3.1. Association of Lead and Other Metals with Metabolic Disorders
Although there is substantial epidemiological evidence that exposure to low levels of various environmental chemicals can influence the development of chronic metabolic diseases including diabetes [22
], there are very few studies specifically designed to examine the effect of lead-exposure on diabetes development. In the absence of such studies, it may be informative to examine investigations on the metabolic effects of other metals. Additional relevant information can be derived from epidemiological studies on lead exposure that while not directly measuring diabetes risk, have examined pathologies related to diabetes (e.g., fatty liver) that can be interpreted as indirect markers of the disease. This section will review these studies as well as the small number of studies that have looked specifically at lead exposure levels and diabetes incidence.
As mentioned above, only a small number of studies have directly examined the correlation between blood lead levels and diabetes incidence. Kolachi et al. found that blood hair and urine lead was higher in diabetic compared to non-diabetic females. However, both cadmium and arsenic were higher in the diabetes group, making it difficult to assign a specific role to lead [11
]. In an earlier study with factory workers in the United Arab Emirates significant positive correlations between blood lead levels and fasting blood glucose were observed, suggesting a possible link between lead exposure and diabetes. This study also found an association between lead exposure and blood pressure [10
Numerous studies have examined the effects of metal exposures on the function of the endocrine pancreas [3
]. Although lead levels were not independently evaluated in these studies, together they suggest a deleterious effect of metal exposure on the islet function and are consistent with the possibility that lead exposure degrades endocrine pancreas function.
Fatty liver, especially the form not associated with excessive alcohol consumption—known as NAFLD (non-alcoholic fatty liver disease) co-exists with type 2 diabetes. In some populations up to 70% of diabetic patients also have NAFLD [23
], which makes NAFLD incidence a reasonable predictor of type 2 diabetes rates. Given the physiological relationship between these two syndromes, an observed correlation between fatty liver and lead exposure could suggest a causative link between exposure to lead and diabetes.
In a recent study of the population living in the Yangtze river delta in China, Zhai et al. found that elevated blood lead levels were associated with an increased risk of NAFLD in both men and women, although the association was significantly stronger in women [5
]. Consistent with this NAFLD study is an earlier study carried out with data from the 2003–2004 NHANES cohort. Cave et al. observed correlation between blood lead levels and a general marker of liver disease—elevated serum alanine aminotransferase (ALT) [4
]. Although altered ALT levels are associated with multiple types of hepatic dysfunction, the observation that they are elevated in lead-exposed individuals is consistent with there being a causative link between lead exposure levels and the kinds of liver dysfunction associated with diabetes, such as NAFLD. It must be noted however that in this study lead levels were evaluated together with the heavy metals mercury and cadmium, so it is not possible to assign the deleterious liver effects specifically to lead exposure.
Although, as discussed above, there are few studies that have specifically examined the effect of lead exposure on diabetes rates in the human population, several studies have looked for correlations between lead exposure and other metabolic and endocrine parameters that are potentially related to diabetes.
Many of these studies examined industrial lead workers who had substantially higher levels of exposure than typically seen today (see above). Although this may reduce the direct relevance of these studies to general human exposure situation, they highlight potential physiological effects of lead that may be minor when exposure levels are low, but that still may pose a long-term health threat as the exposed population ages. Studies examining lead industry workers identified a mild correlation of blood lead levels with systolic blood pressure [25
] and kidney function [26
The findings from highly exposed individual are consistent with observations from non-industrial worker cohorts where correlations between lead levels and kidney function were observed even at much lower levels of exposure. Using data from the normative aging study Tsaih et al. observed a correlation between specific parameters of kidney function and lead levels in blood and bone [29
], and that this effect was stronger in patients with diabetes and hypertension. A similar effect on kidney was seen in a study on teenagers where higher blood lead levels correlated with reduced kidney function (glomerular filtration rate) [30
While these findings do not directly address the question of whether lead-exposure in the human population promotes the development of diabetes, they do demonstrate that lead has deleterious effects on physiological systems that are crucial for the maintenance of normal metabolic balance.
