The level of menadione redox-cycling in pancreatic beta-cells is proportional to the glucose concentration: role of NADH and consequences for insulin secretion

TitleThe level of menadione redox-cycling in pancreatic beta-cells is proportional to the glucose concentration: role of NADH and consequences for insulin secretion
Publication TypeJournal Article
Year of Publication2012
AuthorsHeart E., Palo M., Womack T., Smith P.J, Gray J.P
JournalToxicol Appl PharmacolToxicol Appl Pharmacol
Volume258
Pagination216-25
Date PublishedJan 15
ISBN Number1096-0333 (Electronic)<br/>0041-008X (Linking)
Accession Number22115979
KeywordsAnimals, 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.