Arsenic, one carbon metabolism and diabetes-related outcomes in the Strong Heart Family Study

Miranda J. Spratlen, Maria Grau-Perez, Jason G. Umans, Joseph Yracheta, Lyle G. Best, Kevin Francesconi, Walter Goessler, Poojitha Balakrishnan, Shelley A. Cole, Mary V. Gamble, Barbara V. Howard, Ana Navas-Acien

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Background: Inorganic arsenic exposure and inter-individual differences in its metabolism have been associated with cardiometabolic risk. A more efficient arsenic metabolism profile (lower MMA%, higher DMA%) has been associated with reduced risk for arsenic-related health outcomes; however, this profile has also been associated with increased risk for diabetes-related outcomes. The mechanism behind these contrasting associations is equivocal; we hypothesized one carbon metabolism (OCM) may play a role. Methods: We evaluated the association between OCM-related variables (nutrient intake and genetic variants) and both arsenic metabolism biomarkers (iAs%, MMA% and DMA%) and diabetes-related outcomes (metabolic syndrome, diabetes, HOMA2-IR and waist circumference) in 935 participants free of prevalent diabetes and metabolic syndrome from the Strong Heart Family Study, a family-based prospective cohort comprised of American Indian tribal members aged 14+ years. Results: Of the 935 participants free of both diabetes and metabolic syndrome at baseline, 279 (29.8%) developed metabolic syndrome over a median of 5.3 years of follow-up and of the 1458 participants free of diabetes at baseline, 167 (11.3%) developed diabetes over follow-up. OCM nutrients were not associated with arsenic metabolism, however, higher vitamin B6 was associated with diabetes-related outcomes (higher HOMA2-IR and increased risk for diabetes and metabolic syndrome). A polymorphism in an OCM-related gene, methionine synthase (MTR), was associated with both higher MMA% (β = 2.57, 95% CI: 0.22, 4.92) and lower HOMA2-IR (GMR = 0.79, 95% CI = 0.66, 0.93 per 5 years of follow-up). Adjustment for OCM variables did not affect previously reported associations between arsenic metabolism and diabetes-related outcomes; however, the association between the MTR variant and diabetes-related outcomes were attenuated after adjustment for arsenic metabolism. Conclusions: Our findings suggest MMA% may be a partial mediator in the association between OCM and diabetes-related outcomes. Additional mediation analyses with longer follow-up period are needed to confirm this finding. Further research is needed to determine whether excess B vitamin intake is associated with increased risk for diabetes-related outcomes.

Original languageEnglish (US)
Pages (from-to)728-740
Number of pages13
JournalEnvironment international
StatePublished - Dec 2018
Externally publishedYes


  • American Indians
  • Arsenic
  • Arsenic metabolism
  • Diabetes
  • Metabolic syndrome
  • One carbon metabolism

ASJC Scopus subject areas

  • Environmental Science(all)


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