Insulin resistance is associated with tissue-specific regulation of HIF-1α and HIF-2α during mild chronic intermittent hypoxia

Chronic intermittent hypoxia (CIH) is a feature of obstructive sleep apnea (OSA). Whereas clinical studies have demonstrated the association between OSA and insulin resistance, the molecular mechanisms behind it are still unknown. Herein we investigated the effect of mild CIH on insulin sensitivity and we evaluated the changes in insulin and HIF signaling pathways that occur in CIH-induced insulin resistance.We showed that mild CIH obtained by 5/6 hypoxic (5%O₂) cycles/h, 10.5 h/day during 28 and 35 days increased arterial blood pressure. Insulin resistance and insulinemia increased with CIH duration, being significantly different after 35 days of CIH. Thirty-five days of CIH decreased insulin receptor expression and phosphorylation in skeletal muscle and adipose tissue, but not in the liver. Conversely, Glut2 expression increased in the liver of CIH-animals. Thirty-five days of CIH up-regulated HIF-1α in the liver and down-regulated HIF-1α and HIF-2α in skeletal muscle.We concluded that the effect of CIH on insulin sensitivity and signaling is time-dependent and is associated with changes in HIF signaling in insulin-sensitive tissues.