Metabolic effects of intermittent hypoxia in mice: steady versus high-frequency applied hypoxia daily during the rest period

Intermittent hypoxia (IH) is a frequent occurrence in sleep and respiratory disorders. Both human and murine studies show that IH may be implicated in metabolic dysfunction. Although the effects of nocturnal low-frequency intermittent hypoxia (IHL) have not been extensively examined, it would appear that IHL and high-frequency intermittent hypoxia (IHH) may elicit distinct metabolic adaptations. To this effect, C57BL/6J mice were randomly assigned to IHH (cycles of 90 s 6.4% O2 and 90 s 21% O2 during daylight), IHL (8% O2 during daylight hours), or control (CTL) for 5 wk. At the end of exposures, some of the mice were subjected to a glucose tolerance test (GTT; after intraperitoneal injection of 2 mg glucose/g body wt), and others were subjected to an insulin tolerance test (ITT; 0.25 units Humulin/kg body wt), with plasma leptin and insulin levels being measured in fasting conditions. Skeletal muscles were harvested for GLUT4 and proliferator-activated receptor gamma coactivator 1-α (PGC1-α) expression. Both IHH and IHL displayed reduced body weight increases compared with CTL. CTL mice had higher basal glycemic levels, but GTT kinetics revealed marked differences between IHL and IHH, with IHL manifesting the lowest insulin sensitivity compared with either IHH or CTL, and such findings were further confirmed by ITT. No differences emerged in PGC1-α expression across the three experimental groups. However, while cytosolic GLUT4 protein expression remained similar in IHL, IHH, and CTL, significant decreases in GLUT4 membrane fraction occurred in hypoxia and were most pronounced in IHL-exposed mice. Thus IHH and IHL elicit differential glucose homeostatic responses despite similar cumulative hypoxic profiles.