| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1Program in Cardiovascular Gene Therapy, Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; 2Section of Endocrinology and Metabolism, National Institutes of Health-Yale Mouse Metabolic Phenotyping Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut; 3NMR Laboratory for Physiological Chemistry, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; and 4Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York
Submitted 7 December 2004 ; accepted in final form 6 December 2005
Acute activation of the serine-threonine kinase Akt is cardioprotective and increases glucose uptake, at least in part, through enhanced expression of GLUT4 on the sarcolemma. The effects of chronic Akt activation on glucose uptake in the heart remain unclear. To address this issue, we examined the effects of chronic Akt activation on glucose uptake, glycogen storage, and relevant glucose transporters in the hearts of transgenic mice. We found that chronic cardiac activation of Akt led to a substantial increase in the rate of basal glucose uptake (P < 0.05) but blunted the response to insulin (1.9 vs. 18.1-fold increase compared with baseline) using NMR in ex vivo perfused heart. Basal glucose uptake was also increased in Akt transgenic mice in vivo (P < 0.005). These changes were associated with an increase on glycogen deposition, examined with histochemical staining, biochemical (>6-fold, P < 0.001) and in vivo radioactive (5-fold, P < 0.01) assays. Studies in chimeric hearts of female X-linked transgenic Akt mice suggested that increased glycogen deposition occurred as a cell autonomous effect of transgene expression. Interestingly, although sarcolemmal GLUT1 was not significantly altered, chronic Akt activation actually decreased plasma membrane GLUT4. Moreover, intracellular pools of GLUT1 were modestly reduced, whereas intracellular GLUT4 was substantially reduced. It seems likely that neither GLUT1 nor GLUT4 explains the increase in basal glucose uptake but that these reductions contribute to the loss of insulin responsiveness that we observed. These data demonstrate that chronic Akt activation increases basal glucose uptake and glycogen deposition while inhibiting the response to insulin.
glucose transporters; transgenic mice; heart
This article has been cited by other articles:
|
|
 |
|
  H. Cheng and T. Force Molecular Mechanisms of Cardiovascular Toxicity of Targeted Cancer Therapeutics Circ. Res., January 8, 2010; 106(1): 21 - 34. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Cook, A. Varela-Carver, M. Mongillo, C. Kleinert, M. T. Khan, L. Leccisotti, N. Strickland, T. Matsui, S. Das, A. Rosenzweig, et al. Abnormal myocardial insulin signalling in type 2 diabetes and left-ventricular dysfunction Eur. Heart J., January 1, 2010; 31(1): 100 - 111. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Miyamoto, M. Rubio, and M. A. Sussman Nuclear and mitochondrial signalling Akts in cardiomyocytes Cardiovasc Res, May 1, 2009; 82(2): 272 - 285. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Fazakerley, S. P. Lawrence, V. A. Lizunov, S. W. Cushman, and G. D. Holman A common trafficking route for GLUT4 in cardiomyocytes in response to insulin, contraction and energy-status signalling J. Cell Sci., March 1, 2009; 122(5): 727 - 734. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
