Acute systemic insulin intolerance does not alter the response of the Akt/GSK-3 pathway to environmental hypoxia in human skeletal muscle.

Abstract

To investigate how acute environmental hypoxia regulates blood glucose and downstream intramuscular insulin signaling after a meal in healthy humans. Fifteen subjects were exposed for 4h to normoxia (NOR) or to normobaric hypoxia (HYP, FiO2=0.11) in a randomized order 40min after consumption of a high glycemic meal. A muscle biopsy from m. vastus lateralis and a blood sample were taken before (T0), after 1h (T60) and 4h (T240) in NOR or HYP and blood glucose levels were measured before exposure and every 30min. In HYP, blood glucose was reduced 100min (110.1±5.4 in NOR vs 89.5±4.7mgdl(-1) in HYP) and 130min (98.7±3.8 in NOR vs 85.6±4.9mgdl(-1) in HYP) after completion of a meal, which resulted in an 83% lower AUC in HYP compared to NOR (p=0.006). This coincided with 40% lower GLUT4 protein in the cytosolic fraction (p=0.013) and a tendency to increase in the crude membrane fraction (p=0.070) in HYP compared to NOR. At T240, blood glucose concentration was similar between HYP and NOR, whereas plasma insulin as well as phosphorylation of muscle Akt and GSK-3 was ~2-fold higher in HYP compared to NOR (p<0.05). In contrast, Rac1 protein was less abundant in the membrane fraction in HYP compared to NOR (p=0.003), reflecting lower activation. Acute environmental hypoxia initially reduced blood glucose response to a meal, possibly via an increase in GLUT4 abundance at the sarcolemmal membrane. Later on, whole body insulin intolerance developed independently of defects in conventional insulin signaling in skeletal muscle.