3.2. Rodent Studies
Although there have been more studies in animal models than in humans, there is still a relatively small literature on the effect of lead exposure on metabolism in animal models. Several early studies in the 1970s and 80s suggested that lead exposure could induce hepatic insulin resistance in rats. Singhal et al. [31
] reported that male rats treated with lead acetate by intraperitoneal injection, showed a dose- dependent increase in amounts of the gluconeogenic enzymes phophoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in the liver. Consistent with the lead-induced increases in gluconeogenic gene expression, this study also reported a dose-responsive increase in fasting blood glucose. A similar finding was reported by Stevenson et al. in young female rats exposed to 20, 40 or 80 ppm lead for 56 days in drinking water [32
]. These animals also showed a dose-responsive increase in PEPCK and G6Pase enzyme levels in the liver and significantly elevated fasting blood glucose. Finally, Whittle et al. demonstrated that even small increases in blood lead levels from a control level of 7.9 ± 1.4 µg/dL to 13.8 ± 1.3 μg/dL, for 42 days caused a significant increase in expression of hepatic gluconeogenic enzymes in rats [33
While these findings strongly suggest that lead exposure induces hepatic glucose production and thereby contribute to elevated blood glucose levels, they were somewhat limited in technical scope and do not provide much information about potential mechanisms by which lead has these effects in the liver.
The pro-diabetic effects of lead exposure on the liver were observed in recent studies that examined the effect of lead on hepatic metabolism in normal rats. When rats were exposed to lead acetate in drinking water, increased enzymatic activity of hepatic PEPCK and G6Pase were observed together with a mild increase in fasting glucose and glucose intolerance [34
]. Interestingly, in obese rats the metabolic effects appeared to be stronger with pronounced elevated glycemia and glucose intolerance [35
]. Both studies also explored potential mechanism by which lead might affect metabolic balance. Mostafalou et al. demonstrated that ex vivo, lead treatment suppressed glucose stimulated insulin secretion from islets, possibly by activating glycogen synthase kinase (GSK-3β kinase) [34
]. Tyrrell et al. demonstrated that livers from exposed rats had elevated transcript levels of both PEPCK and G6Pase gluconeogenic genes and also showed that this effect could be recapitulated in vitro in lead-treated hepatoma cell lines [35
]. Together these studies indicate that lead can have direct effects on cells from metabolically relevant organs.
3.3. Epigenetic Effects of Lead Exposure
As described above, a common route of lead exposure in humans occurs early in childhood by ingestion of lead-contaminated household dust [36
]. This exposure route is generally limited to early childhood during the period in which toddlers ingest large amounts of household dust. As children age they dramatically reduce the ingestion of non-food material and their exposure to lead diminishes. This childhood exposure pattern raises the question of whether a limited exposure to lead early in life could induce persistent changes in physiology, even in the absence of continued exposure, that manifest themselves as disease later in life.
A substantial literature exists related to how early in life conditions influence later in life health; essentially the DOHaD or Developmental Origins of Health and Disease hypothesis [37
]. There are multiple examples of specific early in life stresses—for example nutritional deprivation [38
], emotional stress [39
] or chemical exposures [40
]—that have negative effects on various aspects of adult health. These long-lasting health effects of early life stresses, can be attributed to specific epigenetic mechanisms such as altered DNA methylation patterns [37
]. Previous studies have shown that exposure to environmental chemicals can induce epigenetic changes that persist for long periods of time and potentially affect physiology and health [41
]. In the context of childhood lead exposure in humans and its potential adult health effects, it is of interest to know if lead exposures induce detectable epigenetic changes of any variety.
There is clear evidence that lead exposure induces changes in DNA methylation at specific loci in humans. Sen et al. examined umbilical cord blood from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) study participants [42
]. When cord blood from individuals in the lowest and highest lead exposure groups were compared, clear differences in DNA methylation patterns were observed. Analogous findings were also observed in populations of Detroit mothers and infants [43
]. These findings raise several interesting possibilities. First, it is possible that specific DNA methylation patterns might be useful as early biomarkers of prenatal lead exposure. Second, they raise the possibility that early life lead exposures leave long lasting epigenetic imprints that alter physiology and potentially affect health later in life.
An interesting aspect of epigenetic imprinting is the potential for inheritance of imprints across multiple generations. With regard to lead exposure, Sen et al. found that moms with high blood lead had children as well as grandchildren with exposure-specific epigenetic DNA methylation patterns [43
]. If DNA methylation patterns do indeed have the capacity to influence physiology, then these findings raise the possibility that lead exposure in a previous generation could have effects on health in subsequent generations.
The possibility that early life lead exposure induces later in life health problems is supported by multiple studies in rodents. When mice were perinatally exposed to levels of lead similar to those commonly seen in humans, they exhibited neurological deficits in adult mice and late-onset obesity [44
]. In another study perinatal lead exposure was found to affect multiple metabolic and activity parameters over the course of the life of the animal [45
]. Interestingly, these authors observed sex differences in how lead exposure affected metabolic parameters. Finally, analogous to the human studies described above, persistent DNA methylation patterns at specific loci were induced by perinatal-limited exposure to lead [45