GLUT4 and glycogen synthase are key players in bed rest-induced insulin resistance

TY - JOUR

T1 - GLUT4 and glycogen synthase are key players in bed rest-induced insulin resistance

AU - Biensø, Rasmus Sjørup

AU - Jørgensen, Stine Ringholm

AU - Kiilerich, Kristian

AU - Aachmann-Andersen, Niels Jacob

AU - Krogh-Madsen, Rikke

AU - Guerra, Borja

AU - Plomgaard, Peter Stendahl

AU - van Hall, Gerrit

AU - Treebak, Jonas Thue

AU - Saltin, Bengt

AU - Lundby, Carsten

AU - Calbet, Jose A.L.

AU - Pilegaard, Henriette

AU - Wojtaszewski, Jørgen

N1 - CURIS 2012 5200 074

PY - 2012/5

Y1 - 2012/5

N2 - 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.

AB - 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.

KW - Bed Rest

KW - Benzodiazepinones

KW - Blood Glucose

KW - GTPase-Activating Proteins

KW - Gene Expression Regulation

KW - Glucose

KW - Glucose Transporter Type 4

KW - Glycogen

KW - Glycogen Synthase

KW - Humans

KW - Insulin

KW - Insulin Resistance

KW - Male

KW - Muscle, Skeletal

KW - Palmitates

KW - Phosphorylation

KW - Proto-Oncogene Proteins c-akt

U2 - 10.2337/db11-0884

DO - 10.2337/db11-0884

M3 - Journal article

C2 - 22403297

SN - 0012-1797

VL - 61

SP - 1090

EP - 1099

JO - Diabetes

JF - Diabetes

IS - 5

ER -