| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, United Kingdom
Address all correspondence and requests for reprints to: Dr. Geoffrey D. Holman, Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom. E-mail: g.d.holman{at}bath.ac.uk.
Long-term (18 h) metformin treatment of cardiomyocytes increased glucose transport activity 3- to 5-fold, as measured using the phosphorylated sugar 2-deoxy-D-glucose and the nonphosphorylated sugar 3-O-methyl-D-glucose. The affinity for 3-O-methyl-D-glucose transport was not increased by metformin treatment. Total levels of glucose transporter 4 (GLUT4) were not changed by 18-h culture with or without insulin or metformin treatment. GLUT1 levels were elevated after 18 h in culture, but this increase was not altered by insulin or metformin treatment. Metformin-induced stimulation of transport was not inhibited by treatment with wortmannin and was additive with that of insulin. These data suggest that the metformin effect is mediated by a signaling route independent of phosphatidylinositol 3-kinase and Akt. Surprisingly, however, levels of both phospho-AMP-activated protein kinase and phospho-Akt were increased 4- and 3-fold, respectively, after metformin treatment. Chronic treatment with insulin for 18 h led to down-regulation of insulin-stimulated glucose transport. Cotreatment with metformin bypassed this insulin resistance by maintaining high transport levels. These data also indicate an independent point of convergence of metformin and insulin stimuli on GLUT4 regulatory processes. To test the possibility of altered GLUT4 subcellular trafficking, the kinetics of GLUT4 exocytosis and endocytosis were determined. Metformin treatment markedly slowed endocytosis of GLUT4, but exocytosis was not increased. We conclude that metformin treatment leads to a longer residence time of GLUT4 in the plasma membrane due to an AMP-activated protein kinase-dependent reduction in endocytosis. This accounts for metformin’s ability to enhance hexose transport activity above insulin-stimulated and Akt-dependent levels.
This article has been cited by other articles:
 |
|
 |
|
  H. K.R. Karlsson, A. V. Chibalin, H. A. Koistinen, J. Yang, F. Koumanov, H. Wallberg-Henriksson, J. R. Zierath, and G. D. Holman Kinetics of GLUT4 Trafficking in Rat and Human Skeletal Muscle Diabetes, April 1, 2009; 58(4): 847 - 854. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Saeedi, H. L. Parsons, R. B. Wambolt, K. Paulson, V. Sharma, J. R. B. Dyck, R. W. Brownsey, and M. F. Allard Metabolic actions of metformin in the heart can occur by AMPK-independent mechanisms Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2497 - H2506. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Segalen, S. L. Longnus, D. Baetz, L. Counillon, and E. Van Obberghen 5-Aminoimidazole-4-Carboxamide-1-{beta}-D-Ribofuranoside Reduces Glucose Uptake via the Inhibition of Na+/H+ Exchanger 1 in Isolated Rat Ventricular Cardiomyocytes Endocrinology, April 1, 2008; 149(4): 1490 - 1498. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Zhang, H. He, and J. A. Balschi Metformin and phenformin activate AMP-activated protein kinase in the heart by increasing cytosolic AMP concentration Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H457 - H466. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. W. Dolinsky and J. R. B. Dyck Role of AMP-activated protein kinase in healthy and diseased hearts Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H2557 - H2569. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
