H. Takahashi, P. Tran, E. Leroy
Sep 3, 2004
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Journal
Journal of Biological Chemistry
Abstract
d-Glyceraldehyde (d-GLYC) is usually considered to be a stimulator of insulin secretion but theoretically can also form reactive oxygen species (ROS), which can inhibit beta cell function. We examined the time- and concentration-dependent effects of d-GLYC on insulin secretion, insulin content, and formation of ROS. We observed that a 2-h exposure to 0.05–2 mm d-GLYC potentiated glucose-stimulated insulin secretion (GSIS) in isolated Wistar rat islets but that higher concentrations inhibited GSIS. A 24-h exposure to 2 mm d-GLYC inhibited GSIS, decreased insulin content, and increased intracellular peroxide levels (2.14 ± 0.31-fold increase, n = 4, p < 0.05). N-Acetylcysteine (10 mm) prevented the increase in intracellular peroxides and the adverse effects of d-GLYC on GSIS. In the presence of 11.1 but not 3.0 mm glucose, koningic acid (10 μm), a specific glyceraldehyde-3-phosphate dehydrogenase inhibitor, increased intracellular peroxide levels (1.88 ± 0.30-fold increase, n = 9, p < 0.01) and inhibited GSIS (control GSIS = p < 0.001; koningic acid GSIS, not significant). To determine whether oxidative phosphorylation was the source of ROS formation, we cultured rat islets with mitochondrial inhibitors. Neither rotenone or myxothiazol prevented d-GLYC-induced increases in islet ROS. Adenoviral overexpression of manganese superoxide dismutase also failed to prevent the effect of d-GLYC to increase ROS levels. These observations indicate that exposure to excess d-GLYC increases reactive oxygen species in the islet via non-mitochondrial pathways and suggest the hypothesis that the oxidative stress associated with elevated d-GLYC levels could be a mechanism for glucose toxicity in beta cells exposed chronically to high glucose concentrations.