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