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The observed insulin responses to sustained hypoxia at high altitudes has prompted deeper inquiry into the role of oxidative stress in the pathophysiology of type 2 diabetes.
Insight into the development of insulin resistance and type 2 diabetes mellitus (T2DM) may come from, of all places, physically fit, high-altitude climbers on Mount Everest.
Results from the Caudwell Xtreme Everest expedition, coordinated by the University College of London (UCL) Centre for Altitude, Space and Extreme Environment Medicine and published in PLoS ONE in April 2014, suggests that 6 to 8 weeks of exposure to hypoxia at high altitude is linked to increased levels of certain biomarkers of inflammation and oxidative stress, which in turn are linked to insulin resistance.1 The research is part of a larger project looking at hypoxia and human performance at extreme altitude, with the goal of improving the care of patients who experience hypoxia, such as the critically ill.
Why study the development of insulin resistance in extreme athletes, though, who are presumably the opposite of those most at risk for the development of T2DM?
“The Caudwell Xtreme Everest study subjects are like the human equivalent of lab rats. Studying them provided a window of opportunity in which to study sustained severe hypoxia at high altitude that we might not normally get,” explained Mike Grocott, Professor of Anaesthesia and Critical Care at the University of Southampton. Grocott is also cofounder of the UCL Centre for Altitude Space and Extreme Environment Medicine and Director of the Xtreme Everest Hypoxia Research Consortium.
“The results help give a better understanding of how T2DM develops, and are supportive of the suggestion that hypoxic obese tissue may be part of the problem in the development of insulin resistance,” Grocott continued.
The main concept is that insulin responses become more pronounced during hypoxia, while glucose levels remain unchanged, suggesting the development of insulin resistance.2 One hypothesis holds that the well-known link between obesity and increased risk for T2DM could partly be explained by adipocyte hypertrophy. When adipocytes outgrow their nutrient supply, they could induce a mild state of chronic tissue hypoxia. Over time, this could lead to increased levels of reactive oxygen species (ROS), inflammatory markers, and macrophage infiltration, ultimately increasing systemic inflammation and affecting beta cell function.3-5
“Particularly in obese people, the idea is that fat cells effectively outgrow their blood supply and therefore don’t have sufficient oxygen,” explained Grocott. “We very much see 4-HNE [one of the laboratory measures in this study] as a marker of oxidative stress in a variety of circumstances. For example, obstructive sleep apnea and obesity often go together, and it may be that experiencing intermittent night-time hypoxia could be one of the driving processes in the development of T2DM in such individuals.”
The study in brief:
- 22 participants (17 males, mean age 35.3 years), 14 of whom ascended higher than Everest Base Camp, and 8 of whom reached the summit (8448 m)
- Laboratory assessments were made of insulin resistance and biomarkers of oxidative stress and inflammation at baseline (sea level in London), after ascending from Kathmandu (1300 m) to Everest Base Camp (5300 m), and at 1, 6, and 8 weeks thereafter.
- Body weight, glucose, peripheral oxygen saturation (SpO2), and venous blood lactate concentration also were assessed
Key results include:
- SpO2: Fell from 98% at sea level to 82% upon arrival at Everest Base Camp
- Weight: 7.4 kg mean weight loss
- Glucose: Remained stable and within normal range throughout the expedition
- Insulin, C-peptide: Increased by >200% during weeks 6 to 8
- 4-HNE levels: Increased almost 3-fold during weeks 6 to 8
- Interleukin-6 (IL-6): Increased approximately 250% by weeks 6 to 8 and paralleled changes in insulin levels
- Fasting insulin, HOMA-IR, glucagon: Increased and correlated with increased markers of oxidative stress (4-HNE) and inflammation (IL-6)
- Hepatic glucose output: Glucagon and adrenalin levels increased approximately 70% and 300%, respectively, from weeks 6-8
Overall, glucagon, IL-6, and 4-HNE showed the strongest associations with insulin and glucose homeostasis: 4-HNE was the only oxidative stress biomarker strongly associated with HOMA-IR; IL-6 was strongly correlated with glucagon, suggesting a role for IL-6 in modulating the association between chronic hypoxia and pancreatic function.
“Healthy subjects exposed to sustained hypobaric hypoxia at high-altitude appear to become insulin-resistant while they are in negative-energy balance,” the authors concluded. “Normo-glycemia was maintained by a compensatory increase in beta-cell secretion and reduced hepatic extraction leading to sustained hyperinsulinemia during the last two weeks of the expedition.”
In addition to the insight provided into the pathologic mechanisms that underlie insulin resistance, this research could aid development of interventions to prevent the development or progression of T2DM, and help target areas of research for new treatments.
“In the management of obesity, weight loss and exercise are the primary interventions,” Grocott noted. “In terms of adjunctive therapies, one might look at the use of antioxidants. That’s speculative,” he added,” but I think it’s an interesting avenue to pursue.”
Find more information about the Caudwell Xtreme Everest Project: