Journal
TOXICOLOGY AND APPLIED PHARMACOLOGY
Volume 258, Issue 2, Pages 216-225Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2011.11.002
Keywords
Insulin secretion; Redox cycling; NADH; Cytosolic oxidoreductase; Plasma membrane electron transport (PMET); NQO1
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Funding
- Alexander Trust Fund
- USCGA Center for Advanced Studies
- Marine Biological Laboratory
- James A. and Faith Miller Memorial Fund
- Elisabet Samuelsson Fund
- National Institutes of Health [R56DK088093]
- American Diabetes Association [7-08-JF-18]
- Society of Toxicology Undergraduate Toxicology Education
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Pancreatic beta-cells release insulin in response to elevation of glucose from basal (4-7 mM) to stimulatory (8-16 mM) levels. Metabolism of glucose by the beta-cell results in the production of low levels of reactive oxygen intermediates (ROI), such as hydrogen peroxide (H2O2), a newly recognized coupling factor linking glucose metabolism to insulin secretion. However, high and toxic levels of H2O2 inhibit insulin secretion. Menadione, which produces H2O2 via redox cycling mechanism in a dose-dependent manner, was investigated for its effect on (beta-cell metabolism and insulin secretion in INS-1 832/13, a rat beta-cell insulinoma cell line, and primary rodent islets. Menadione-dependent redox cycling and resulting H2O2 production under stimulatory glucose exceeded several-fold those reached at basal glucose. This was paralleled by a differential effect of menadione (0.1-10 mu M) on insulin secretion, which was enhanced at basal, but inhibited at stimulatory glucose. Redox cycling of menadione and H2O2 formation was dependent on glycolytically-derived NADH, as inhibition of glycolysis and application of non-glycogenic insulin secretagogues did not support redox cycling. In addition, activity of plasma membrane electron transport, a system dependent in part on glycolytic'ally-derived NADH, was also inhibited by menadione. Menadione-dependent redox cycling was sensitive to the NQO1 inhibitor dicoumarol and the flavoprotein inhibitor diphenylene iodonium, suggesting a role for NQO1 and other oxidoreductases in this process. These data may explain the apparent dichotomy between the stimulatory and inhibitory effects of H2O2 and menadione on insulin secretion. Published by Elsevier Inc.
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