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

J. Biol. Chem., Vol. 281, Issue 41, 30593-30602, October 13, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/41/30593    most recent M511908200v1 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 Ronnebaum, S. M. Articles by Jensen, M. V. Search for Related Content PubMed PubMed Citation Articles by Ronnebaum, S. M. Articles by Jensen, M. V. Social Bookmarking                      What's this?

A Pyruvate Cycling Pathway Involving Cytosolic NADP-dependent Isocitrate Dehydrogenase Regulates Glucose-stimulated Insulin Secretion^*

Sarah M. Ronnebaum, Olga Ilkayeva, Shawn C. Burgess, Jamie W. Joseph, Danhong Lu, Robert D. Stevens, Thomas C. Becker, A. Dean Sherry, Christopher B. Newgard^¶1, and Mette V. Jensen

From the Sarah W. Stedman Nutrition and Metabolism Center and Departments of Pharmacology and Cancer Biology, ^¶Biochemistry, and Medicine, Duke University Medical Center, Durham, North Carolina 27704 and Ralph and Mary Nell Rogers NMR Center and Advanced Imaging Research Center, Departments of Radiology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75235

Glucose-stimulated insulin secretion (GSIS) from pancreatic islet -cells is central to control of mammalian fuel homeostasis. Glucose metabolism mediates GSIS in part via ATP-regulated K⁺ (K_ATP) channels, but multiple lines of evidence suggest participation of other signals. Here we investigated the role of cytosolic NADP-dependent isocitrate dehydrogenase (ICDc) in control of GSIS in -cells. Delivery of small interfering RNAs specific for ICDc caused impairment of GSIS in two independent robustly glucose-responsive rat insulinoma (INS-1-derived) cell lines and in primary rat islets. Suppression of ICDc also attenuated the glucose-induced increments in pyruvate cycling activity and in NADPH levels, a predicted by-product of pyruvate cycling pathways, as well as the total cellular NADP(H) content. Metabolic profiling of eight organic acids in cell extracts revealed that suppression of ICDc caused increases in lactate production in both INS-1-derived cell lines and primary islets, consistent with the attenuation of pyruvate cycling, with no significant changes in other intermediates. Based on these studies, we propose that a pyruvate cycling pathway involving ICDc plays an important role in control of GSIS.

Received for publication, November 4, 2005 , and in revised form, August 2, 2006.

^* This work was supported by National Institutes of Health Grants DK42583 (to C. B. N.) and DK58398 (to C. B. N. and A. D. S.) and a sponsored research agreement with Takeda Pharmaceuticals (to C. B. N.). 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.

¹ To whom correspondence should be addressed: Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Independence Park Facility, 4321 Medical Park Dr., Ste. 200, Durham, NC 27704. Tel.: 919-668-6059; Fax: 919-477-0632; E-mail: newga002{at}mc.duke.edu.

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

This article has been cited by other articles:

				T. J. S. Merritt, C. Kuczynski, E. Sezgin, C.-T. Zhu, S. Kumagai, and W. F. Eanes Quantifying Interactions Within the NADP(H) Enzyme Network in Drosophila melanogaster Genetics, June 1, 2009; 182(2): 565 - 574. [Abstract] [Full Text] [PDF]

				E. Heart, G. W. Cline, L. P. Collis, R. L. Pongratz, J. P. Gray, and P. J. S. Smith Role for malic enzyme, pyruvate carboxylation, and mitochondrial malate import in glucose-stimulated insulin secretion Am J Physiol Endocrinol Metab, June 1, 2009; 296(6): E1354 - E1362. [Abstract] [Full Text] [PDF]

				J. Kim, K. Y. Kim, H.-S. Jang, T. Yoshida, K. Tsuchiya, K. Nitta, J.-W. Park, J. V. Bonventre, and K. M. Park Role of cytosolic NADP+-dependent isocitrate dehydrogenase in ischemia-reperfusion injury in mouse kidney Am J Physiol Renal Physiol, March 1, 2009; 296(3): F622 - F633. [Abstract] [Full Text] [PDF]

