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

J. Biol. Chem., Vol. 279, Issue 9, 7470-7475, February 27, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/9/7470    most recent M307921200v1 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 Liu, Y. Q. Articles by Leahy, J. L. Search for Related Content PubMed PubMed Citation Articles by Liu, Y. Q. Articles by Leahy, J. L. Social Bookmarking                      What's this?

Chronic High Glucose Lowers Pyruvate Dehydrogenase Activity in Islets through Enhanced Production of Long Chain Acyl-CoA

PREVENTION OF IMPAIRED GLUCOSE OXIDATION BY ENHANCED PYRUVATE RECYCLING THROUGH THE MALATE-PYRUVATE SHUTTLE^*

Ye Qi Liu, Jacob A. Moibi, and Jack L. Leahy

From the Division of Endocrinology, Diabetes, and Metabolism, University of Vermont, Burlington, Vermont 05405

In islet -cells, the high expression of pyruvate carboxylase and the functional importance of the downstream anaplerosis pathways result in a unique characteristic whereby high glucose and fatty acids both increase production of a key fatty acid metabolite, long chain acyl-CoA, for signaling and enzyme regulation in -cells. We showed previously in islets that pyruvate dehydrogenase (PDH) activity is lowered by excess fatty acids (the so-called Randle effect). We have now investigated PDH activity and pyruvate metabolism in islets after 48-h culture at 16.7 mmol/liter glucose. Active PDH V_max was lowered 65% by 48 h of high glucose, and this effect was markedly attenuated by co-culture with triacsin C, which inhibits acyl-CoA synthase. Despite the large reduction in PDH activity, glucose oxidation was twice normal. The reason was continued metabolism of pyruvate through pyruvate carboxylase (V_max, 83% of control) and diversion of flux through the pyruvate-malate shuttle. The result was a 3-fold increase of the pyruvate concentration that overcame the lowered PDH activity by mass action as shown by glucose oxidation measured with [6-¹⁴C]glucose being twice normal. In addition, glucose-induced insulin secretion was 3-fold increased after 48 h of high glucose, and this effect was totally blocked by co-culture with triacsin C. These results show that a unique feature of islet -cells is not only fatty acids but also excess glucose that impairs PDH activity. Also, a specialized trait of -cells is a long chain acyl-CoA-mediated defense mechanism that prevents a reduction in glucose oxidation and consequently in insulin secretion.

Received for publication, July 21, 2003 , and in revised form, October 20, 2003.

^* This work was supported by Grants DK56818 and P20 RR/DE17702 from the National Institutes of Health and the Centers of Biomedical Research Excellence Program, NCRR, National Institutes of Health, respectively (to J. L. L. and Y. Q. L., respectively) and by grants from the American Diabetes Association (to J. L. L. and Y. Q. L.). 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.

Recipient of a Junior Faculty Award from the American Diabetes Association. Present address: Kosair Children's Hospital Research Institute, Dept. of Pediatrics, University of Louisville School of Medicine, 570 S. Preston St., Suite 304, Louisville, KY 40202.

To whom correspondence should be addressed: University of Vermont College of Medicine, Given C331, Burlington, VT 05405. Tel.: 802-656-2530; Fax: 802-656-8031; E-mail: jleahy{at}zoo.uvm.edu.

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

This article has been cited by other articles:

				F. Diraison, M. A. Ravier, S. K. Richards, R. M. Smith, H. Shimano, and G. A. Rutter SREBP1 is required for the induction by glucose of pancreatic {beta}-cell genes involved in glucose sensing J. Lipid Res., April 1, 2008; 49(4): 814 - 822. [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]

				Y. Q. Liu, J. Han, P. N. Epstein, and Y. S. Long Enhanced rat {beta}-cell proliferation in 60% pancreatectomized islets by increased glucose metabolic flux through pyruvate carboxylase pathway Am J Physiol Endocrinol Metab, March 1, 2005; 288(3): E471 - E478. [Abstract] [Full Text] [PDF]

				T. Brun, I. Franklin, L. St-Onge, A. Biason-Lauber, E. J. Schoenle, C. B. Wollheim, and B. R. Gauthier The diabetes-linked transcription factor PAX4 promotes {beta}-cell proliferation and survival in rat and human islets J. Cell Biol., December 20, 2004; 167(6): 1123 - 1135. [Abstract] [Full Text] [PDF]