Could Arsenic Exposure Contribute to Type 1 Diabetes in Youths?

Liam Davenport

November 30, 2016

Alterations in the metabolism of arsenic appear to be associated with an increased risk of type 1 diabetes among young people, say US researchers, who nevertheless underscore the need for further research on the issue in this patient population.

Arsenic is toxic and a carcinogen but occurs naturally in the environment, most commonly in groundwater. It can also contaminate dietary sources, such as rice, grains, and certain fruit juices and, as such, is increasingly seen as a health concern.

In their new paper, Maria Grau Pérez, department of environmental health sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, and colleagues found that relative changes in plasma arsenic and arsenic metabolites significantly increased the likelihood of having type 1 diabetes. Moreover, this association was, in part, moderated by plasma folate levels, which are involved in one-carbon metabolism and have previously been shown to influence arsenic metabolism.

The research, which was published online recently in Diabetes Care, is the first to demonstrate such associations in children, although they have previously been observed in adults.

The team writes: "These findings provide novel evidence that links arsenic and diabetes in youth and support the need for additional research that focuses specifically on the relationship with arsenic metabolism…on type 1 and type 2 diabetes development."

And senior study author Ana Navas-Acien, MD, PhD, professor of environmental health sciences, Mailman School of Public Health, Columbia University, New York, told Medscape Medical News that these new results underline the importance of clinicians being aware of the potential for arsenic exposure.

Three Possibilities Could Explain Results

Approached for comment, Christoph Buettner, MD, PhD, professor of medicine and neuroscience, and Kathryn Bambino, PhD, a postdoctoral fellow in the department of environmental medicine and public health, both at Mount Sinai School of Medicine, New York, agreed that the novelty of the study is that it examines the association between arsenic and diabetes in children.

"This study provides some evidence of an association between arsenic and type 1 diabetes, which suggests increased exposure, altered metabolism, or decreased clearance of arsenic metabolites is associated with type 1 diabetes in adolescents," Dr Bambino told Medscape Medical News.

But "it's important to note that at this stage it is unclear which of these three possibilities accounts for this association and if it bears any causality to diabetes or if diabetes simply alters the metabolism or clearance of arsenic," Dr Buettner stressed.

It is also unclear how accurate plasma arsenic is as a measure of arsenic exposure, and high arsenic metabolites may simply reflect a general alteration in metabolism, rather than one specific to arsenic, or a decrease in clearance.

"Carefully controlled animal studies should be able to establish causality," he added.

Dr Navas-Acien agreed that it was it is not possible to determine causality in the association between arsenic metabolism and the development of type 1 diabetes, due to the cross-sectional nature of the study.

Hence, it's feasible that the relationship could be the other way around — that is, early diabetes could have an impact on the metabolism in the body and "affect the way that arsenic is handled," she acknowledged.

Studies in adult populations have found that there is a "prospective association," in that alterations in arsenic metabolism "could precede and increase the risk of future diabetes development," she noted.

However, she added that this is the first time this has been evaluated in children, "so we are looking to be very careful with the temporality or even to imply that what we found in adults could also apply to what we find in children.

"To know in which direction it's going we absolutely need longitudinal studies, with repeated measures, in the children before they have the disease, once the disease evolves, and over time," she added. "That will be very important."

Research such as this could help in the development of prevention programs, Dr Navas-Acien said — "either to prevent diabetes for individuals who are exposed to arsenic or who have a different way of metabolizing arsenic or to prevent the consequences of those metabolic changes to arsenic among those who have diabetes."

Biomarkers of Arsenic Concentration and Metabolism

To examine the association between arsenic and both type 1 and type 2 diabetes, the researchers used data on 688 participants aged between 10 and 22 years from the SEARCH for Diabetes in Youth case-control study performed in Columbia, South Carolina and Denver, Colorado.

