title: The proteomic signature of insulin-resistant human skeletal muscle reveals increased glycolytic and decreased mitochondrial enzymes.
abstract: OBJECTIVE
  The molecular mechanisms underlying insulin resistance in skeletal muscle are incompletely understood. Here, we aimed to obtain a global picture of changes in protein abundance in skeletal muscle in obesity and type 2 diabetes, and those associated with whole-body measures of insulin action.
  
  
  METHODS
  Skeletal muscle biopsies were obtained from ten healthy lean (LE), 11 obese non-diabetic (OB), and ten obese type 2 diabetic participants before and after hyperinsulinaemic-euglycaemic clamps. Quantitative proteome analysis was performed by two-dimensional differential-gel electrophoresis and tandem-mass-spectrometry-based protein identification.
  
  
  RESULTS
  Forty-four protein spots displayed significant (p < 0.05) changes in abundance by at least a factor of 1.5 between groups. Several proteins were identified in multiple spots, suggesting post-translational modifications. Multiple spots containing glycolytic and fast-muscle proteins showed increased abundance, whereas spots with mitochondrial and slow-muscle proteins were downregulated in the OB and obese type 2 diabetic groups compared with the LE group. No differences in basal levels of myosin heavy chains were observed. The abundance of multiple spots representing glycolytic and fast-muscle proteins correlated negatively with insulin action on glucose disposal, glucose oxidation and lipid oxidation, while several spots with proteins involved in oxidative metabolism and mitochondrial function correlated positively with these whole-body measures of insulin action.
  
  
  CONCLUSIONS
  Our data suggest that increased glycolytic and decreased mitochondrial protein abundance together with a shift in muscle properties towards a fast-twitch pattern in the absence of marked changes in fibre-type distribution contribute to insulin resistance in obesity with and without type 2 diabetes. The roles of several differentially expressed or post-translationally modified proteins remain to be elucidated.
authors.affiliation: Medizinische Klinik I, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil, Klinikum der Ruhr Universität Bochum, Bürkle-de-la-Camp-Platz 1, Bochum, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Giebelstein
authors.forename: G
authors.initials: G
authors.lastname: Poschmann
authors.forename: K
authors.initials: K
authors.lastname: Højlund
authors.forename: W
authors.initials: W
authors.lastname: Schechinger
authors.forename: J W
authors.initials: JW
authors.lastname: Dietrich
authors.forename: K
authors.initials: K
authors.lastname: Levin
authors.forename: H
authors.initials: H
authors.lastname: Beck-Nielsen
authors.forename: K
authors.initials: K
authors.lastname: Podwojski
authors.forename: K
authors.initials: K
authors.lastname: Stühler
authors.forename: H E
authors.initials: HE
authors.lastname: Meyer
authors.forename: H H
authors.initials: HH
authors.lastname: Klein
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005260:Female; D015309:Glucose Clamp Technique; D006019:Glycolysis; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D040901:Proteomics; D053719:Tandem Mass Spectrometry
chemical_list: D007328:Insulin