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

J. Biol. Chem., Vol. 282, Issue 14, 10341-10351, April 6, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/14/10341    most recent M610631200v1 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 Gleason, C. E. Articles by Birnbaum, M. J. Search for Related Content PubMed PubMed Citation Articles by Gleason, C. E. Articles by Birnbaum, M. J. Social Bookmarking                      What's this?

The Role of AMPK and mTOR in Nutrient Sensing in Pancreatic -Cells^*

Catherine E. Gleason, Danhong Lu, Lee A. Witters^¶, Christopher B. Newgard, and Morris J. Birnbaum¹

From the Howard Hughes Medical Institute and Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, the Sarah W. Stedman Nutrition and Metabolism Center and Departments of Pharmacology and Cancer Biology, Medicine and Biochemistry, Medical Center, Duke University, Durham, North Carolina 27704, and the ^¶Departments of Medicine, Biochemistry, Dartmouth Medical School and the Department of Biological Sciences, Dartmouth College, Hanover, New Hampshire 03755

The AMP-activated protein kinase (AMPK) is a central regulator of the energy status of the cell, based on its unique ability to respond directly to fluctuations in the ratio of AMP:ATP. Because glucose and amino acids stimulate insulin release from pancreatic -cells by the regulation of metabolic intermediates, AMPK represents an attractive candidate for control of -cell function. Here, we show that inhibition of AMPK in -cells by high glucose inversely correlates with activation of the mammalian Target of Rapamycin (mTOR) pathway, another cellular sensor for nutritional conditions. Forced activation of AMPK by AICAR, phenformin, or oligomycin significantly blocked phosphorylation of p70S6K, a downstream target of mTOR, in response to the combination of glucose and amino acids. Amino acids also suppressed the activity of AMPK, and this at a minimum required the presence of leucine and glutamine. It is unlikely that the ability of AMPK to sense both glucose and amino acids plays a role in regulation of insulin secretion, as inhibition of AMPK by amino acids did not influence insulin secretion. Moreover, activation of AMPK by AICAR or phenformin did not antagonize glucose-stimulated insulin secretion, and insulin secretion was also unaffected in response to suppression of AMPK activity by expression of a dominant negative AMPK construct (K45R). Taken together, these results suggest that the inhibition of AMPK activity by glucose and amino acids might be an important component of the mechanism for nutrient-stimulated mTOR activity but not insulin secretion in the -cell.

Received for publication, November 16, 2006 , and in revised form, February 5, 2007.

^* This work was supported in part by National Institutes of Health Grants, DK049210 (to M. J. B.), DK42583 (to C. B. N.), and T32-GM07229 (to C. E. G.). 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 A member of the Cox Institute. To whom correspondence should be addressed: University of Pennsylvania, 415 Curie Blvd, CRB Rm. 320, Philadelphia, PA, 19104. Tel.: 215-898-5001; Fax: 215-573-9138; E-mail: birnbaum{at}mail.med.upenn.edu.

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

This article has been cited by other articles:

				G. R. Steinberg and B. E. Kemp AMPK in Health and Disease Physiol Rev, July 1, 2009; 89(3): 1025 - 1078. [Abstract] [Full Text] [PDF]

				S. S. Zhang, E. Hao, J. Yu, W. Liu, J. Wang, F. Levine, and G.-S. Feng Coordinated regulation by Shp2 tyrosine phosphatase of signaling events controlling insulin biosynthesis in pancreatic {beta}-cells PNAS, May 5, 2009; 106(18): 7531 - 7536. [Abstract] [Full Text] [PDF]

				F. Zhang, D. Dey, R. Branstrom, L. Forsberg, M. Lu, Q. Zhang, and A. Sjoholm BLX-1002, a novel thiazolidinedione with no PPAR affinity, stimulates AMP-activated protein kinase activity, raises cytosolic Ca2+, and enhances glucose-stimulated insulin secretion in a PI3K-dependent manner Am J Physiol Cell Physiol, February 1, 2009; 296(2): C346 - C354. [Abstract] [Full Text] [PDF]

				S.-E Choi, S.-M. Lee, Y.-J. Lee, L.-J. Li, S.-J. Lee, J.-H. Lee, Y. Kim, H.-S. Jun, K.-W. Lee, and Y. Kang Protective Role of Autophagy in Palmitate-Induced INS-1 {beta}-Cell Death Endocrinology, January 1, 2009; 150(1): 126 - 134. [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]