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Humans living at a higher altitude are less prone to suffer from impaired glucose homeostasis and type 2 diabetes mellitus (T2DM), which might at least partly be explained by lower oxygen availability at higher altitudes. The present systematic review aimed to provide an overview of the current literature on the effects of hypoxia exposure on glucose homeostasis in metabolically compromised humans. Several databases were searched up to August 10th, 2020. The search strategy identified 368 unique records. Following assessment for eligibility based on the selection criteria, 16 studies were included in this review. Six studies (2 controlled studies; 4 uncontrolled studies) demonstrated beneficial effects of hypoxia exposure on glucose homeostasis, while 10 studies (8 controlled studies; 2 uncontrolled studies) reported no improvement in glucose homeostasis following hypoxia exposure. Notably, passive hypoxia exposure seemed to improve glucose homeostasis, whereas hypoxic exercise training (2–8 weeks) appeared to have no additional/synergistic effects on glucose homeostasis compared to normoxia exposure. Due to the heterogeneity in study populations and intervention duration (acute studies / 2–8 wks training), it is difficult to indicate which factors may explain conflicting study outcomes. Moreover, these results should be interpreted with some caution, as several studies did not include a control group. Taken together, hypoxia exposure under resting and exercise conditions might provide a novel therapeutic strategy to improve glucose homeostasis in metabolically compromised individuals, but more randomized controlled trials are warranted before strong conclusions on the effects of hypoxia exposure on glucose homeostasis can be drawn.

Objective Recent studies suggest that hypoxia exposure may improve glucose homeostasis, but well-controlled human studies are lacking. We hypothesized that mild intermittent hypoxia (MIH) exposure decreases tissue oxygen partial pressure (pO2) and induces metabolic improvements in people who are overweight/obese. Methods In a randomized, controlled, single-blind crossover study, 12 men who were overweight/obese were exposed to MIH (15 % O2, 3 × 2 h/day) or normoxia (21 % O2) for 7 consecutive days. Adipose tissue (AT) and skeletal muscle (SM) pO2, fasting/postprandial substrate metabolism, tissue-specific insulin sensitivity, SM oxidative capacity, and AT and SM gene/protein expression were determined. Furthermore, primary human myotubes and adipocytes were exposed to oxygen levels mimicking the hypoxic and normoxic AT and SM microenvironments. Results MIH decreased systemic oxygen saturation (92.0 ± 0.5 % vs 97.1 ± 0.3, p, Highlights • MIH exposure decreases oxygen partial pressure in human adipose tissue and skeletal muscle. • MIH exposure induces a shift in substrate utilization toward glycolytic metabolism. • Hypoxia exposure increases insulin-independent glucose uptake in primary human myotubes, at least in part through AMPK. • MIH does not alter adipose tissue, hepatic and peripheral insulin sensitivity.

Obesity is a complex disorder of excessive adiposity, and is associated with adverse health effects such as cardiometabolic complications, which are to a large extent attributable to dysfunctional white adipose tissue. Adipose tissue dysfunction is characterized by adipocyte hypertrophy, impaired adipokine secretion, a chronic low‐grade inflammatory status, hormonal resistance and altered metabolic responses, together contributing to insulin resistance and related chronic diseases. Adipose tissue hypoxia, defined as a relative oxygen deficit, in obesity has been proposed as a potential contributor to adipose tissue dysfunction, but studies in humans have yielded conflicting results. Here, we will review the role of adipose tissue oxygenation in the pathophysiology of obesity‐related complications, with a specific focus on human studies. We will provide an overview of the determinants of adipose tissue oxygenation, as well as the role of adipose tissue oxygenation in glucose homeostasis, lipid metabolism and inflammation. Finally, we will discuss the putative effects of physiological and experimental hypoxia on adipose tissue biology and whole‐body metabolism in humans. We conclude that several lines of evidence suggest that alteration of adipose tissue oxygenation may impact metabolic homeostasis, thereby providing a novel strategy to combat chronic metabolic diseases in obese humans.