Abstract
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 approximately 50%. Although phosphatidylinositol 3-kinase signaling was slightly attenuated, phosphorylation of its downstream effectors such as protein kinase B and protein kinase C-lambda remained intact. Nor was any effect of dexamethasone treatment observed on insulin- or arsenite-induced translocation of glucose transporter 4 (GLUT4) 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3-L1 Cells / drug effects
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3T3-L1 Cells / metabolism
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Adipocytes / drug effects
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Adipocytes / metabolism
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Animals
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Arsenites / pharmacology
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Cell Cycle Proteins / drug effects
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Dexamethasone / pharmacology*
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Dual Specificity Phosphatase 1
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Dual-Specificity Phosphatases
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Enzyme Activation / drug effects
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Glucose / pharmacokinetics
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Glucose Transporter Type 4
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Immediate-Early Proteins / drug effects
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Immediate-Early Proteins / genetics
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Immediate-Early Proteins / metabolism*
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Insulin Resistance*
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Lentivirus / genetics
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Mice
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Mitogen-Activated Protein Kinase 3 / drug effects
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Mitogen-Activated Protein Kinase 3 / metabolism
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Mitogen-Activated Protein Kinase Phosphatases
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Monosaccharide Transport Proteins / drug effects
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Monosaccharide Transport Proteins / metabolism
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Muscle Proteins / drug effects
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Muscle Proteins / metabolism
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Phosphatidylinositol 3-Kinases / drug effects
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoprotein Phosphatases / drug effects
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Phosphoprotein Phosphatases / genetics
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Phosphoprotein Phosphatases / metabolism*
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Protein Phosphatase 1
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Protein Transport / drug effects
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Protein Tyrosine Phosphatases / drug effects
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Protein Tyrosine Phosphatases / genetics
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Protein Tyrosine Phosphatases / metabolism*
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Signal Transduction
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p38 Mitogen-Activated Protein Kinases / drug effects
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p38 Mitogen-Activated Protein Kinases / metabolism*
Substances
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Arsenites
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Cell Cycle Proteins
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Glucose Transporter Type 4
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Immediate-Early Proteins
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Monosaccharide Transport Proteins
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Muscle Proteins
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Slc2a4 protein, mouse
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Dexamethasone
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Phosphatidylinositol 3-Kinases
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Mitogen-Activated Protein Kinase 3
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p38 Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase Phosphatases
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Phosphoprotein Phosphatases
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Protein Phosphatase 1
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DUSP1 protein, human
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DUSP9 protein, human
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Dual Specificity Phosphatase 1
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Dual-Specificity Phosphatases
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Dusp1 protein, mouse
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Protein Tyrosine Phosphatases
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Glucose
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arsenite