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

Abstract

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.

Keywords: American Indians; Arsenic; Arsenic metabolism; Diabetes; Metabolic syndrome; One carbon metabolism.

Figure 1.

Study Flow Diagram

Figure 2.. Role of One Carbon Metabolism Related Nutrients and Genes in One Carbon Metabolism Pathway.

Genes are identified in pink and nutrients are identified in green. a) the PEMT gene encodes the PEMT enzyme which converts phosphatidylethanolamine to phosphatidylcholine which supports the remethylation of homocysteine through the choline dependent pathway; b) the CBS gene encodes the CBS enzyme which uses c) vitamin B₆ as a co-factor to convert homocysteine into cystathionine; d) Vitamin B₆ is also used as a co-factor in the e) SHMT1-catalyzed conversion of tetrahydrofolate to 5,10 methylene tetrahydrofolate; f) the MTHFD1 gene encodes a protein with three enzymatic activities, each involved in the conversion of tetrahydrofolate to 5,10 methylene tetrahydrofolate; g) the MTHFR gene encodes the rate limiting enzyme MTHFR which catalyzes the conversion of 5,10 methylene tetrahydrofolate to 5-methyl tetrahydrofolate using h) vitamin B₂, in the form of flavin adenine dinucleotide, as a co-factor; 5-methyl tetrahydrofolate can also enter the one carbon metabolism pathway through intake of i) dietary folate; j) MTR catalyzes the conversion of homocysteine to methionine using k) B₁₂ as a co-factor and 5-methyl tetrahydrofolate as the methyl donor; MTR is reactivated through reductive remethylation by l) MTRR. Abbreviations: CBS (Cystathionine beta synthase); MTHFD1 (Methylenetetrahydrofolate Dehydrogenase); MTHFR (Methylenetetrahydrofolate reductase); MTR (Methionine synthase); MTRR (Methionine synthase reductase); PEMT (Phosphatidylethanolamine N-Methyltransferase), SHMT1 (Serine hydroxymethyltransferase)