title: Skeletal muscle insulin resistance induced by adipocyte-conditioned medium: underlying mechanisms and reversibility.
abstract: Insulin resistance in skeletal muscle is an early event in the development of diabetes, with obesity being one of the major contributing factors. In vitro, conditioned medium (CM) from differentiated human adipocytes impairs insulin signaling in human skeletal muscle cells, but it is not known whether insulin resistance is reversible and which mechanisms may underlie this process. CM induced insulin resistance in human myotubes at the level of insulin-stimulated Akt and GSK-3 phosphorylation. In addition, insulin-resistant skeletal muscle cells exhibit enhanced production of reactive oxygen species and ceramide as well as a downregulation of myogenic transcription factors such as myogenin and MyoD. However, insulin resistance was not paralleled by increased apopotosis. Regeneration of myotubes for 24 or 48 h after induction of insulin resistance restored normal insulin signaling. However, the expression level of myogenin could not be reestablished. In addition to decreasing myogenin expression, CM also decreased the release of IL-6 and IL-8 and increased monocyte chemotactic protein-1 (MCP-1) secretion from skeletal muscle cells. Although regeneration of myotubes reestablished normal secretion of IL-6, the release of IL-8 and MCP-1 remained impaired for 48 h after withdrawal of CM. In conclusion, our data show that insulin resistance in skeletal muscle cells is only partially reversible. Although some characteristic features of insulin-resistant myotubes normalize in parallel to insulin signaling after withdrawal of CM, others such as IL-8 and MCP-1 secretion and myogenin expression remain impaired over a longer period. Thus, we propose that the induction of insulin resistance may cause irreversible changes of protein expression and secretion in skeletal muscle cells.
authors: Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Düsseldorf, Germany.
authors: Henrike
authors: H
authors: Sell
authors: Kristin
authors: K
authors: Eckardt
authors: Annika
authors: A
authors: Taube
authors: Daniel
authors: D
authors: Tews
authors: Mihaela
authors: M
authors: Gurgui
authors: Gerhild
authors: G
authors: Van Echten-Deckert
authors: Jürgen
authors: J
authors: Eckel
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000328:Adult; D017209:Apoptosis / Q000502:physiology; D002518:Ceramides / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D002648:Child; D017077:Culture Media, Conditioned; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007333:Insulin Resistance / Q000502:physiology*; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism*; D017570:MyoD Protein / Q000378:metabolism; D032448:Myoblasts, Skeletal / Q000378:metabolism; D018008:Myogenin / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D002518:Ceramides; D018932:Chemokine CCL2; D017077:Culture Media, Conditioned; D015850:Interleukin-6; D016209:Interleukin-8; D017570:MyoD Protein; D018008:Myogenin; D017382:Reactive Oxygen Species; D009569:Nitric Oxide