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.
Highlights
Ascent to high altitude is associated with a fall in barometric pressure, and with it a reduction in oxygen availability (‘hypobaric hypoxia’)
The two groups were well matched for BMI and circulating levels of biomarkers involved in glycaemic control, indices of insulin resistance, inflammation (IL-6, C Reactive Protein (CRP), TNF-a, Migration Inhibitory Factor (MIF)), oxidative stress and SpO2
Gluco-Insular Response Our results are in accord with those from the simulated ascent of Everest in Operation Everest II, whose study duration (40 days) and intensity of exposure to hypoxia was similar for the 6 healthy male participants to that which our subjects faced [12]: in both studies, glucose- insulin response was dependent on the duration and intensity of exposure to hypoxia, with a paradoxical increase in insulin levels during weight loss [14]
Summary
Ascent to high altitude is associated with a fall in barometric pressure, and with it a reduction in oxygen availability (‘hypobaric hypoxia’). Data have been inconsistent or contradictory [3,4,5,6,12,13,14]: beneficial effects of hypoxia on peripheral insulin action and body weight regulation have, for instance, been suggested [5,6,15] whereas a deterioration of insulin signalling has been reported in other studies [3,7] The source of such conflicting data may relate to inter-study differences in 1) sample size, 2) intensity of exposure to hypoxia (rate of ascent and maximum height gained: ascent profile) 3) duration of exposure to hypoxia, 4) subjects’ phenotypic characteristics, 5) exposure to other environmental stressors (e.g. physical exertion and altered energy balance), and 6) testing conditions (chamber, high-altitude) [16]. Insulin concentrations at the end of the study were typically 2-fold greater than those at the start, while glucose levels remained unaltered, suggesting the development of insulin resistance [14]
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