Arsenic Exposure Induces Glucose Intolerance and Alterations in Global Energy Metabolism

Presentation Number: SAT 264
Date of Presentation: April 1st, 2017

Andrew G Kirkley*1, Christopher M Carmean2, Daniel Ruiz1, Honggang Ye1, Wakanene Kamau1, Shane M Regnier1, Ananta Poudel1, Manami Hara1 and Robert M Sargis1
1University of Chicago, Chicago, IL, 2Kobe University Graduate School of Medicine, Kobe, Japan


Background: Over the last several decades, obesity and diabetes rates have increased dramatically worldwide. Recently, the contribution of pollutants acting as endocrine disrupting chemicals (EDCs) has been recognized as a potential contributor to the pathogenesis of metabolic disease. One such pollutant, arsenic, contaminates the drinking water of over 100 million people globally, and has been associated with insulin resistance and diabetes in epidemiological studies. Despite these clinical observations the precise metabolic derangements induced by arsenic remain poorly characterized.

Methods: In the present study, we examined the impact of arsenic exposure on metabolic outcomes in male C57BL/6J mice. 8-­week old mice were exposed to inorganic arsenite (As3+) in their drinking water at a concentration of 50 mg/L for 8 weeks. Body weight, food and water consumption were measured weekly. Glucose homeostasis was assessed by glucose tolerance test (IP­-GTT). Peripheral insulin sensitivity was measured by insulin tolerance test (IP-­ITT). Global metabolism and feeding behavior were analyzed in a subset of mice in metabolic cages. Pancreatic and adipose tissue mass were measured at sacrifice. Pancreatic endocrine cell areas were assessed via immunofluorescence microscopy.

Results: As3+ exposure did not significantly alter body weight over the course of the study; however, exposure markedly impaired glucose tolerance. As assessed by IP-ITT, no significant difference in peripheral insulin sensitivity was noted between the groups. Relative to the rise in blood glucose, reduced insulin secretion was observed in As3+-exposed mice during the early period of the IP-GTT. Total pancreatic mass was reduced by As3+ exposure; however, β-­cell, α-cell, δ-cell, and total islet area were not altered. In metabolic cage analysis, As3+ altered the normal diurnal rhythm of food intake, increasing food consumption during the normal feeding period (dark cycle) and decreasing it during the normal sleeping period (light cycle). Terminal analyses revealed a reduction in perirenal adipose mass and a trend toward reduced visceral adiposity in As3+-exposed mice.

Conclusions: Taken together, these data suggest that arsenic exposure impairs glucose homeostasis through an impairment in β-cell function not associated with β-cell loss. Further work is required to determine the precise mechanisms driving this impairment. Elucidation of the mechanisms underlying the observed behavioral and β-­cell-specific dysfunctions may inform future intervention strategies aimed at combating the deleterious effects of this ubiquitous pollutant.


Disclosure: RMS: National Pharmacy and Therapeutics Committee, CVS Health. Nothing to Disclose: AGK, CMC, DR, HY, WK, SMR, AP, MH