title: Role of glycogen content in insulin resistance in human muscle cells.
abstract: We have used primary human muscle cell cultures to investigate the role of glycogen loading in cellular insulin resistance. Insulin pre-treatment for 2 h markedly impaired insulin signaling, as assessed by protein kinase B (PKB) phosphorylation. In contrast, insulin-dependent glycogen synthesis, glycogen synthase (GS) activation, and GS sites 3 de-phosphorylation were impaired only after 5 h of insulin pre-treatment, whereas 2-deoxyglucose transport was only decreased after 18 h pre-treatment. Insulin-resistant glycogen synthesis was associated closely with maximal glycogen loading. Both glucose limitation and 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR) treatment during insulin pre-treatment curtailed glycogen accumulation, and concomitantly restored insulin-sensitive glycogen synthesis and GS activation, although GS de-phosphorylation and PKB phosphorylation remained impaired. Conversely, glycogen super-compensation diminished insulin-sensitive glycogen synthesis and GS activity. Insulin acutely promoted GS translocation to particulate subcellular fractions; this was abolished by insulin pre-treatment, as was GS dephosphorylation therein. Limiting glycogen accumulation during insulin pre-treatment re-instated GS dephosphorylation in particulate fractions, whereas glycogen super-compensation prevented insulin-stimulated GS translocation and dephosphorylation. Our data suggest that diminished insulin signaling alone is insufficient to impair glucose disposal, and indicate a role for glycogen accumulation in inducing insulin resistance in human muscle cells.
authors.affiliation: Institute of Cellular Medicine, The Medical School, Framlington Place, Newcastle University, Newcastle upon Tyne, United Kingdom. g.j.litherland@ncl.ac.uk
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Litherland
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Morris
authors.forename: Mark
authors.initials: M
authors.lastname: Walker
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Yeaman
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000096:biosynthesis*; D006006:Glycogen Synthase / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D007333:Insulin Resistance; D032448:Myoblasts, Skeletal / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D007328:Insulin; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D006003:Glycogen; D003847:Deoxyglucose; D006006:Glycogen Synthase; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D000091162:AMP-Activated Protein Kinase Kinases; C031143:AICA ribonucleotide; D005947:Glucose