				P. Marmol, B. Pardo, A. Wiederkehr, A. del Arco, C. B. Wollheim, and J. Satrustegui Requirement for Aralar and Its Ca2+-binding Sites in Ca2+ Signal Transduction in Mitochondria from INS-1 Clonal {beta}-Cells J. Biol. Chem., January 2, 2009; 284(1): 515 - 524. [Abstract] [Full Text] [PDF]

				M. V. Jensen, J. W. Joseph, S. M. Ronnebaum, S. C. Burgess, A. D. Sherry, and C. B. Newgard Metabolic cycling in control of glucose-stimulated insulin secretion Am J Physiol Endocrinol Metab, December 1, 2008; 295(6): E1287 - E1297. [Abstract] [Full Text] [PDF]

				S. M. Ronnebaum, M. V. Jensen, H. E. Hohmeier, S. C. Burgess, Y.-P. Zhou, S. Qian, D. MacNeil, A. Howard, N. Thornberry, O. Ilkayeva, et al. Silencing of Cytosolic or Mitochondrial Isoforms of Malic Enzyme Has No Effect on Glucose-stimulated Insulin Secretion from Rodent Islets J. Biol. Chem., October 24, 2008; 283(43): 28909 - 28917. [Abstract] [Full Text] [PDF]

				N. M. Hasan, M. J. Longacre, S. W. Stoker, T. Boonsaen, S. Jitrapakdee, M. A. Kendrick, J. C. Wallace, and M. J. MacDonald Impaired Anaplerosis and Insulin Secretion in Insulinoma Cells Caused by Small Interfering RNA-mediated Suppression of Pyruvate Carboxylase J. Biol. Chem., October 17, 2008; 283(42): 28048 - 28059. [Abstract] [Full Text] [PDF]

				S. M. Ronnebaum, J. W. Joseph, O. Ilkayeva, S. C. Burgess, D. Lu, T. C. Becker, A. D. Sherry, and C. B. Newgard Chronic Suppression of Acetyl-CoA Carboxylase 1 in {beta}-Cells Impairs Insulin Secretion via Inhibition of Glucose Rather Than Lipid Metabolism J. Biol. Chem., May 23, 2008; 283(21): 14248 - 14256. [Abstract] [Full Text] [PDF]

				C. Guay, S. R. M. Madiraju, A. Aumais, E. Joly, and M. Prentki A Role for ATP-Citrate Lyase, Malic Enzyme, and Pyruvate/Citrate Cycling in Glucose-induced Insulin Secretion J. Biol. Chem., December 7, 2007; 282(49): 35657 - 35665. [Abstract] [Full Text] [PDF]

				J. W. Joseph, M. L. Odegaard, S. M. Ronnebaum, S. C. Burgess, J. Muehlbauer, A. D. Sherry, and C. B. Newgard Normal Flux through ATP-Citrate Lyase or Fatty Acid Synthase Is Not Required for Glucose-stimulated Insulin Secretion J. Biol. Chem., October 26, 2007; 282(43): 31592 - 31600. [Abstract] [Full Text] [PDF]

				M. J. MacDonald, A. D. Smith III, N. M. Hasan, G. Sabat, and L. A. Fahien Feasibility of Pathways for Transfer of Acyl Groups from Mitochondria to the Cytosol to Form Short Chain Acyl-CoAs in the Pancreatic Beta Cell J. Biol. Chem., October 19, 2007; 282(42): 30596 - 30606. [Abstract] [Full Text] [PDF]

				J. W. Joseph, M. V. Jensen, O. Ilkayeva, F. Palmieri, C. Alarcon, C. J. Rhodes, and C. B. Newgard The Mitochondrial Citrate/Isocitrate Carrier Plays a Regulatory Role in Glucose-stimulated Insulin Secretion J. Biol. Chem., November 24, 2006; 281(47): 35624 - 35632. [Abstract] [Full Text] [PDF]