Title | The level of menadione redox-cycling in pancreatic beta-cells is proportional to the glucose concentration: role of NADH and consequences for insulin secretion |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | Heart E., Palo M., Womack T., Smith P.J, Gray J.P |
Journal | Toxicol Appl PharmacolToxicol Appl Pharmacol |
Volume | 258 |
Pagination | 216-25 |
Date Published | Jan 15 |
ISBN Number | 1096-0333 (Electronic)<br/>0041-008X (Linking) |
Accession Number | 22115979 |
Keywords | Animals, Cell Line, Tumor, Dose-Response Relationship, Drug, Glucose/*metabolism, Hydrogen Peroxide/*metabolism, Insulin-Secreting Cells/*metabolism, Insulin/*secretion, Insulinoma/metabolism, Islets of Langerhans, Male, Mice, NAD(P)H Dehydrogenase (Quinone)/drug effects/metabolism, NAD/metabolism, Oxidation-Reduction, Pancreatic Neoplasms/metabolism, Rats, Reactive Oxygen Species/metabolism, Vitamin K 3/administration & dosage/*pharmacology |
Abstract | Pancreatic beta-cells release insulin in response to elevation of glucose from basal (4-7mM) to stimulatory (8-16mM) levels. Metabolism of glucose by the beta-cell results in the production of low levels of reactive oxygen intermediates (ROI), such as hydrogen peroxide (H(2)O(2)), a newly recognized coupling factor linking glucose metabolism to insulin secretion. However, high and toxic levels of H(2)O(2) inhibit insulin secretion. Menadione, which produces H(2)O(2) 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 H(2)O(2) production under stimulatory glucose exceeded several-fold those reached at basal glucose. This was paralleled by a differential effect of menadione (0.1-10muM) on insulin secretion, which was enhanced at basal, but inhibited at stimulatory glucose. Redox cycling of menadione and H(2)O(2) 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 glycolytically-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 H(2)O(2) and menadione on insulin secretion. |