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

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted 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 Herrero, L. Articles by Hegardt, F. G. Search for Related Content PubMed PubMed Citation Articles by Herrero, L. Articles by Hegardt, F. G. Social Bookmarking                What's this?

Alteration of the Malonyl-CoA/Carnitine Palmitoyltransferase I Interaction in the ß-Cell Impairs Glucose-Induced Insulin Secretion

¹ Department of Biochemistry and Molecular Biology, University of Barcelona, School of Pharmacy, Barcelona, Spain
² Department of Cell Physiology and Metabolism, University Medical Centre, Geneva, Switzerland
³ Molecular Nutrition Unit, Department of Nutrition, University of Montreal and the Montreal Diabetes Research Center, Montreal, Quebec, Canada

Carnitine palmitoyltransferase I, which is expressed in the pancreas as the liver isoform (LCPTI), catalyzes the rate-limiting step in the transport of fatty acids into the mitochondria for their oxidation. Malonyl-CoA derived from glucose metabolism regulates fatty acid oxidation by inhibiting LCPTI. To examine directly whether the availability of long-chain fatty acyl-CoA (LC-CoA) affects the regulation of insulin secretion in the ß-cell and whether malonyl-CoA may act as a metabolic coupling factor in the ß-cell, we infected INS(832/13) cells and rat islets with an adenovirus encoding a mutant form of LCPTI (Ad-LCPTI M593S) that is insensitive to malonyl-CoA. In Ad-LCPTI M593S–infected INS(832/13) cells, LCPTI activity increased sixfold. This was associated with enhanced fatty acid oxidation, at any glucose concentration, and a 60% suppression of glucose-stimulated insulin secretion (GSIS). In isolated rat islets in which LCPTI M593S was overexpressed, GSIS decreased 40%. The impairment of GSIS in Ad-LCPTI M593S–infected INS(832/13) cells was not recovered when cells were incubated with 0.25 mmol/l palmitate, indicating the deep metabolic influence of a nonregulated fatty acid oxidation system. At high glucose concentration, overexpression of a malonyl-CoA–insensitive form of LCPTI reduced partitioning of exogenous palmitate into lipid esterification products and decreased protein kinase C activation. Moreover, LCPTI M593S expression impaired K_ATP channel–independent GSIS in INS(832/13) cells. The LCPTI M593S mutant caused more pronounced alterations in GSIS and lipid partitioning (fat oxidation, esterification, and the level of nonesterified palmitate) than LCPTI wt in INS(832/13) cells that were transduced with these constructs. The results provide direct support for the hypothesis that the malonyl-CoA/CPTI interaction is a component of a metabolic signaling network that controls insulin secretion.

Abbreviations: ACC, acetyl-CoA carboxylase; ASP, acid-soluble product; CE, cholesterol ester; CPTI, carnitine palmitoyltransferase I; DAG, diacylglycerol; ECF, enhanced chemifluorescence; FFA, free fatty acid; GSIS, glucose-stimulated insulin secretion; KRBH, Krebs-Ringer bicarbonate HEPES; LC-CoA, long-chain fatty acyl-CoA; LCPTI, liver carnitine palmitoyltransferase I; MCD, malonyl-CoA decarboxylase; MCDc, MCD in the cytosol; NEFA, nonesterified fatty acid; NE palm, nonesterified labeled palmitate; PKC, protein kinase C

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

This article has been cited by other articles:

				S. Salinari, A. Bertuzzi, M. Manco, and G. Mingrone NEFA-glucose comodulation model of beta-cell insulin secretion in 24-h multiple-meal test Am J Physiol Endocrinol Metab, June 1, 2007; 292(6): E1890 - E1898. [Abstract] [Full Text] [PDF]

				D. Sebastian, L. Herrero, D. Serra, G. Asins, and F. G. Hegardt CPT I overexpression protects L6E9 muscle cells from fatty acid-induced insulin resistance Am J Physiol Endocrinol Metab, March 1, 2007; 292(3): E677 - E686. [Abstract] [Full Text] [PDF]

				D. B. Carlson, N. B. Litherland, H. M. Dann, J. C. Woodworth, and J. K. Drackley Metabolic Effects of Abomasal L-Carnitine Infusion and Feed Restriction in Lactating Holstein Cows J Dairy Sci, December 1, 2006; 89(12): 4819 - 4834. [Abstract] [Full Text] [PDF]

				C. J. Nolan, M. S.R. Madiraju, V. Delghingaro-Augusto, M.-L. Peyot, and M. Prentki Fatty Acid Signaling in the {beta}-Cell and Insulin Secretion Diabetes, December 1, 2006; 55(Supplement_2): S16 - S23. [Abstract] [Full Text] [PDF]

				S. M. Ronnebaum, O. Ilkayeva, S. C. Burgess, J. W. Joseph, D. Lu, R. D. Stevens, T. C. Becker, A. D. Sherry, C. B. Newgard, and M. V. Jensen A Pyruvate Cycling Pathway Involving Cytosolic NADP-dependent Isocitrate Dehydrogenase Regulates Glucose-stimulated Insulin Secretion J. Biol. Chem., October 13, 2006; 281(41): 30593 - 30602. [Abstract] [Full Text] [PDF]