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

The level of mendione redox-cycling in pancreatic β-cells is proportional to the glucose concentration: role of NADH and consequences for insulin secretion
The level of mendione redox-cycling in pancreatic β-cells is proportional to the glucose concentration: role of NADH and consequences for insulin secretion
Pancreatic β-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 β-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 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 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 µM) 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 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 H2O2 and menadione on insulin secretion.
Insulin secretionRedox cyclingNADHCytosolic oxidoreductasePlasma membrane electron transport (PMET)NQO1
216-225
Heart, Emma
f8b99fd2-026e-43cd-9db6-67edd6d18c98
Womack, Trayce
562b764f-53ad-4fae-a456-11cf73ca649f
Smith, Peter J. S.
003de469-9420-4f12-8f0e-8e8d76d28d6c
Gray, Joshua P.
87bb062f-a135-4f9b-9b65-02ade9a7fece
Palo, Meridith
2147ba05-5f99-4cf3-9ecd-bc71ce2585c9
Heart, Emma
f8b99fd2-026e-43cd-9db6-67edd6d18c98
Palo, Meridith
2147ba05-5f99-4cf3-9ecd-bc71ce2585c9
Womack, Trayce
562b764f-53ad-4fae-a456-11cf73ca649f
Smith, Peter J. S.
003de469-9420-4f12-8f0e-8e8d76d28d6c
Gray, Joshua P.
87bb062f-a135-4f9b-9b65-02ade9a7fece

Heart, Emma, Womack, Trayce, Smith, Peter J. S. and Gray, Joshua P. , Palo, Meridith (ed.) (2012) The level of mendione redox-cycling in pancreatic β-cells is proportional to the glucose concentration: role of NADH and consequences for insulin secretion. Toxicology and Applied Pharmacology, 258, 216-225. (doi:10.1016/j.taap.2011.11.002).

Record type: Article

Abstract

Pancreatic β-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 β-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 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 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 µM) 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 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 H2O2 and menadione on insulin secretion.

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Accepted/In Press date: 7 November 2011
Published date: January 2012
Keywords: Insulin secretionRedox cyclingNADHCytosolic oxidoreductasePlasma membrane electron transport (PMET)NQO1
Organisations: Faculty of Natural and Environmental Sciences

Identifiers

Local EPrints ID: 203567
URI: http://eprints.soton.ac.uk/id/eprint/203567
PURE UUID: 4802d2a3-cb68-4ed2-926a-eec44f464d60
ORCID for Peter J. S. Smith: ORCID iD orcid.org/0000-0003-4400-6853

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Date deposited: 17 Nov 2011 16:55
Last modified: 15 Mar 2024 03:39

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Contributors

Author: Emma Heart
Editor: Meridith Palo
Author: Trayce Womack
Author: Joshua P. Gray

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