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

¹ Endocrine Biology Program, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina
² Division of Computational Biology, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina
³ Flow Cytometry and Confocal Core, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina
⁴ Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
⁵ Obesity Research Center, Boston University School of Medicine, Boston, Massachusetts

Address correspondence and reprint requests to Sheila Collins, PhD, or Jingbo Pi, MD, PHD, Endocrine Biology Program, The Hamner Institutes for Health Sciences, 6 Davis Dr., Research Triangle Park, NC 27709. E-mail: scollins{at}thehamner.org or jpi{at}thehamner.org

Abbreviations: CAT, catalase; CM-H₂DCFDA, 5-(and-6)-chloromethyl-2', 7'-dichlorodihydrofluorescein diacetate, acetyl ester; DEM, diethyl maleate; FBS, fetal bovine serum; GCLC, -glutamate cysteine ligase catalytic subunit; GPx, glutathione peroxidase; GSH, reduced glutathione; GSIS, glucose-stimulated insulin secretion; GSSG, oxidized glutathione; HNE, 4-hydroxynonenal; HO-1, heme oxygenase 1; MGO, methylglyoxal; NAC, N-acetyl-L-cysteine; NQO-1, NAD(P)H:quinone oxidoreductase 1; Nrf2, transcription factor NF-E2–related factor 2; ·O₂^–, superoxide; PEG-CAT, CAT-polyethylene glycol; PEG-SOD, SOD-polyethylene glycol; RIA, radioimmunoassay; ROS, reactive oxygen species; SOD, superoxide dismutase

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 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 diethyl maleate, 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. Because 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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