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Submitted on June 5, 2003
Accepted on April 6, 2004
From the department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands; UMR 6548 - Université de Nice, Nice, France.
* To whom correspondence should be addressed.
Prolonged use of glucocorticoids induces pronounced insulin-resistance in vivo. In vitro, treatment of 3T3-L1 adipocytes with dexamethasone for 48 h reduces the maximal level of insulin- and stress(arsenite)-induced glucose uptake by 
50%. Though PI-3'kinase signaling was slightly attenuated, phosphorylation of its downstream effectors such as PKB and PKC-
remained intact. Nor was any effect of dexamethasone-treatment observed on insulin- or arsenite-induced translocation of the GLUT4 glucose transporter toward the plasma-membrane. However, for a maximal response to either arsenite- or insulin-induced glucose uptake in these cells, functional p38 MAPK signaling is required. Dexamethasone-treatment markedly attenuated p38 MAPK phosphorylation coincident with an up-regulation of the MAPK phosphatases MKP-1 and MKP-4. Employing lentivirus-mediated ectopic expression in fully differentiated 3T3-L1 adipocytes, demonstrated a differential effect of these phosphatases : Whereas MKP-1 was a more potent inhibitor of insulin-induced glucose uptake, MKP-4 more efficiently inhibited arsenite-induced glucose uptake. This coincided with the effects of these phosphatases on p38 MAPK phosphorylation, i.e. MKP-1 and MKP-4 attenuated p38 MAPK phosphorylation by insulin and arsenite respectively. Taken together, these data provide evidence that in 3T3-L1 adipocytes dexamethasone inhibits the activation of the GLUT4 in the plasma-membrane by a p38 MAPK-dependent process, rather than in a defect in GLUT4 translocation per se.
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