A State-of-the-Science Review of Arsenic's Effects on Glucose Homeostasis in Experimental Models.

BackgroundThe 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.ObjectivesWe 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.MethodsWe 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.ResultsWhile several mechanisms may be involved, our findings support that arsenite has effects on whole-body glucose homeostasis, insulin-stimulated glucose uptake, glucose-stimulated insulin secretion, hepatic glucose metabolism, and both adipose and pancreatic β-cell dysfunction.DiscussionThis review applies state-of-the-science approaches to identify the current knowledge gaps in our understanding of arsenite on diabetes development. https://doi.org/10.1289/EHP4517

Chronic Arsenic Exposure Impairs Adaptive Thermogenesis in Male C57BL/6J Mice

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 parts per billion (ppb) for 9 weeks 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 unilocular lipid droplet size in both subcutaneous inguinal white adipose tissue (iWAT) and brown adipose tissue (BAT). This hypertrophy appeared to be specific to BAT and WAT, as no lipidosis was observed in liver. RNA sequencing analysis of iWAT indicated that arsenic dysregulated mitochondrial processes, including fatty acid metabolism. Western blotting confirmed that arsenic significantly decreased TOMM20 in both BAT and WAT, 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 mitochondria of thermogenic tissues involved in energy expenditure and glucose regulation, providing novel mechanistic evidence for arsenic's role in T2D development

The Effects of Chronic Arsenic Exposure on Thermogenesis and Type 2 Diabetes

The prevalence of type 2 diabetes (T2D) has nearly doubled since 1980. T2D is characterized by hyperglycemia, insulin resistance, and long-term complications. Poor nutrition, sedentary lifestyle, and obesity, are among the strongest risk factors for the development of this metabolic disease. Environmental pollutants however, also have the potential to alter glucose homeostasis and lead to the development of T2D. Arsenic is one of these chemicals, with epidemiologic studies worldwide supporting this association. The precise mechanism of action by which arsenic exhibits its diabetogenic effects however, remains unclear. Since the late 2000s, select heat-producing adipose depots have been identified and shown to be intricately involved in glucose metabolism. Brown and beige adipocytes are important regulators of energy expenditure and both lipid and glucose homeostasis. This dissertation aims to identify whether arsenic increases the risk of T2D development among obese individuals, and identify its effects on thermogenic adipocytes involved in glucose metabolism and energy expenditure. Chapter 1 is a state-of-the-science review of the disruptive effects of arsenic exposure on glucose homeostasis, with an emphasis on findings from experimental studies. Chapter 2 is a cross-sectional analysis of a unique arsenic exposed population in Northern Chile. This chapter examines the effects of arsenic exposure on T2D development, and evaluates whether arsenic and obesity may act synergistically to increase T2D risk. While proposed pathways for arsenic’s role in T2D include alterations in pancreatic β-cell function and insulin secretion, these findings are reported only at high arsenic exposure concentrations. Therefore, further investigation to elucidate arsenic’s diabetogenic molecular targets in mammalian models is required at relevant public health concentrations. Chapter 3 examines the effects of chronic low-dose arsenic exposure on thermogenesis and recruitable beige adipocytes involved in key metabolic pathways in vivo. Chapter 4 informs current statistical methodologies for indirect calorimetry analysis by implementing longitudinal data analysis techniques and randomization-based inference to better capture how environmental chemical exposures alter energy expenditure over time. Lastly, Chapter 5 summarizes the current state of arsenic research within the context of metabolic biology, and highlights how interdisciplinary research has the potential to inform current environmental standards and public health interventions

The Effects of Chronic Arsenic Exposure on Thermogenesis and Type 2 Diabetes

The prevalence of type 2 diabetes (T2D) has nearly doubled since 1980. T2D is characterized by hyperglycemia, insulin resistance, and long-term complications. Poor nutrition, sedentary lifestyle, and obesity, are among the strongest risk factors for the development of this metabolic disease. Environmental pollutants however, also have the potential to alter glucose homeostasis and lead to the development of T2D. Arsenic is one of these chemicals, with epidemiologic studies worldwide supporting this association. The precise mechanism of action by which arsenic exhibits its diabetogenic effects however, remains unclear. Since the late 2000s, select heat-producing adipose depots have been identified and shown to be intricately involved in glucose metabolism. Brown and beige adipocytes are important regulators of energy expenditure and both lipid and glucose homeostasis. This dissertation aims to identify whether arsenic increases the risk of T2D development among obese individuals, and identify its effects on thermogenic adipocytes involved in glucose metabolism and energy expenditure. Chapter 1 is a state-of-the-science review of the disruptive effects of arsenic exposure on glucose homeostasis, with an emphasis on findings from experimental studies. Chapter 2 is a cross-sectional analysis of a unique arsenic exposed population in Northern Chile. This chapter examines the effects of arsenic exposure on T2D development, and evaluates whether arsenic and obesity may act synergistically to increase T2D risk. While proposed pathways for arsenic’s role in T2D include alterations in pancreatic β-cell function and insulin secretion, these findings are reported only at high arsenic exposure concentrations. Therefore, further investigation to elucidate arsenic’s diabetogenic molecular targets in mammalian models is required at relevant public health concentrations. Chapter 3 examines the effects of chronic low-dose arsenic exposure on thermogenesis and recruitable beige adipocytes involved in key metabolic pathways in vivo. Chapter 4 informs current statistical methodologies for indirect calorimetry analysis by implementing longitudinal data analysis techniques and randomization-based inference to better capture how environmental chemical exposures alter energy expenditure over time. Lastly, Chapter 5 summarizes the current state of arsenic research within the context of metabolic biology, and highlights how interdisciplinary research has the potential to inform current environmental standards and public health interventions

Obesity and increased susceptibility to arsenic-related type 2 diabetes in Northern Chile

BackgroundThe 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.ObjectivesWe 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.MethodsWe 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.ResultsThe 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.ConclusionsThese findings identify increased odds of T2D with arsenic exposure, which are significantly increased in individuals with excess BMI

Socioeconomic status and the association between arsenic exposure and type 2 diabetes

ObjectiveEvaluate whether arsenic-related diabetes risks differ between people of low and high socioeconomic status (SES).MethodsWe used data collected between October 2007-December 2010 from a population-based cancer case-control study (N = 1301) 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.ResultsAmong 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 interval (CI) 1.29-3.49, p = 0.004). However, those in the high SES group were not at increased risk (OR = 1.12 [95% CI = 0.72-1.73]).ConclusionsOur findings provide evidence that risks of arsenic-related diabetes may be higher in Chile in people with low versus high SES