Background: 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. Objectives: 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. Methods: 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. Results: 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. Conclusions: These findings identify increased odds of T2D with arsenic exposure, which are significantly increased in individuals with excess BMI.

Background Elevated body mass index (BMI) is a risk factor for cardiovascular disease, diabetes, cancer, and other diseases. Inflammation or oxidative stress induced by high BMI may explain some of these effects. Millions of people drink arsenic-contaminated water worldwide, and ingested arsenic has also been associated with inflammation, oxidative stress, and cancer. Objectives To assess the unique situation of people living in northern Chile exposed to high arsenic concentrations in drinking water and investigate interactions between arsenic and BMI, and associations with lung and bladder cancer risks. Methods Information on self-reported body mass index (BMI) at various life stages, smoking, diet, and lifetime arsenic exposure was collected from 532 cancer cases and 634 population-based controls. Results In subjects with BMIs <90th percentile in early adulthood (27.7 and 28.6 kg/m2 in males and females, respectively), odds ratios (OR) for lung and bladder cancer combined for arsenic concentrations of <100, 100–800 and >800 μg/L were 1.00, 1.64 (95% CI, 1.19–2.27), and 3.12 (2.30–4.22). In subjects with BMIs ≥90th percentile in early adulthood, the corresponding ORs were higher: 1.00, 1.84 (0.75–4.52), and 9.37 (2.88–30.53), respectively (synergy index=4.05, 95% CI, 1.27–12.88). Arsenic-related cancer ORs >20 were seen in those with elevated BMIs in both early adulthood and in later life. Adjustments for smoking, diet, and other factors had little impact. Conclusion These findings provide novel preliminary evidence supporting the notion that environmentally-related cancer risks may be markedly increased in people with elevated BMIs, especially in those with an elevated BMI in early-life.

BACKGROUND: The prevalence of type 2 diabetes (T2D) has more than doubled since 1980. Poor nutrition, sedentary lifestyle, and obesity are among the primary risk factors. While an estimated 70% of cases are attributed to excess adiposity, there is an increased interest in understanding the contribution of environmental agents to diabetes causation and severity. Arsenic is one of these environmental chemicals, with multiple epidemiology studies supporting its association with T2D. Despite extensive research, the molecular mechanism by which arsenic exerts its diabetogenic effects remains unclear. OBJECTIVES: We conducted a literature search focused on arsenite exposure in vivo and in vitro, using relevant end points to elucidate potential mechanisms of oral arsenic exposure and diabetes development. METHODS: We explored experimental results for potential mechanisms and elucidated the distinct effects that occur at high vs. low exposure. We also performed network analyses relying on publicly available data, which supported our key findings. RESULTS: While several mechanisms may be involved, our findings support that arsenite has effects on whole-body glucose homeostasis, insulinstimulated glucose uptake, glucose-stimulated insulin secretion, hepatic glucose metabolism, and both adipose and pancreatic b-cell dysfunction. DISCUSSION: This review applies state-of-the-science approaches to identify the current knowledge gaps in our understanding of arsenite on diabetes development.

Objective: Evaluate whether arsenic-related diabetes risks differ between people of low and high socioeconomic status (SES). Methods: We used data collected between October 2007-December 2010 from a populationbased cancer case-control study (N=1,301) in Northern Chile, an area with high arsenic water concentrations (>800 μg/L) and comprehensive records of past exposure. Information on lifetime exposure and potential confounders were obtained using structured interviews, questionnaires, and residential histories. Type 2 diabetes was defined as physician-diagnosed diabetes or oral hypoglycemic medication use. SES was measured using a 14-point scale based on ownership of household appliances, cars, internet access, or use of domestic help. Logistic regression was used to assess the relationship between arsenic and diabetes within strata of SES. Results: Among those with low SES, the odds ratio (OR) for diabetes comparing individuals in the highest to lowest tertile of lifetime average arsenic exposure was 2.12 [95% confidence

The global prevalence of type 2 diabetes (T2D) has doubled since 1980. Human epidemiological studies support arsenic exposure as a risk factor for T2D, although the precise mechanism is unclear. We hypothesized that chronic arsenic ingestion alters glucose homeostasis by impairing adaptive thermogenesis, i.e., body heat production in cold environments. Arsenic is a pervasive environmental contaminant, with more than 200 million people worldwide currently exposed to arsenic-contaminated drinking water. Male C57BL/6J mice exposed to sodium arsenite in drinking water at 300 μg/L for 9 wk experienced significantly decreased metabolic heat production when acclimated to chronic cold tolerance testing, as evidenced by indirect calorimetry, despite no change in physical activity. Arsenic exposure increased total fat mass and subcutaneous inguinal white adipose tissue (iWAT) mass. RNA sequencing analysis of iWAT indicated that arsenic dysregulated mitochondrial processes, including fatty acid metabolism. Western blotting in WAT confirmed that arsenic significantly decreased TOMM20, a correlate of mitochondrial abundance; PGC1A, a master regulator of mitochondrial biogenesis; and, CPT1B, the rate-limiting step of fatty acid oxidation (FAO). Our findings show that chronic arsenic exposure impacts the mitochondrial proteins of thermogenic tissues involved in energy expenditure and substrate regulation, providing novel mechanistic evidence for arsenic’s role in T2D development.