title: p38 MAPK activation upregulates proinflammatory pathways in skeletal muscle cells from insulin-resistant type 2 diabetic patients.
abstract: Skeletal muscle is the key site of peripheral insulin resistance in type 2 diabetes. Insulin-stimulated glucose uptake is decreased in differentiated diabetic cultured myotubes, which is in keeping with a retained genetic/epigenetic defect of insulin action. We investigated differences in gene expression during differentiation between diabetic and control muscle cell cultures. Microarray analysis was performed using skeletal muscle cell cultures established from type 2 diabetic patients with a family history of type 2 diabetes and clinical evidence of marked insulin resistance and nondiabetic control subjects with no family history of diabetes. Genes and pathways upregulated with differentiation in the diabetic cultures, compared with controls, were identified using Gene Spring and Gene Set Enrichment Analysis. Gene sets upregulated in diabetic myotubes were associated predominantly with inflammation. p38 MAPK was identified as a key regulator of the expression of these proinflammatory gene sets, and p38 MAPK activation was found to be increased in the diabetic vs. control myotubes. Although inhibition of p38 MAPK activity decreased cytokine gene expression from the cultured diabetic myotubes significantly, it did not improve insulin-stimulated glucose uptake. Increased cytokine expression driven by increased p38 MAPK activation is a key feature of cultured myotubes derived from insulin-resistant type 2 diabetic patients. p38 MAPK inhibition decreased cytokine expression but did not affect the retained defect of impaired insulin action in the diabetic muscle cells.
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle, United Kingdom;
authors.forename: Audrey E
authors.initials: AE
authors.lastname: Brown
authors.affiliation: Receptor Systems Biology Laboratory, Hagedorn Research Institute, Novo Nordisk, Gentofte, Denmark;
authors.forename: Jane
authors.initials: J
authors.lastname: Palsgaard
authors.affiliation: Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Rehannah
authors.initials: R
authors.lastname: Borup
authors.affiliation: School of Mathematics and Statistics, Newcastle University, Newcastle, United Kingdom; and.
authors.forename: Peter
authors.initials: P
authors.lastname: Avery
authors.affiliation: Unilever Discover, Colworth Science Park, Sharnbrook, Bedford, United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: Gunn
authors.affiliation: Receptor Systems Biology Laboratory, Hagedorn Research Institute, Novo Nordisk, Gentofte, Denmark;
authors.forename: Pierre
authors.initials: P
authors.lastname: De Meyts
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle, United Kingdom;
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Yeaman
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle, United Kingdom; mark.walker@ncl.ac.uk.
authors.forename: Mark
authors.initials: M
authors.lastname: Walker
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism*; D007333:Insulin Resistance / Q000276:immunology; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D018836:Inflammation Mediators; D048051:p38 Mitogen-Activated Protein Kinases
keywords: cytokines; human skeletal muscle cells; inflammation; insulin resistance; p38 mitogen-activated protein kinase