Targeted metabolomics to understand the association between arsenic metabolism and diabetes-related outcomes: Preliminary evidence from the Strong Heart Family Study

Environ Res. 2019 Jan;168:146-157. doi: 10.1016/j.envres.2018.09.034. Epub 2018 Sep 27.


Background: Inorganic arsenic exposure is ubiquitous and both 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. This profile, however, has also been associated with increased risk for diabetes-related outcomes.

Objectives: The mechanism behind these conflicting associations is unclear; we hypothesized the one-carbon metabolism (OCM) pathway may play a role.

Methods: We evaluated the influence of OCM on the relationship between arsenic metabolism and diabetes-related outcomes (HOMA2-IR, waist circumference, fasting plasma glucose) using metabolomic data from an OCM-specific and P180 metabolite panel measured in plasma, arsenic metabolism measured in urine, and HOMA2-IR and FPG measured in fasting plasma. Samples were drawn from baseline visits (2001-2003) in 59 participants from the Strong Heart Family Study, a family-based cohort study of American Indians aged ≥14 years from Arizona, Oklahoma, and North/South Dakota.

Results: In unadjusted analyses, a 5% increase in DMA% was associated with higher HOMA2-IR (geometric mean ratio (GMR)= 1.13 (95% CI: 1.03, 1.25)) and waist circumference (mean difference=3.66 (0.95, 6.38). MMA% was significantly associated with lower HOMA2-IR and waist circumference. After adjustment for OCM-related metabolites (SAM, SAH, cysteine, glutamate, lysophosphatidylcholine 18.2, and three phosphatidlycholines), associations were attenuated and no longer significant.

Conclusions: These preliminary results indicate that the association of lower MMA% and higher DMA% with diabetes-related outcomes may be influenced by OCM status, either through confounding, reverse causality, or mediation.

Keywords: American Indians; Metabolomics; arsenic metabolism; diabetes; one carbon metabolism.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Arizona
  • Arsenic* / metabolism
  • Arsenic* / toxicity
  • Cohort Studies
  • Diabetes Mellitus* / epidemiology
  • Diabetes Mellitus* / metabolism
  • Environmental Exposure
  • Female
  • Humans
  • Indians, North American
  • Male
  • Metabolomics
  • Middle Aged
  • Oklahoma


  • Arsenic