title: The level of menadione redox-cycling in pancreatic β-cells is proportional to the glucose concentration: role of NADH and consequences for insulin secretion.
abstract: Pancreatic β-cells release insulin in response to elevation of glucose from basal (4-7mM) to stimulatory (8-16mM) levels. Metabolism of glucose by the β-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 β-cell metabolism and insulin secretion in INS-1 832/13, a rat β-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 (0.1-10μM) 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.
authors: Cellular Dynamics Program, Marine Biological Laboratory, Woods Hole, MA 02543, United States.
authors: Emma
authors: E
authors: Heart
authors: Meridith
authors: M
authors: Palo
authors: Trayce
authors: T
authors: Womack
authors: Peter J S
authors: PJ
authors: Smith
authors: Joshua P
authors: JP
authors: Gray
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007340:Insulinoma / Q000378:metabolism; D007515:Islets of Langerhans; D008297:Male; D051379:Mice; D009243:NAD / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D010190:Pancreatic Neoplasms / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D024483:Vitamin K 3 / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D007328:Insulin; D017382:Reactive Oxygen Species; D009243:NAD; D024483:Vitamin K 3; D006861:Hydrogen Peroxide; D016660:NAD(P)H Dehydrogenase (Quinone); C507703:NQO1 protein, rat; D005947:Glucose