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

Reactive Oxygen Species as a Signal in Glucose-Stimulated Insulin Secretion Jingbo Pi 1 , Yushi Bai 1 , Qiang Zhang 2 , Victoria Wong 3 , Lisa M. Floering 1 , Kiefer Daniel 1 , Jeffrey M. Reece 4 , Jude T. Deeney 5 , Melvin E. Andersen 2 , Barbara E. Corkey 5 and Sheila Collins 1 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 Abstract One of the unique features of β-cells is their relatively low expression of many antioxidant enzymes. This could render β-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 H 2 O 2 . In both models, insulin secretion could be stimulated by provision of either exogenous H 2 O 2 or diethyl maleate, which raises intracellular H 2 O 2 levels. Provision of exogenous H 2 O 2 scavengers, including cell permeable catalase and N -acetyl- l -cysteine, inhibited glucose-stimulated H 2 O 2 accumulation and insulin secretion (GSIS). In contrast, cell permeable superoxide dismutase, which metabolizes superoxide into H 2 O 2 , had no effect on GSIS. Because oxidative stress is an important risk factor for β-cell dysfunction in diabetes, the relationship between glucose-induced H 2 O 2 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 H 2 O 2 derived from glucose metabolism