Academic journal article Environmental Health Perspectives

Low-Level Arsenic Impairs Glucose-Stimulated Insulin Secretion in Pancreatic Beta Cells: Involvement of Cellular Adaptive Response to Oxidative Stress

Academic journal article Environmental Health Perspectives

Low-Level Arsenic Impairs Glucose-Stimulated Insulin Secretion in Pancreatic Beta Cells: Involvement of Cellular Adaptive Response to Oxidative Stress

Article excerpt

BACKGROUND: Chronic exposure of humans to inorganic arsenic, a potent environmental oxidative stressor, is associated with incidence of type 2 diabetes (T2D). A key driver in the pathogenesis of T2D is impairment of pancreatic [beta]-cell function, with the hallmark of [beta]-cell function being glucose-stimulated insulin secretion (GSIS). Reactive oxygen species (ROS) derived from glucose metabolism serve as one of the metabolic signals for GSIS. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a central transcription factor regulating cellular adaptive response to oxidative stress.

OBJECTIVES: We tested the hypothesis that activation of Nrf2 and induction of antioxidant enzymes in response to arsenic exposure impedes glucose-triggered ROS signaling and thus GSIS.

METHODS and RESULTS: Exposure of INS-1 (832/13) cells to low levels of arsenite led to decreased GSIS in a dose- and time-dependent fashion. Consistent with our hypothesis, a significantly enhanced Nrf2 activity, determined by its nuclear accumulation and induction of its target genes, was observed in arsenite-exposed cells. In keeping with the activation of Nrf2-mediated antioxidant response, intracellular glutathione and intracellular hydrogen peroxide--scavenging activity was dose dependently increased by arsenite exposure. Although die basal cellular peroxide level was significantly enhanced, the net percentage increase in glucose-stimulated intracellular peroxide production was markedly inhibited in arsenite-exposed cells. In contrast, insulin synthesis and the consensus GSIS pathway, including glucose transport and metabolism, were not significantly reduced by arsenite exposure.

CONCLUSIONS: Our studies suggest that low levels of arsenic provoke a cellular adaptive oxidative stress response that increases antioxidant levels, dampens ROS signaling involved in GSIS, and thus disturbs [beta]-cell function.

KEY WORDS: arsenic, diabetes, insulin secretion, Nrf2, oxidative stress, pancreatic beta cells, ROS. Environ Health Perspect 118:864-870 (2010). doi:10.1289/ehp.090l608 [Online 25 January 2010]

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Type 2 diabetes (T2D) has become a serious public health problem throughout the world. Zimmet et al. (2001) estimated that approximately 150 million people worldwide had T2D in the year 2000, and they predicted that this number could double by 2025. In the United States alone, T2D affected > 7% of the population and. resulted in an estimated $174 billion total annual economic cost in 2007 (American Diabetes Association 2008). Obesity has been recognized as the leading cause of T2D, whereas many factors, including genetic elements and lifestyle, are involved in the incidence of obesity. However, a link between environmental exposures and diabetes has also been established (Navas-Acien et al. 2008) but has received little attention by the medical community.

Arsenic is a naturally occurring element that is ubiquitous in the environment in both organic and inorganic forms (Nordstrom 2002). Human exposure to the generally more toxic inorganic arsenic (iAs) occurs in occupational or environmental settings, as well as through medicinal arsenical use (Abernathy et al. 1999). The main source of human environmental exposure is through consumption of water containing elevated levels of arsenic, primarily from natural contamination (Gebel 1999). The U.S. Environmental Protection Agency set the arsenic standard for drinking water at 0.01 ppm in 2006. An estimated 13 million Americans were exposed to higher levels of arsenic (> 0.01 ppm) through public water systems by 2006.

Chronic exposure to high levels of iAs is associated with a wide range of human ailments including cancer, arteriosclerosis, hypertension, and T2D. Although the evidence for a causal association between iAs exposure and T2D is not unequivocally established (Navas-Acien et al. 2006), epidemiological studies carried out in Taiwan (Chiu et al. …

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