Chronic hypoxia increases insulin-stimulated glucose uptake in mouse soleus muscle.
People living at high altitude appear to have lower blood glucose levels and decreased incidence of diabetes. Faster glucose uptake and increased insulin sensitivity are likely explanations for these findings: skeletal muscle is the largest glucose sink in the body, and its adaptation to the hypoxia of altitude may influence glucose uptake and insulin sensitivity. This study tested the hypothesis that chronic normobaric hypoxia increases insulin-stimulated glucose uptake in soleus muscles and decreases plasma glucose levels. Adult male C57BL/6J mice were kept in normoxia [fraction of inspired O₂ = 21% (Control)] or normobaric hypoxia [fraction of inspired O₂ = 10% (Hypoxia)] for 4 wk. Then blood glucose and insulin levels, in vitro muscle glucose uptake, and indexes of insulin signaling were measured. Chronic hypoxia lowered blood glucose and plasma insulin [glucose: 14.3 ± 0.65 mM in Control vs. 9.9 ± 0.83 mM in Hypoxia (P < 0.001); insulin: 1.2 ± 0.2 ng/ml in Control vs. 0.7 ± 0.1 ng/ml in Hypoxia (P < 0.05)] and increased insulin sensitivity determined by homeostatic model assessment 2 [21.5 ± 3.8 in Control vs. 39.3 ± 5.7 in Hypoxia (P < 0.03)]. There was no significant difference in basal glucose uptake in vitro in soleus muscle (1.59 ± 0.24 and 1.71 ± 0.15 μmol·g⁻¹·h⁻¹ in Control and Hypoxia, respectively). However, insulin-stimulated glucose uptake was 30% higher in the soleus after 4 wk of hypoxia than Control (6.24 ± 0.23 vs. 4.87 ± 0.37 μmol·g⁻¹·h⁻¹, P < 0.02). Muscle glycogen content was not significantly different between the two groups. Levels of glucose transporters 4 and 1, phosphoinositide 3-kinase, glycogen synthase kinase 3, protein kinase B/Akt, and AMP-activated protein kinase were not affected by chronic hypoxia. Akt phosphorylation following insulin stimulation in soleus muscle was significantly (25%) higher in Hypoxia than Control (P < 0.05). Neither glycogen synthase kinase 3 nor AMP-activated protein kinase phosphorylation changed after 4 wk of hypoxia. These results demonstrate that the adaptation of skeletal muscles to chronic hypoxia includes increased insulin-stimulated glucose uptake.
Department of Physiology, University of Kentucky, Lexington, 40536, USA.
J L
JL
Gamboa
Mary L
ML
Garcia-Cazarin
Francisco H
FH
Andrade
D000091162:AMP-Activated Protein Kinase Kinases; D000531:Altitude; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism; D006400:Hematocrit; D007004:Hypoglycemic Agents / Q000494:pharmacology; D000860:Hypoxia / Q000503:physiopathology*; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D006003:Glycogen; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D000091162:AMP-Activated Protein Kinase Kinases; D005947:Glucose