title: GLUT4 and glycogen synthase are key players in bed rest-induced insulin resistance.
abstract: To elucidate the molecular mechanisms behind physical inactivity-induced insulin resistance in skeletal muscle, 12 young, healthy male subjects completed 7 days of bed rest with vastus lateralis muscle biopsies obtained before and after. In six of the subjects, muscle biopsies were taken from both legs before and after a 3-h hyperinsulinemic euglycemic clamp performed 3 h after a 45-min, one-legged exercise. Blood samples were obtained from one femoral artery and both femoral veins before and during the clamp. Glucose infusion rate and leg glucose extraction during the clamp were lower after than before bed rest. This bed rest-induced insulin resistance occurred together with reduced muscle GLUT4, hexokinase II, protein kinase B/Akt1, and Akt2 protein level, and a tendency for reduced 3-hydroxyacyl-CoA dehydrogenase activity. The ability of insulin to phosphorylate Akt and activate glycogen synthase (GS) was reduced with normal GS site 3 but abnormal GS site 2+2a phosphorylation after bed rest. Exercise enhanced insulin-stimulated leg glucose extraction both before and after bed rest, which was accompanied by higher GS activity in the prior-exercised leg than the rested leg. The present findings demonstrate that physical inactivity-induced insulin resistance in muscle is associated with lower content/activity of key proteins in glucose transport/phosphorylation and storage.
authors.affiliation: Copenhagen Muscle Research Centre, University of Copenhagen, Copenhagen, Denmark. rsbiensoe@bio.ku.dk
authors.forename: Rasmus S
authors.initials: RS
authors.lastname: Biensø
authors.forename: Stine
authors.initials: S
authors.lastname: Ringholm
authors.forename: Kristian
authors.initials: K
authors.lastname: Kiilerich
authors.forename: Niels-Jacob
authors.initials: NJ
authors.lastname: Aachmann-Andersen
authors.forename: Rikke
authors.initials: R
authors.lastname: Krogh-Madsen
authors.forename: Borja
authors.initials: B
authors.lastname: Guerra
authors.forename: Peter
authors.initials: P
authors.lastname: Plomgaard
authors.forename: Gerrit
authors.initials: G
authors.lastname: van Hall
authors.forename: Jonas T
authors.initials: JT
authors.lastname: Treebak
authors.forename: Bengt
authors.initials: B
authors.lastname: Saltin
authors.forename: Carsten
authors.initials: C
authors.lastname: Lundby
authors.forename: Jose A L
authors.initials: JA
authors.lastname: Calbet
authors.forename: Henriette
authors.initials: H
authors.lastname: Pilegaard
authors.forename: Jørgen F P
authors.initials: JF
authors.lastname: Wojtaszewski
mesh_terms: D001510:Bed Rest / Q000009:adverse effects*; D001570:Benzodiazepinones; D001786:Blood Glucose; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D005947:Glucose / Q000008:administration & dosage; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism; D006006:Glycogen Synthase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D010168:Palmitates / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism
chemical_list: C550536:4-(2-hydroxyphenyl)-1,5-benzodiazepin-2-one; D001570:Benzodiazepinones; D001786:Blood Glucose; D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; D007328:Insulin; D010168:Palmitates; C495692:SLC2A4 protein, human; C518767:TBC1D4 protein, human; D006003:Glycogen; D006006:Glycogen Synthase; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose