Braving the Element: Pancreatic β-Cell Dysfunction and Adaptation in Response to Arsenic Exposure

Abstract

Type 2 diabetes mellitus (T2DM) is a serious global health problem, currently affecting an estimated 451 million people worldwide. T2DM is characterized by hyperglycemia and low insulin relative to the metabolic demand. The precise contributing factors for a given individual vary, but generally include a combination of insulin resistance and insufficient insulin secretion. Ultimately, the progression to diabetes occurs only after β-cells fail to meet the needs of the individual. The stresses placed upon β-cells in this context manifest as increased oxidative damage, local inflammation, and ER stress, often inciting a destructive spiral of β-cell death, increased metabolic stress due to further insufficiency, and additional β-cell death. Several pathways controlling insulin resistance and β-cell adaptation/survival are affected by a class of exogenous bioactive compounds deemed endocrine disrupting chemicals (EDCs). Epidemiological studies have shown that, in several regions throughout the world, exposure to the EDC inorganic arsenic (iAs) correlates significantly with T2DM. It has been proposed that a lifetime of exposure to iAs may exacerbate problems with both insulin sensitivity as well as β-cell function/survival, promoting the development of T2DM. This review focuses on the mechanisms of iAs action as they relate to known adaptive and maladaptive pathways in pancreatic β-cells.

Arsenic Exposure Decreases Adiposity During High‐Fat Feeding

“…We favor the hypothesis that interindividual variation in arsenic metabolism and/or excretion is most likely to explain the observed variation, as water intake variability was not nearly as high as differences in arsenic accumulation. Our interanimal variation in hepatic arsenic accumulation quantitatively agreed with prior publications (21,40). Recently, Stýblo et al (17) reported that mouse strain differences may cause up to a 7‐fold difference in liver arsenic accumulation, showing similar variability in 4 of the 12 strains evaluated by their group (SE values of approximately 20%).…”

“…These findings largely agree with recent studies showing that arsenic‐induced impairment of β‐cell function is offset by improvements in insulin sensitivity at higher levels of arsenic exposure and in the context of hypercaloric feeding (32,33). Given the uncertain relationship between arsenic exposure and obesity (21,34,35), we believe that this study provides new evidence that arsenic exposure in the context of diet‐induced weight gain has an antiobesogenic effect in mice. Accounting for the dramatic interanimal variations in liver arsenic levels and treating other phenotypic end points as dependent variables enhanced our ability to interpret the effects of arsenic exposure on metabolic outcomes.…”

“…At 8 weeks of age, mice were provided bottles of reverse osmosis–purified drinking water +/− 50 mg/L of sodium arsenite (NaAsO 2 , iAs; Sigma Aldrich, St. Louis, Missouri). Though to date a variety of genetic backgrounds have been utilized for arsenic studies in mice, the most common has been the C57BL/6 background (17,21,27), which was selected on that basis for the present study. This exposure protocol has been used previously, resulting in liver arsenic accumulation comparable with previous mouse studies and below levels observed in some chronically exposed humans (16,23).…”

“…Given the links between increased adiposity and diabetes as well as widespread persistent global exposure to arsenic, the potential relationship between arsenic exposure, adiposity, and metabolic health is of interest. Whether arsenic exposure via drinking water specifically promotes obesity is a controversial topic, with mixed results in both clinical studies (8,18‐20) and animal models (21,22). Studies have previously demonstrated that arsenic accumulates in the liver, pancreas, muscle, and other metabolically relevant tissues (23‐26); however, to our knowledge, there have been no reports evaluating a potential dose‐response relationship between tissue arsenic levels and adiposity or other metabolic phenotypes.…”

Subacute Testicular Toxicity to Cadmium Exposure Intraperitoneally and Orally

“…The lower oxidative stress may have occurred due to the adaptation to ROS generation caused by continuous exposure to Cd. This adaptive mechanism is reported in patients with β -thalassemia in order to maintain homeostasis due to Fe overload [63], in pancreatic β -cells after As exposure [64], and in zebrafish after fluoroquinolone exposure [65]. Thus, it is suggested that the testis also has an oxidative adaptive mechanism in case of continuous exposure to Cd.…”