Effects of Prolonged Exposure to Hypobaric Hypoxia on Oxidative Stress, Inflammation and Gluco-Insular Regulation: The Not-So-Sweet Price for Good Regulation

Abstract

ObjectivesThe mechanisms by which low oxygen availability are associated with the development of insulin resistance remain obscure. We thus investigated the relationship between such gluco-insular derangements in response to sustained (hypobaric) hypoxemia, and changes in biomarkers of oxidative stress, inflammation and counter-regulatory hormone responses.MethodsAfter baseline testing in London (75 m), 24 subjects ascended from Kathmandu (1,300 m) to Everest Base Camp (EBC;5,300 m) over 13 days. Of these, 14 ascended higher, with 8 reaching the summit (8,848 m). Assessments were conducted at baseline, during ascent to EBC, and 1, 6 and 8 week(s) thereafter. Changes in body weight and indices of gluco-insular control were measured (glucose, insulin, C-Peptide, homeostasis model assessment of insulin resistance [HOMA-IR]) along with biomarkers of oxidative stress (4-hydroxy-2-nonenal-HNE), inflammation (Interleukin-6 [IL-6]) and counter-regulatory hormones (glucagon, adrenalin, noradrenalin). In addition, peripheral oxygen saturation (SpO2) and venous blood lactate concentrations were determined.ResultsSpO2 fell significantly from 98.0% at sea level to 82.0% on arrival at 5,300 m. Whilst glucose levels remained stable, insulin and C-Peptide concentrations increased by >200% during the last 2 weeks. Increases in fasting insulin, HOMA-IR and glucagon correlated with increases in markers of oxidative stress (4-HNE) and inflammation (IL-6). Lactate levels progressively increased during ascent and remained significantly elevated until week 8. Subjects lost on average 7.3 kg in body weight.ConclusionsSustained hypoxemia is associated with insulin resistance, whose magnitude correlates with the degree of oxidative stress and inflammation. The role of 4-HNE and IL-6 as key players in modifying the association between sustained hypoxia and insulin resistance merits further investigation.

Does hypoxia play a role in the development of sarcopenia in humans? Mechanistic insights from the Caudwell Xtreme Everest Expedition

“…We have previously described the development of increased insulin resistance with prolonged exposure to hypobaric hypoxia [20]. However, the multivariate model reported in the present study suggests a concomitant decline of FFM and insulin concentrations during the expedition.…”

Heightened Exercise-Induced Oxidative Stress at Simulated Moderate Level Altitude vs. Sea Level in Trained Cyclists

“…At rest, the ascent (Møller et al, 2001;Siervo et al, 2014;Taylor et al, 2012) and descent (González et al, 2005) from altitude has been shown to cause marked increases in lipid peroxidation. The participants in the current study had not been exposed to altitude for at least 4 months, minimizing the impact of prior exposure perturbing basal or exercise-induced redox state, which has previously been demonstrated in active individuals (Sanchari et al, 2010;Sinha et al, 2009).…”

“…Despite lower partial oxygen pressures at altitude, an exaggerated rate of reactive oxygen and nitrogen species (RONS) production is known to be coupled with weakened enzymatic and nonenzymatic antioxidants systems, eliciting increased oxidative stress. For example, previous investigations in humans have observed elevated blood biomarkers of oxidative stress (e.g., lipid peroxidation (Siervo et al, 2014;Taylor et al, 2010)) and a decline in reduced: oxidized glutathione ratio (Joanny et al, 2001;Taylor et al, 2010) at rest, relative to measures at sea level.…”

“…Many of the studies in the literature investigating acute hypoxic exercise have not reported whether participants have been previously exposed to altitude or not, a factor that appears to markedly influence acute redox responses following exercise. Translation of previous studies conducted at high altitude (3000 m above sea level) (Joanny et al, 2001;Siervo et al, 2014;Sinha et al, 2009;Vij et al, 2005) is therefore difficult, given that competitive athletes are typically not exposed to elevations above 2500 m. Furthermore, because V O2max is reduced at altitude (Ferretti et al, 1997), cycling at the same absolute power output in hypoxia will result in higher relative exercise intensity (% V O2max). To determine whether differences in responses are due to hypoxia per se, rather than an increase in relative exercise intensity, trials can be instead matched based on a fraction of altitude-specific V O2max.…”

“…There is evidence that the ascent (Møller et al, 2001;Siervo et al, 2014;Taylor et al, 2012) and descent (González et al, 2005) to and from altitude can increase basal markers of oxidative stress, with regular exercise under these conditions known to cause a reduction (Debevec et al, 2014). Interestingly, there is evidence that individuals who are acclimatized to altitude demonstrate an exaggerated increase in markers of oxidative stress compared with nonacclimatized individuals following both groups cycling at 4500 m (Sinha et al, 2010).…”