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Insulin resistance in adult cardiomyocytes undergoing dedifferentiation: role of GLUT4 expression and translocation.
Myocardium undergoing remodeling in vivo exhibits insulin resistance that has been attributed to a shift from the insulin-sensitive glucose transporter GLUT4 to the fetal, less insulin-sensitive, isoform GLUT1. To elucidate the role of altered GLUT4 expression in myocardial insulin resistance, glucose uptake and the expression of the glucose transporter isoforms GLUT4 and GLUT1 were measured in adult rat cardiomyocytes (ARC). ARC in culture spontaneously undergo dedifferentiation, hypertrophy-like spreading, and return to a fetal-like gene expression pattern. Insulin stimulation of 2-deoxy-D-glucose uptake was completely abolished on day 2 and 3 of culture and recovered thereafter. Although GLUT4 protein level was reduced, the time-course of unresponsiveness to insulin did not correlate with altered expression of GLUT1 and GLUT4. However, translocation of GLUT4 to the sarcolemma in response to insulin was completely abolished during transient insulin resistance. Insulin-mediated phosphorylation of Akt was not reduced, indicating that activation of phosphatidylinositol 3-kinase (PI3K) was preserved. On the other hand, total and phosphorylated Cbl was reduced during insulin resistance, suggesting that activation of Cbl/CAP is essential for insulin-mediated GLUT4 translocation, in addition to activation of PI3K. Pharmacological inhibition of contraction in insulin-sensitive ARC reduced insulin sensitivity and lowered phosphorylated Cbl. The results suggest that transient insulin resistance in ARC is related to impairment of GLUT4 translocation. A defect in the PI3K-independent insulin signaling pathway involving Cbl seems to contribute to reduced insulin responsiveness and may be related to contractile arrest.
1-Phosphatidylinositol 3-Kinase/physiology, Animals, Atrial Natriuretic Factor/biosynthesis, Atrial Natriuretic Factor/genetics, Biological Transport, Active/drug effects, Calcium Channel Blockers/pharmacology, Cell Differentiation, Cell Size, Cells, Cultured/cytology, Cells, Cultured/drug effects, Deoxyglucose/metabolism, Diacetyl/analogs & derivatives, Diacetyl/pharmacology, Enzyme Activation, Gene Expression Regulation, Glucose Transporter Type 1, Glucose Transporter Type 4, Insulin/pharmacology, Insulin Resistance/physiology, Monosaccharide Transport Proteins/biosynthesis, Monosaccharide Transport Proteins/genetics, Muscle Proteins, Myocardial Contraction/drug effects, Myocytes, Cardiac/cytology, Myocytes, Cardiac/drug effects, Phosphorylation, Protein Processing, Post-Translational, Protein Transport/physiology, Protein-Serine-Threonine Kinases/metabolism, Proto-Oncogene Proteins/genetics, Proto-Oncogene Proteins/metabolism, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-cbl, RNA, Messenger/biosynthesis, Rats, Sarcolemma/metabolism, Ubiquitin-Protein Ligases/genetics, Ubiquitin-Protein Ligases/metabolism, Verapamil/pharmacology
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