Department of Physiology, University of Kentucky, Lexington, 40536, USA.
Am J Physiol Regul Integr Comp Physiol. 2011 Jan;300(1):R85-91. doi: 10.1152/ajpregu.00078.2010. Epub 2010 Oct 20.
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.
生活在高海拔地区的人似乎血糖水平较低，糖尿病发病率也较低。葡萄糖摄取加快和胰岛素敏感性增强可能是这些发现的原因：骨骼肌是体内最大的葡萄糖消耗器官，其对高原缺氧的适应可能会影响葡萄糖摄取和胰岛素敏感性。本研究检验了一个假设，即慢性常压缺氧会增加比目鱼肌中胰岛素刺激的葡萄糖摄取并降低血浆葡萄糖水平。成年雄性 C57BL/6J 小鼠在常氧（吸入氧分数为 21%（对照））或常压缺氧（吸入氧分数为 10%（缺氧））中饲养 4 周。然后测量血糖和胰岛素水平、体外肌肉葡萄糖摄取以及胰岛素信号转导指标。慢性缺氧降低了血糖和血浆胰岛素[血糖：对照 14.3±0.65mM，缺氧 9.9±0.83mM（P<0.001）；胰岛素：对照 1.2±0.2ng/ml，缺氧 0.7±0.1ng/ml（P<0.05）]，并通过稳态模型评估 2 增加了胰岛素敏感性[对照 21.5±3.8，缺氧 39.3±5.7（P<0.03）]。体外比目鱼肌基础葡萄糖摄取无显著差异（对照 1.59±0.24μmol·g⁻¹·h⁻¹，缺氧 1.71±0.15μmol·g⁻¹·h⁻¹）。然而，与对照相比，缺氧 4 周后比目鱼肌的胰岛素刺激葡萄糖摄取增加了 30%（对照 6.24±0.23μmol·g⁻¹·h⁻¹，缺氧 4.87±0.37μmol·g⁻¹·h⁻¹，P<0.02）。两组肌肉糖原含量无显著差异。葡萄糖转运蛋白 4 和 1、磷酸肌醇 3-激酶、糖原合酶激酶 3、蛋白激酶 B/Akt 和 AMP 激活的蛋白激酶水平不受慢性缺氧的影响。与对照相比，缺氧后比目鱼肌中胰岛素刺激后的 Akt 磷酸化显著增加（25%，P<0.05）。糖原合酶激酶 3 或 AMP 激活的蛋白激酶磷酸化在缺氧 4 周后没有变化。这些结果表明，骨骼肌对慢性缺氧的适应包括增加胰岛素刺激的葡萄糖摄取。
