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

Abstract

Coderre. Stimulation of glucose uptake by chronic vanadate pretreatment in cardiomyocytes requires PI 3-kinase and p38 MAPK activation. Am J Physiol Endocrinol Metab 284: E1055-E1064, 2003. First published December 10, 2002 10.1152 10. /ajpendo.00134.2002 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 M) 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. insulin signaling; protein kinase B/Akt; diabetes; vanadium; heart; phosphatidylinositol 3-kinase DESPITE THE ABILITY OF THE HEART to use multiple substrates to meet its energy requirements, this organ has one of the highest rates of glucose utilization in vivo (18,45). Decreased glucose uptake has been observed in both type 1 and type 2 diabetic subjects (25,29,45), and it has been proposed that abnormal regulation of this process has a role in the development of cardiac dysfunction (13). In db/db mice, a model of type 2 diabetes characterized by a reduction in glucose utilization and myocardial dysfunction, selective overexpression of the major glucose transporter GLUT4 expressed in the heart normalized these abnormalities (4). Interestingly, vanadate administration to streptozotocin-induced diabetic rats improved both insulin action and myocardial function in these animals (49). Furthermore, it has been shown that chronic vanadate exposure augments glucose uptake and improves ischemic tolerance in the hypertrophied heart (41). Together, these data suggest that glucose is an important cardiac substrate and that vanadate, by stimulating glucose uptake, could have a beneficial effect on the diabetic heart.Vanadium is a trace element found in most cells in concentrations ranging from 0.1 to 1 M (31). Vanadium compounds, such as vanadate, are inhibitors of protein tyrosine...

The release of the adipocytokine visfatin is regulated by glucose and insulin

“…Interestingly, PI3-kinase or AKT inhibition resulted in an approximately equivalent effect against glucose-induced visfatin secretion as co-incubation with insulin alone. This effect of PI3-kinase inhibition is consistent with results by others on glucose signal transduction [20,21], and comparable results have been obtained for the activation of AKT [22]. The time required for visfatin release during glucose incubation indicates that upregulation of protein synthesis is an underlying mechanism of elevated plasma concentrations, which was confirmed by visfatin mRNA analysis.…”

Insulin stimulates fatty acid transport by regulating expression of FAT/CD36 but not FABPpm

“…We examined through which of the postreceptor signaling pathways insulin provoked an increase in total FAT/ CD36 content. As has been shown previously (26,29), exposure (5 min) of cardiac myocytes to insulin increased the phosphorylation of Akt (Ser 473 and Thr 308 ), ERK1/2, and PKC / , and these insulin-induced phosphorylations were blocked by LY-29004, UO-126, and PKC-ps, respectively (data not shown). Blocking of the PKC / -signaling pathway did not inhibit the insulin-induced expression of FAT/CD36 (P Ͼ 0.05; Fig.…”

“…Recent studies have provided evidence that different signaling pathways can contribute to protein synthesis in cardiac myocytes (15,32), and insulin can activate a number of signaling pathways (26,29). Blocking insulin signaling through the MAP kinase-and PKC / -signaling pathways failed to inhibit the insulin-induced increase in FAT/CD36 Fig.…”

Molecular mechanism of bis(maltolato)oxovanadium(IV)-induced insulin signaling in 3T3-L1 and IM9 cells: impact of dexamethasone

“…0-fold) at 18 h in IM9 cells. These results are in agreement with earlier reports where exposure of cells to inorganic-or organic-based vanadium compounds was found to increase the tyr-phosphorylation of IRK and IRS-1 in dose-and time-dependent manners (Band et al 1997, Cuncic et al 1999, Tardif et al 2003, and the effect of vanadate on tyr-phosphorylation of IRK was cell-specific (Band et al 1997). …”