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.

Measurements of jugular, portal, femoral, and calf vein cross-sectional area for the assessment of venous blood redistribution with long duration spaceflight (Vessel Imaging Experiment)

“…Additionally, the blood stagnation inside the jugular vein may contribute to increased intracranial pressure (Besnard et al 2002;Zhang and Hargens 2014), potentially resulting in impaired cerebrovascular reactivity (Zuj et al 2012). Several studies have reported an increase in circulating insulin in astronauts during spaceflight (Macho et al 2003;Hughson et al unpublished data, personal communication 2015) and an increase in glycemia and insulin resistance during bed rest (Cree et al 2010, Biensø et al 2012. These changes may be in part due to altered abdominal organ function from splanchnic venous pooling.…”

Dysregulation of muscle glycogen synthase in recovery from exercise in type 2 diabetes

“…In line with previous studies of insulinresistant conditions including individuals with obesity, PCOS and type 2 diabetes [4-6, 25, 29], we did, however, observe a lack of insulin-induced dephosphorylation of GS at sites 2+2a in both type 2 diabetes and obesity. These phosphosites have previously been found to be responsive to insulin stimulation in a number of healthy lean participant populations [4,25,43].…”

Severe spasticity in lower extremities is associated with reduced adiposity and lower fasting plasma glucose level in persons with spinal cord injury

“…In addition, mechanisms through which severe spasticity ameliorates the derangement of body compositions and glucose homeostasis could be investigated. For example, differences in the expression of glucose transport protein, GLUT4 proteins, 30 IGF-1 concentration 7,29 and muscle fiber type composition 22,23 have been suggested as related mechanisms.…”