HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 21, 20389-20396, May 27, 2005

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 280/21/20389    most recent M411869200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Martens, G. A. Articles by Pipeleers, D. Search for Related Content PubMed PubMed Citation Articles by Martens, G. A. Articles by Pipeleers, D. Social Bookmarking                      What's this?

Glucose Suppresses Superoxide Generation in Metabolically Responsive Pancreatic Cells^*

Geert A. Martens, Ying Cai, Simon Hinke, Geert Stangé, Mark Van de Casteele, and Daniel Pipeleers

From the Diabetes Research Center, Brussels Free University-VUB, Laarbeeklaan 103, B-1090 Brussels, Belgium

High rates of glucose metabolism and mitochondrial electron transport have been associated with increased mitochondrial production of reactive oxygen species (ROS). This mechanism was also proposed as a possible cause for dysfunction and death of pancreatic cells exposed to high glucose levels. We examined whether high rates of glucose metabolism increase ROS production in purified rat cells. Glucose up to 20 mM did not stimulate H₂O₂ or superoxide production, whereas it dose-dependently increased cellular NAD(P)H and FADH₂ levels with an EC₅₀ around 8 mM. On the contrary, glucose concentration-dependently suppressed H₂O₂ and superoxide formation, with a major effect between 0 and 5 mM, parallel to an increase in cellular NAD(P)H levels. This suppressive effect was more marked in cells with higher NAD(P)H responsiveness to glucose; it was not observed in glucagon-containing cells, which lacked a glucose-induced increase in NAD(P)H. Suppression was also induced by the mitochondrial substrates leucine and succinate. Experiments with electron transport chain inhibitors indicate a role of respiratory complex I in ROS production at low mitochondrial activity and low NADH levels. Superoxide production at low glucose is potentially cytotoxic, because scavenging by the superoxide dismutase mimetic agent manganese(III)tetrakis(4-benzoic acid)porphyrin was found to reduce the rate of cell apoptosis. Analysis of islets cultured at 20 mM glucose confirmed that this condition does not induce ROS production in cells as a result of their increased rates of glucose metabolism. Our study indicates the need of cells for basal nutrients maintaining mitochondrial NADH production at levels that suppress ROS accumulation from an inadequate respiratory complex I activity and thus inhibit a potential apoptotic pathway.

Received for publication, October 19, 2004 , and in revised form, February 17, 2005.

^* This work was supported by the Research Foundation Flanders (Fonds Voor Wetenschappelijk Onderzoek-Vlaanderen, Grant FWO-G.0357.03 and PhD grant 101/8 to G. A. M.) and by the Inter-University Poles of Attraction Program (IUAP P5/17) from the Belgian Science Policy. The Diabetes Research Center is a partner of the Juvenile Diabetes Research Center for Beta Cell Therapy in Diabetes. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Fig. S1.

To whom correspondence should be addressed. Tel.: 32-2-477-4541; Fax: 32-2-477-4545; E-mail: Daniel.Pipeleers{at}vub.ac.be.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				C. Leloup, C. Tourrel-Cuzin, C. Magnan, M. Karaca, J. Castel, L. Carneiro, A.-L. Colombani, A. Ktorza, L. Casteilla, and L. Penicaud Mitochondrial Reactive Oxygen Species Are Obligatory Signals for Glucose-Induced Insulin Secretion Diabetes, March 1, 2009; 58(3): 673 - 681. [Abstract] [Full Text] [PDF]

				N. Quoix, R. Cheng-Xue, L. Mattart, Z. Zeinoun, Y. Guiot, M. C. Beauvois, J.-C. Henquin, and P. Gilon Glucose and Pharmacological Modulators of ATP-Sensitive K+ Channels Control [Ca2+]c by Different Mechanisms in Isolated Mouse {alpha}-Cells Diabetes, February 1, 2009; 58(2): 412 - 421. [Abstract] [Full Text] [PDF]

				A. El Ouaamari, N. Baroukh, G. A. Martens, P. Lebrun, D. Pipeleers, and E. van Obberghen miR-375 Targets 3'-Phosphoinositide-Dependent Protein Kinase-1 and Regulates Glucose-Induced Biological Responses in Pancreatic {beta}-Cells Diabetes, October 1, 2008; 57(10): 2708 - 2717. [Abstract] [Full Text] [PDF]

				N. Hou, S. Torii, N. Saito, M. Hosaka, and T. Takeuchi Reactive Oxygen Species-Mediated Pancreatic {beta}-Cell Death Is Regulated by Interactions between Stress-Activated Protein Kinases, p38 and c-Jun N-Terminal Kinase, and Mitogen-Activated Protein Kinase Phosphatases Endocrinology, April 1, 2008; 149(4): 1654 - 1665. [Abstract] [Full Text] [PDF]

				C. Tang, P. Han, A. I. Oprescu, S. C. Lee, A. V. Gyulkhandanyan, G. N.Y. Chan, M. B. Wheeler, and A. Giacca Evidence for a Role of Superoxide Generation in Glucose-Induced {beta}-Cell Dysfunction In Vivo Diabetes, November 1, 2007; 56(11): 2722 - 2731. [Abstract] [Full Text] [PDF]

				G. A. Martens, A. Vervoort, M. Van de Casteele, G. Stange, K. Hellemans, H. V. Van Thi, F. Schuit, and D. Pipeleers Specificity in Beta Cell Expression of L-3-Hydroxyacyl-CoA Dehydrogenase, Short Chain, and Potential Role in Down-regulating Insulin Release J. Biol. Chem., July 20, 2007; 282(29): 21134 - 21144. [Abstract] [Full Text] [PDF]

				G. A. Martens, Q. Wang, K. Kerckhofs, G. Stange, Z. Ling, and D. Pipeleers Metabolic Activation of Glucose Low-Responsive {beta}-Cells by Glyceraldehyde Correlates with Their Biosynthetic Activation in Lower Glucose Concentration Range But Not at High Glucose Endocrinology, November 1, 2006; 147(11): 5196 - 5204. [Abstract] [Full Text] [PDF]

				M. Z. Khaldi, H. Elouil, Y. Guiot, J. C. Henquin, and J. C. Jonas Antioxidants N-acetyl-L-cysteine and manganese(III)tetrakis (4-benzoic acid)porphyrin do not prevent beta-cell dysfunction in rat islets cultured in high glucose for 1 wk Am J Physiol Endocrinol Metab, July 1, 2006; 291(1): E137 - E146. [Abstract] [Full Text] [PDF]

				A. Wiederkehr and C. B. Wollheim Minireview: Implication of Mitochondria in Insulin Secretion and Action Endocrinology, June 1, 2006; 147(6): 2643 - 2649. [Abstract] [Full Text] [PDF]

				J. Yang, R. K. Wong, M. Park, J. Wu, J. R. Cook, D. A. York, S. Deng, J. Markmann, A. Naji, B. A. Wolf, et al. Leucine Regulation of Glucokinase and ATP Synthase Sensitizes Glucose-Induced Insulin Secretion in Pancreatic {beta}-Cells Diabetes, January 1, 2006; 55(1): 193 - 201. [Abstract] [Full Text] [PDF]