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The prevalence of type 2 diabetes (T2D) has nearly doubled since 1980. Elevated body mass index (BMI) is the leading risk factor for T2D, mediated by inflammation and oxidative stress. Arsenic shares similar pathogenic processes, and may contribute to hyperglycemia and β-cell dysfunction.We assessed a unique situation of individuals living in Northern Chile with data on lifetime arsenic exposure to evaluate the relationship between arsenic and T2D, and investigate possible interactions with BMI.We analyzed data collected from October 2007-December 2010 from an arsenic-cancer case-control study. Information on self-reported weight, height, smoking, diet, and other factors were obtained. Diabetes was defined by self-reported physician-diagnoses or use of hypoglycemic medication. A total of 1053 individuals, 234 diabetics and 819 without known diabetes were included.The T2D odds ratio (OR) for cumulative arsenic exposures of 610–5279 and ≥ 5280 μg/L-years occurring 40 years or more before interview were 0.97 (95% CI: 0.66–1.43) and 1.53 (95% CI: 1.05–2.23), respectively. Arsenic-associated T2D ORs were greater in subjects with increased BMIs. For example, the ORs for past cumulative exposures ≥ 5280 μg/L-years was 1.45 (95% CI: 0.74–2.84) in participants with BMIs < 25 kg/m2 but 2.64 (95% CI: 1.14–6.11) in those with BMIs ≥ 30 kg/m2 (synergy index = 2.49, 95% CI: 0.87–7.09). Results were similar when people with cancer were excluded.These findings identify increased odds of T2D with arsenic exposure, which are significantly increased in individuals with excess BMI.Northern Chile is one of the driest places on earth.Historical arsenic water measurements allow for estimation of lifetime exposure.Increased odds of type 2 diabetes with arsenic exposure observed.Synergistic relationship between arsenic and obesity on type 2 diabetes identified.