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Reactive Oxygen Species as a Signal in Glucose-Stimulated Insulin Secretion

¹Endocrine Biology Program, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709
²Division of Computational Biology, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709
³Flow Cytometry and Confocal Core, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709
⁴Laboratory of Signal Transduction, NIEHS, Research Triangle Park, NC 27709
⁵Obesity Research Center, Boston University School of Medicine, Boston, MA 02118

Correspondence: jpi{at}thehamner.org

Correspondence: scollins{at}thehamner.org

One of the unique features of ß-cells is their relatively low expression of many antioxidant enzymes. This could render ß-cells susceptible to oxidative damage, but may also provide a system that is sensitive to reactive oxygen species (ROS) as signals. In isolated mouse islets and INS-1(832/13) cells, glucose increases intracellular accumulation of H₂O₂. In both models insulin secretion could be stimulated by provision of either exogenous H₂O₂ or diethylmaleate, which raises intracellular H₂O₂ levels. Provision of exogenous H₂O₂ scavengers, including cell permeable catalase and N-acetyl-L-cysteine, inhibited glucose-stimulated H₂O₂ accumulation and insulin secretion (GSIS). In contrast, cell permeable superoxide dismutase, which metabolizes superoxide into H₂O₂, had no effect on GSIS. Since oxidative stress is an important risk factor for ß-cell dysfunction in diabetes, the relationship between glucose-induced H₂O₂ generation and GSIS was investigated under various oxidative stress conditions. Acute exposure of isolated mouse islets or INS-1(832/13) cells to oxidative stressors including arsenite, 4-hydroxynonenal and methylglyoxal led to decreased GSIS. This impaired GSIS was associated with increases in a battery of endogenous antioxidant enzymes. Taken together these findings suggest that H₂O₂ derived from glucose metabolism is one of the metabolic signals for insulin secretion, whereas oxidative stress may disturb its signaling function.

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