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The Association of Arsenic Exposure and Metabolism With Type 1 and Type 2 Diabetes in Youth: The SEARCH Case-Control Study

Grau-Perez M, Kuo CC, Spratlen M, Thayer KA, Mendez MA, Hamman RF, Dabelea D, Adgate JL, Knowler WC, Bell RA, Miller FW, Liese AD, Zhang C, Douillet C, Drobná Z, Mayer-Davis EJ, Styblo M, Navas-Acien A.
Diabetes Care (2017) DOI: https://doi.org/10.2337/dc16-0810 PMID: 27810988



Little is known about arsenic and diabetes in youth. We examined the association of arsenic with type 1 and type 2 diabetes in the SEARCH for Diabetes in Youth Case-Control (SEARCH-CC) study. Because one-carbon metabolism can influence arsenic metabolism, we also evaluated the potential interaction of folate and vitamin B12 with arsenic metabolism on the odds of diabetes.
Six hundred eighty-eight participants <22 years of age (429 with type 1 diabetes, 85 with type 2 diabetes, and 174 control participants) were evaluated. Arsenic species (inorganic arsenic [iAs], monomethylated arsenic [MMA], dimethylated arsenic [DMA]), and one-carbon metabolism biomarkers (folate and vitamin B12) were measured in plasma. We used the sum of iAs, MMA, and DMA (∑As) and the individual species as biomarkers of arsenic concentrations and the relative proportions of the species over their sum (iAs%, MMA%, DMA%) as biomarkers of arsenic metabolism.
Median ∑As, iAs%, MMA%, and DMA% were 83.1 ng/L, 63.4%, 10.3%, and 25.2%, respectively. ∑As was not associated with either type of diabetes. The fully adjusted odds ratios (95% CI), rescaled to compare a difference in levels corresponding to the interquartile range of iAs%, MMA%, and DMA%, were 0.68 (0.50-0.91), 1.33 (1.02-1.74), and 1.28 (1.01-1.63), respectively, for type 1 diabetes and 0.82 (0.48-1.39), 1.09 (0.65-1.82), and 1.17 (0.77-1.77), respectively, for type 2 diabetes. In interaction analysis, the odds ratio of type 1 diabetes by MMA% was 1.80 (1.25-2.58) and 0.98 (0.70-1.38) for participants with plasma folate levels above and below the median (P for interaction = 0.02), respectively.
Low iAs% versus high MMA% and DMA% was associated with a higher odds of type 1 diabetes, with a potential interaction by folate levels. These data support further research on the role of arsenic metabolism in type 1 diabetes, including the interplay with one-carbon metabolism biomarkers.


Figure 1. Triplot representing the compositional means for arsenic metabolism biomarkers.

Triplot representing the compositional means for arsenic metabolism biomarkers (iAs%, MMA%, and DMA%) in control participants and participants with type 1 diabetes (T1D) and type 2 diabetes (T2D). The P values comparing the arsenic metabolism biomarker compositional means were 0.02 for T1D vs. control, 0.12 for T2D vs. control, and 0.87 for T1D vs. T2D.

Figure 2. ORs and 95% CI for type 1 and type 2 diabetes.

ORs and 95% CI for type 1 and type 2 diabetes by MMA% in plasma and by folate and vitamin B12 levels. ORs were obtained by comparing the 75th vs. 25th percentiles of MMA% distribution among control participants. The 75th and 25th percentiles of MMA% distribution among control participants were 14.9% and 6.3%, respectively. ORs were also adjusted for age (continuous), sex, BMI (continuous), parental educational level (≤12, >12 years), race/ethnicity (non-Hispanic white, African American, Hispanic), total folate levels (continuous), and/or vitamin B12 levels (continuous). The area of each data marker is proportional to each subsample size.


Table 1. Participant characteristics by diabetes status.

Table 2. ORs (95% CI) for type 1 and type 2 diabetes and interquartile range increase.

ORs (95% CI) for type 1 and type 2 diabetes and interquartile range increase (i.e., participants in the 75th vs. 25th percentiles) in measures of arsenic species in plasma

Supplemental Materials

Supplementary Tables and Figures