).
Mercury can cause cardiovascular damage, and egg white proteins are protective against that damage, in rats (Rizzetti et al. 2017).
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).
Fatty Liver Disease
U.S. adults with higher levels of mercury and lead in their bodies have higher levels of non-alcoholic fatty liver disease (NAFLD) markers (Wahlang et al. 2019). U.S. adolescents have a higher risk of NAFLD if they have higher levels of mercury in their bodies, especially non-Hispanic whites, and those of normal or under weight (Chen et al. 2019). In Taiwan, heavy metal levels in soil was associated with a higher risk of fatty liver disease in men, especially lean men (Lin et al. 2017). In Korea, people with higher cadmium levels had a higher risk of NAFLD, at levels lower than previously reported (Park et al. 2020).
Cadmium levels in young adulthood was associated with a higher risk of NAFLD 23 years later in life the general U.S. population (Li et al. 2021).
Chronic lead exposure during early childhood is associated with higher levels of liver disease markers in young Mexican adults (Betanzos-Robledo et al. 2021).
Blood mercury levels were positively associated with NAFLD in both overweight and non-obese people in Korea (Yang et al. 2021).
Chinese people with higher lead levels had a higher risk of fatty liver disease, and in animals, lead exposure caused fatty liver, increased visceral fat, and changes to gut microbiota (Wan et al. 2022). Koreans with higher metal levels also have higher NFALD risk (Nguyen and Kim, 2022).
In rodent studies, metals are some of the multiple chemicals associated with NAFLD (Al-Eryani et al. 2015). In zebrafish, used to study the effects of contaminants, cadmium exposure caused higher total cholesterol and triglyceride levels, and accelerated fatty liver changes (Kim et al. 2018). In mice as well, cadmium exposure can cause NAFLD (He et al. 2019). Whole life, low dose cadmium exposure in mice alters high-fat diet induced NAFLD with outcomes dependent on the cadmium exposure levels. Liver injury and lipid deposition were exacerbated by 5 ppm Cd exposure but attenuated by 0.5 ppm Cd exposure (Young et al. 2022).
In Chinese people with type 2 diabetes, higher copper and lead levels were associated with an increased cancer risk, as were lower zinc and chromium levels (Li et al. 2020).
In Chinese people with diabetes, deficient essential trace elements and accumulated toxic metals were highly associated with the presence of diabetic retinopathy (Zhu and Hua, 2020).
Can Removing Metals from the Body Reduce Diabetes Complications?
Perhaps! Chelation therapy is used to treat lead poisoning by binding with metals and removing them from the body. If someone with diabetes has higher levels of heavy metals, removing them via chelation can help reduce their risk of complications or improve their outcomes (for kidney and cardiovascular disease so far) (Glicklich and Frishman, 2021). A review of chelation therapy and cardiovascular disease found that most found improved outcomes, and that repeated chelation for cardiovascular treatment may provide more benefit to people with diabetes (Ravelli et al. 2022). 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; Moreno et al. 2019; Ouyang et al. 2015), as well as improved markers of kidney disease in people with and without diabetes (Glicklich et al. 2020).