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Environ Health Perspect. 2010 Jun;118(6):864-70. doi: 10.1289/ehp.0901608. Epub 2010 Jan 25.

Low-level arsenic impairs glucose-stimulated insulin secretion in pancreatic beta cells: involvement of cellular adaptive response to oxidative stress.

Author information

1
Division of Translational Biology, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709 , USA.

Abstract

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 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 beta-cell function.

PMID:
20100676
PMCID:
PMC2898865
DOI:
10.1289/ehp.0901608
[Indexed for MEDLINE]
Free PMC Article

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