Stimulation of glucose uptake by chronic vanadate pretreatment in cardiomyocytes requires PI 3-kinase and p38 MAPK activation

Annie Tardif, Nathalie Julien, Jean-Louis Chiasson, Lise Coderre
American Journal of Physiology. Endocrinology and Metabolism 2003, 284 (6): E1055-64
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.

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