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 1,458 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 all diabetes-related outcomes were attenuated or reversed direction after adjustment for arsenic metabolism Conclusions: Our findings suggest MMA% may be a partial mediator in the association between OCM and diabetes-related outcomes. Formal mediation analyses with longer follow-up period are needed to confirm this finding. Additional research is needed to determine whether excess B vitamin intake is associated with increased risk for diabetes-related outcomes.

Influence of Dietary Compounds on Arsenic Metabolism and Toxicity. Part II—Human Studies

“…In the study by Spratlen et al [30], vitamin B 2 intake was positively related with urinary %DMA, while no such relationship was shown in other studies [27,28,[31][32][33]. In contrast, a negative association with %iAs was shown in the study by Spratlen et al [30], while no such relationship was observed in other studies [27,28,[31][32][33]. There was no significant relationship between vitamin B 2 intake and urinary excretion of tAs [34].…”

“…Both studies showed a negative association with urinary %iAs [24,30], while the study by Argos et al [34] showed a positive association with tAs in the urine. On the other hand, in several studies, there was no relationship between vitamin B 6 intake and urinary %iAs metabolite excretion [27,28,31,33].…”

“…Additionally, in several studies, there were no relationships [28,[31][32][33]. In the study by Spratlen et al [30], vitamin B 2 intake was positively related with urinary %DMA, while no such relationship was shown in other studies [27,28,[31][32][33]. In contrast, a negative association with %iAs was shown in the study by Spratlen et al [30], while no such relationship was observed in other studies [27,28,[31][32][33].…”

“…One study showed a positive association between vitamin B 2 intake and urinary %MMA [27], while another study showed a negative association with this form [30]. Additionally, in several studies, there were no relationships [28,[31][32][33]. In the study by Spratlen et al [30], vitamin B 2 intake was positively related with urinary %DMA, while no such relationship was shown in other studies [27,28,[31][32][33].…”

“…None of the studies observed a relationship between folic acid intake and urinary %MMA and %DMA [27,28,[30][31][32][33]. In contrast, the study by Howe et al [35] showed that intake of sum of vitamins B 2 , B 6 , B 12 and folate had a negative association with the proportion of monomethyl arsenic species.…”