Stimulation of glucose uptake by chronic vanadate pretreatment in cardiomyocytes requires PI 3-kinase and p38 MAPK activation.
Vanadate, an inhibitor of tyrosine phosphatases, has insulin-mimetic properties. It has been shown that acute vanadate administration enhances glucose uptake independently of phosphatidylinositol (PI) 3-kinase and p38 MAPK. However, therapeutic vanadate use requires chronic administration, and this could potentially involve a different signaling pathway(s). Thus, we examined the mechanisms by which chronic vanadate exposure (16 h) stimulates glucose uptake in primary cultures of adult cardiomyocytes. The effect of vanadate on the activation of insulin-signaling molecules was evaluated 60 min after its withdrawal and in the absence of insulin. We therefore evaluated the persistent effect of vanadate on the insulin-signaling cascade. Our results demonstrate that preincubation with low vanadate concentrations (25-75 microM) induces a dose-dependent increase in glucose uptake. The augmentation of this process was not due to alterations in GLUT1 or GLUT4 protein levels, transcription, or de novo protein synthesis. Chronic vanadate exposure was associated with activation of the insulin receptor, insulin receptor substrate-1 (IRS-1), PKB/Akt, and p38 MAPK. Furthermore, inhibition of PI 3-kinase or p38 MAPK by wortmannin and PD-169316, respectively, significantly inhibited vanadate-mediated glucose uptake in cardiomyocytes. Thus, over time, different (albeit overlapping) signaling cascades may be activated by vanadate.
Tardif
Annie
A
Research Center, Centre hospitalier de l'Université de Montréal (CHUM), and Department of Medicine, University of Montreal, Montreal, Canada H2W 1T7.
Julien
Nathalie
N
Chiasson
Jean-Louis
JL
Coderre
Lise
L
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D006321:Heart / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology; D015151:Immunoblotting; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011233:Precipitin Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013268:Stimulation, Chemical; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism; D014638:Vanadates / Q000494:pharmacology*; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases
D000730:Androstadienes; D004791:Enzyme Inhibitors; D007093:Imidazoles; D014638:Vanadates; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C408604:2-(4-nitrophenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazole; D005947:Glucose; D000077191:Wortmannin