Plasma levels of inorganic arsenic (iAs) were measured in stored blood samples, alongside levels of monomethylated arsenic (MMA) and dimethylated arsenic (DMA), which have been shown in adult studies to be linked to an increased prevalence and incidence of diabetes, and a sum of the three was also calculated — all of these measures were used as biomarkers of arsenic concentrations.

In addition, the relative proportions of the species over their sum, expressed as iAs%, MMA% and DMA%, served as biomarkers of arsenic metabolism.

As one-carbon metabolism nutrients, such as folate and vitamin B12, are associated with both arsenic metabolism and diabetes-related outcomes, the researchers also measured total folate and vitamin B12 plasma concentrations and analyzed the interaction with the impact of arsenic metabolism on diabetes.

The analysis included 429 individuals with type 1 diabetes, 85 with type 2 diabetes, and 174 controls, who had at average age of 14.7 years, 15.8 years, and 14.1 years, respectively.

Compared with controls, type 1 diabetes individuals were more likely to be male and non-Hispanic white, have higher parental education, be leaner, and have higher vitamin B12 levels. Individuals with type 2 diabetes were, compared with controls, more likely to belong to a racial/ethnic minority, be obese, have lower parental education, and have lower plasma folate and vitamin B12 levels.

There was no association between the sum of iAs, MMA, and DMA (biomarker of arsenic concentrations) and either type 1 or type 2 diabetes, although type 1 diabetes was associated with lower iAs concentrations in multivariate analysis and with higher MMA and DMA in analyses that excluded arsenic outliers.

For biomarkers of arsenic, low iAs% and high MMA% and DMA% were significantly associated with the development of type 1 diabetes, with a potential interaction by folate levels.

Specifically, the fully adjusted odds ratios, considering age, sex, body mass index, parental education, race/ethnicity, and total folate and vitamin B12 plasma concentrations for the development of type 1 diabetes were 0.68, 1.33, and 1.28 for iAs%, MMA%, and DMA%, respectively.

The fully adjusted ORs odds ratios for the development of type 2 diabetes were 0.82, 1.09, and 1.17 for iAs%, MMA%, and DMA%, although these did not reach statistical significance.

Dr Navas-Acien noted that although the association between arsenic metabolism and type 2 diabetes was not statistically significant, this was likely to be a consequence of the relatively low numbers of individuals with type 2 diabetes in the study.

"Type 2 diabetes is a disease that should not exist in children," she said.

Beware of Potential Arsenic Exposure From Groundwater and Risks

Reiterating to Medscape Medical News the importance of clinicians being aware of potential arsenic exposure, Dr Navas-Acien said arsenic is "ubiquitous in the environment, and the major source is groundwater in many populations.

"For instance, we have many parts of the USA where groundwater is the main source of drinking water for many communities, [and] the problem with groundwater is that it's not regulated. So if the clinician doesn't do something, the families are often not aware that they should be checking their water. They are really left alone.

"Then the other major issue for everybody, but especially for children, is rice. We know that rice crops get arsenic from the soil and the water and, as they grow, they accumulate arsenic.

"This is a very challenging problem because rice is such an important staple and food for all of us, and it's generally considered to be a relatively healthy carbohydrate."

She emphasized that, although families and individuals should not stop eating rice, the relatively high levels of arsenic in rice means that "it's good to have a diverse diet."

But Dr Bambino said the source of arsenic in the current study is not clear.

"The authors claim that the arsenic exposure is likely coming from food due to the fact that participants reside near large municipalities with water supplies....If this is the case, a dietary record should be done to assess intake of food products likely to be contaminated with arsenic."

She added: "Because of the association between exposure to high levels of arsenic and the risk of cancer and other chronic diseases, there should be strict standards for arsenic in both drinking water and food. There are water sources in the United States that are not regulated by the Environmental Protection Agency (ie, private wells) that present additional risk."

This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Environmental Health Sciences. The authors report no relevant financial relationships.

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Diabetes Care. Published online November 11, 2016. Abstract

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