Chronic hypoxia increases insulin‐stimulated glucose uptake in mouse skeletal muscle

Abstract

High altitude populations 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 glucose uptake in mouse skeletal muscle. Adult male C57BL/6J mice were kept in normoxia (FIO2=21%, Control) or normobaric hypoxia (FIO2=10%, Hypoxia) for 4 weeks. Blood glucose and insulin concentrations were lower in the Hypoxia group (glucose: Control, 14.3 ± 0.65 vs. Hypoxia, 9.9 ± 0.83 mM, p<0.001; and insulin: Control, 1.2 ± 0.2 vs. Hypoxia, 0.7 ± 0.1 ng/ml, p<0.05). There was no difference in basal glucose uptake in soleus muscle (1.59±0.24 vs 1.71±0.15 umol/g/h; Control and Hypoxia respectively). However, insulin‐stimulated glucose uptake was 30% higher after 4 weeks of hypoxia (6.24±0.23 umol/g/h) compared to Control (4.87±0.37 umol/g/h, p<0.02). There was no significant difference in muscle glycogen content. While the content of glucose transporters 4 and 1 (GLUT4 and GLUT1), phosphoinositide 3‐kinase (PI3K), glycogen synthase kinase 3 (GSK3), and protein kinase B/AKT was not affected by chronic hypoxia, AKT phosphorylation following insulin stimulation in soleus muscle was significantly higher (25% greater in Hypoxia vs. Control, p<0.05). GSK3 phosphorylation was not different. These results demonstrate that increased insulin‐stimulated glucose uptake in skeletal muscles is the likely mechanism leading to lower blood glucose and insulin levels in mice adapted to chronic hypoxia. The molecular mechanisms mediating this adaptation may be useful for the treatment of insulin resistant states.