| Autor: |
Fu, Jingqi1,2, Woods, Courtney G.3, Yehuda-Shnaidman, Einav1, Qiang Zhang3, Wong, Victoria4, Collins, Sheila1, Sun, Guifan2, Andersen, Melvin E.3, Jingbo Pi1 jpi@thehamner.org |
| Předmět: |
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| Zdroj: |
Environmental Health Perspectives. Jun2010, Vol. 118 Issue 6, p864-870. 7p. 1 Diagram, 5 Graphs. |
| Abstrakt: |
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 β-cell function, with the hallmark of β-cell function being glucosestimulated 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 the 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 β-cell function. [ABSTRACT FROM AUTHOR] |
| Databáze: |
GreenFILE |
| Externí odkaz: |
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