Impact of nocturnal hypoxia on glycaemic control, appetite, gut microbiota and inflammation in adults with type 2 diabetes mellitus: A single-blind cross-over trial.

High altitude residents have a lower incidence of type 2 diabetes mellitus (T2DM). Therefore, we examined the effect of repeated overnight normobaric hypoxic exposure on glycaemic control, appetite, gut microbiota and inflammation in adults with T2DM. Thirteen adults with T2DM [glycated haemoglobin (HbA1c): 61.1 ± 14.1 mmol mol-1; aged 64.2 ± 9.4 years; four female] completed a single-blind, randomised, sham-controlled, cross-over study for 10 nights, sleeping when exposed to hypoxia (fractional inspired O2 [ F I O 2 ${{F}_{{\mathrm{I}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ] = 0.155; ∼2500 m simulated altitude) or normoxic conditions ( F I O 2 ${{F}_{{\mathrm{I}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$  = 0.209) in a randomised order. Outcome measures included: fasted plasma [glucose]; [hypoxia inducible factor-1α]; [interleukin-6]; [tumour necrosis factor-α]; [interleukin-10]; [heat shock protein 70]; [butyric acid]; peak plasma [glucose] and insulin sensitivity following a 2 h oral glucose tolerance test; body composition; appetite indices ([leptin], [acyl ghrelin], [peptide YY], [glucagon-like peptide-1]); and gut microbiota diversity and abundance [16S rRNA amplicon sequencing]. During intervention periods, accelerometers measured physical activity, sleep duration and efficiency, whereas continuous glucose monitors were used to assess estimated HbA1c and glucose management indicator and time in target range. Overnight hypoxia was not associated with changes in any outcome measure (P > 0.05 with small effect sizes) except fasting insulin sensitivity and gut microbiota alpha diversity, which exhibited trends (P = 0.10; P = 0.08 respectively) for a medium beneficial effect (d = 0.49; d = 0.59 respectively). Ten nights of overnight moderate hypoxic exposure did not significantly affect glycaemic control, gut microbiome, appetite, or inflammation in adults with T2DM. However, the intervention was well tolerated and a medium effect-size for improved insulin sensitivity and reduced alpha diversity warrants further investigation. KEY POINTS: Living at altitude lowers the incidence of type 2 diabetes mellitus (T2DM). Animal studies suggest that exposure to hypoxia may lead to weight loss and suppressed appetite. In a single-blind, randomised sham-controlled, cross-over trial, we assessed the effects of 10 nights of hypoxia (fractional inspired O2 ∼0.155) on glucose homeostasis, appetite, gut microbiota, inflammatory stress ([interleukin-6]; [tumour necrosis factor-α]; [interleukin-10]) and hypoxic stress ([hypoxia inducible factor 1α]; heat shock protein 70]) in 13 adults with T2DM. Appetite and inflammatory markers were unchanged following hypoxic exposure, but an increased insulin sensitivity and reduced gut microbiota alpha diversity were associated with a medium effect-size and statistical trends, which warrant further investigation using a definitive large randomised controlled trial. Hypoxic exposure may represent a viable therapeutic intervention in people with T2DM and particularly those unable or unwilling to exercise because barriers to uptake and adherence may be lower than for other lifestyle interventions (e.g. diet and exercise).

Selection pressure at altitude for genes related to alcohol metabolism: A role for endogenous enteric ethanol synthesis?

NEW FINDINGS: What is the topic of this review? Highland natives have undergone natural selection for genetic variants advantageous in adaptation to the hypobaric hypoxia experienced at high altitude. Why genes related to alcohol metabolism appear consistently selected for has not been greatly considered. We hypothesize that altitude-related changes in the gut microbiome offer one possible explanation. What advances does it highlight? Low intestinal oxygen tension might favour the production of ethanol through anaerobic fermentation by the gut microbiome. Subsequent increases in endogenous ethanol absorption could therefore provide a selection pressure for gene variants favouring its increased degradation, or perhaps reduced degradation if endogenously synthesized ethanol acts as a metabolic signalling molecule. ABSTRACT: Reduced tissue availability of oxygen results from ascent to high altitude, where atmospheric pressure, and thus the partial pressure of inspired oxygen, fall (hypobaric hypoxia). In humans, adaptation to such hypoxia is necessary for survival. These functional changes remain incompletely characterized, although metabolic adaptation (rather than simple increases in convective oxygen delivery) appears to play a fundamental role. Those populations that have remained native to high altitude have undergone natural selection for genetic variants associated with advantageous phenotypic traits. Interestingly, a consistent genetic signal has implicated alcohol metabolism in the human adaptive response to hypobaric hypoxia. The reasons for this remain unclear. One possibility is that increased alcohol synthesis occurs through fermentation by gut bacteria in response to enteric hypoxia. There is growing evidence that anaerobes capable of producing ethanol become increasingly prevalent with high-altitude exposure. We hypothesize that: (1) ascent to high altitude renders the gut luminal environment increasingly hypoxic, favouring (2) an increase in the population of enteric fermenting anaerobes, hence (3) the synthesis of alcohol which, through systemic absorption, leads to (4) selection pressure on genes relating to alcohol metabolism. In theory, alcohol could be viewed as a toxic product, leading to selection of gene variants favouring its metabolism. On the contrary, alcohol is a metabolic substrate that might be beneficial. This mechanism could also account for some of the interindividual differences of lowlanders in acclimatization to altitude. Future research should be aimed at determining any shifts to favour ethanol-producing anaerobes after ascent to altitude.