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

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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.

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