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

Abstract

BackgroundChronic 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 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.ObjectivesWe 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 resultsExposure 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.ConclusionsOur 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.

Melatonin Antagonizes Mn-Induced Oxidative Injury Through the Activation of Keap1–Nrf2–ARE Signaling Pathway in the Striatum of Mice

“…Consistently with previous research, this result was considered to be related to the dosage of MnCl 2 . Fu et al (2010) reported that the low levels of arsenic significantly enhanced the Nrf2 activity and induced its downstream proteins. It also suggested that the expression of Nrf2 and the downstream protein could be reduced with increasing iron concentration (Zhao et al 2013).…”

Environmental pollutants and type 2 diabetes: a review of mechanisms that can disrupt beta cell function

“…The latter was deduced from altered expression of the following genes: (1) Pdx1 (previously known as Iuf1) [93][94][95], a transcription factor that is essential for pancreas development, insulin production and glucose homeostasis [96]; and (2) the insulin gene [97]. Other studies reported effects on glucose uptake, induction of ROS production, interference with the activity of key antioxidant enzymes [98], apoptosis, necrosis and inflammation reactions [39,93] (Fig. 2).…”

Oxidovanadium(IV) sulfate-induced glucose uptake in HepG2 cells through IR/Akt pathway and hydroxyl radicals

“…ROS clearly possess the capacity to behave in a random and can directly or indirectly activate cellular stress-sensitive signaling pathways [46]. It is well known that ROS generation is believed to be essential in triggering signaling response of insulin [47].…”