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. 2015 Apr;38(4):620-7.
doi: 10.2337/dc14-1641. Epub 2015 Jan 12.

Arsenic Exposure, Arsenic Metabolism, and Incident Diabetes in the Strong Heart Study

Chin-Chi Kuo  1 , Barbara V Howard  2 , Jason G Umans  2 , Matthew O Gribble  3 , Lyle G Best  4 , Kevin A Francesconi  5 , Walter Goessler  5 , Elisa Lee  6 , Eliseo Guallar  7 , Ana Navas-Acien  8
Affiliations

Arsenic Exposure, Arsenic Metabolism, and Incident Diabetes in the Strong Heart Study

Chin-Chi Kuo et al. Diabetes Care. 2015 Apr.

Abstract

Objective: Little is known about arsenic metabolism in diabetes development. We investigated the prospective associations of low-moderate arsenic exposure and arsenic metabolism with diabetes incidence in the Strong Heart Study.

Research design and methods: A total of 1,694 diabetes-free participants aged 45-75 years were recruited in 1989-1991 and followed through 1998-1999. We used the proportions of urine inorganic arsenic (iAs), monomethylarsonate (MMA), and dimethylarsinate (DMA) over their sum (expressed as iAs%, MMA%, and DMA%) as the biomarkers of arsenic metabolism. Diabetes was defined as fasting glucose ≥ 126 mg/dL, 2-h glucose ≥ 200 mg/dL, self-reported diabetes history, or self-reported use of antidiabetic medications.

Results: Over 11,263.2 person-years of follow-up, 396 participants developed diabetes. Using the leave-one-out approach to model the dynamics of arsenic metabolism, we found that lower MMA% was associated with higher diabetes incidence. The hazard ratios (95% CI) of diabetes incidence for a 5% increase in MMA% were 0.77 (0.63-0.93) and 0.82 (0.73-0.92) when iAs% and DMA%, respectively, were left out of the model. DMA% was associated with higher diabetes incidence only when MMA% decreased (left out of the model) but not when iAs% decreased. iAs% was also associated with higher diabetes incidence when MMA% decreased. The association between MMA% and diabetes incidence was similar by age, sex, study site, obesity, and urine iAs concentrations.

Conclusions: Arsenic metabolism, particularly lower MMA%, was prospectively associated with increased incidence of diabetes. Research is needed to evaluate whether arsenic metabolism is related to diabetes incidence per se or through its close connections with one-carbon metabolism.

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Figures

Figure 1
Figure 1
The triplot presents the distribution of arsenic metabolism biomarkers in participants with and without incident diabetes (red dots and gray dots, respectively). The large dark-red and black solid dots represent the compositional arsenic metabolism mean for participants with and without incident diabetes, respectively. iAs% is presented along the blue axis, MMA% along the red axis, and DMA% along the green axis. Compared with the black dot (participants without incident diabetes), the dark-red dot (participants with incident diabetes) was much closer to the apex of DMA% and farther away from the apex of MMA%, indicating that participants with incident diabetes had lower MMA% and higher DMA% at baseline.
Figure 2
Figure 2
Hazard ratios for incident diabetes by arsenic metabolism biomarkers. Solid lines (shaded area) represent adjusted hazard ratios (95% CI) based on restricted quadratic splines with knots at the 10th, 50th, and 90th percentiles. The reference value was set at the 10th percentile of each arsenic metabolism biomarker. The solid line represents the hazard ratio for iAs% when it replaces MMA% (red line) and DMA% (blue line) in the left panel, the hazard ratio for MMA% when it replaces iAs% (red line) and DMA% (green line) in the middle panel, and the hazard ratio for DMA% when it replaces iAs% (blue line) and MMA% (green line) in the right panel. The histogram represents the distributions of arsenic metabolism biomarkers (iAs%, MMA%, and DMA%) among the study participants. The extreme tails of the histogram were truncated because 12 participants had an iAs% >30%, 25 had an MMA% >30%, 10 had a DMA% <45%, and 1 had a DMA% >95%.
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