DR CHRISTIAN BRINKMANN (Orcid ID : 0000-0001-8419-7565)

Article type : Review Article

Accepted Article
Exercise during short-term exposure to hypoxia or hyperoxia

- novel treatment strategies for type 2 diabetic patients?!

Short running title:

Exercise, hypoxia, hyperoxia and diabetes

Brinkmann C1,2, Bloch W1, Brixius K1

1
Institute of Cardiovascular Research and Sport Medicine,
Department of Molecular and Cellular Sport Medicine,
German Sport University Cologne, Cologne, Germany
2
Institute of Cardiovascular Research and Sport Medicine,
Department of Preventive and Rehabilitative Sport Medicine,
German Sport University Cologne, Cologne, Germany

Corresponding author:

Dr. Christian Brinkmann

German Sport University

Am Sportpark Müngersdorf 6

50933 Cologne, Germany

Tel: 00-49-221-4982-5440
This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/sms.12937
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 Fax: 00-49-221-4982-

ch.brinkmann@gmx.net
Accepted Article
Exercise during short-term exposure to hypoxia or hyperoxia

- novel treatment strategies for type 2 diabetic patients?!

Abstract

Both hypoxia (decreased oxygen availability) and hyperoxia (increased oxygen availability)

have been shown to alter exercise adaptations in healthy subjects. This review aims to

clarify the possible benefits of exercise during short-term exposure to hypoxia or hyperoxia

for patients with type 2 diabetes mellitus (T2DM). There is evidence that exercise during

short-term exposure to hypoxia can acutely increase skeletal muscle glucose uptake more

than exercise in normoxia, and that post-exercise insulin sensitivity in T2DM patients is more

increased when exercise is performed under hypoxic conditions. Furthermore, interventional

studies show that glycemic control can be improved through regular physical exercise in

short-term hypoxia at a lower workload than in normoxia, and that exercise training in short-

term hypoxia can contribute to increased weight loss in overweight/obese (insulin-resistant)

subjects. While numerous studies involving healthy subjects report that regular exercise in

hypoxia can increase vascular health (skeletal muscle capillarization and vascular dilator

function) to a higher extent than exercise training in normoxia, there is no convincing

evidence yet that hypoxia has such additive effects in T2DM patients in the long term. Some

studies indicate that the use of hyperoxia during exercise can decrease lactate

concentrations and subjective ratings of perceived exertion. Thus, there are interesting

starting points for future studies to further evaluate possible beneficial effects of exercise in

short-term hypoxia or hyperoxia at different oxygen concentrations and exposure durations.

In general, exposure to hypoxia/hyperoxia should be considered with caution. Possible

health risks -especially for T2DM patients- are also analyzed in this review.

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 Key words: physical training, type 2 diabetes, hypoxia, hyperoxia
Accepted Article
Introduction

Type 2 diabetes mellitus (T2DM) is a severe global public health problem of the 21st century

(Zimmet et al., 2014). Considering the positive relationships between diabetes,

cardiovascular complications and premature death (Khaw et al., 2001), effective therapeutic

concepts are crucial when treating diabetes. In this context, exercise training interventions

are promising for improving glycemic control and cardiovascular health (Colberg et al., 2016)

and finding more effective (training) strategies against this metabolic disease is a major

challenge.

Some reviews and meta-analyses involving primarily training studies with healthy subjects

imply that inhalation of air with reduced oxygen (hypoxia) during exercise can increase

insulin sensitivity and improve cardiovascular health more than exercise with normal ambient

air (normoxia) (Montero & Lundby, 2016; Wee & Climstein, 2015). Furthermore, the use of

oxygen-enriched air (hyperoxia) has been shown to acutely increase endurance

performance and accelerate recovery processes in athletes (Sperlich et al., 2016). Breathing

hypoxic or hyperoxic air mixtures during exercise could also play a role in increasing

exercise adaptations and exercise tolerance in T2DM patients.

Various technological devices have already been developed to generate hypoxia. Some of

them can also generate hyperoxia and allow an alternation between hypoxic and hyperoxic

conditions. Artificially generated hypoxia or hyperoxia can be achieved by changing either

the fraction of oxygen (FiO2) (normobaric hypoxia/hyperoxia) or by changing the barometric

pressure (hypo-/hyperbaric hypoxia/hyperoxia). The fraction of oxygen is always constant at

natural altitude (FiO2: ≈ 21%), while the barometric pressure decreases with increasing

altitude. The devices can be used during exercise and air can be inspired in special

chambers, in which exercise can be performed, or by using respiration masks connected to

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 the device with a flexible tube.
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This narrative review aims to clarify any possible benefits of exercise in artificially generated

short-term hypoxia, hyperoxia or during alternating hypoxia-hyperoxia intervals for T2DM

patients, and provides an overview of recently published articles that compared the effects of

acute or chronic exercise during exposure to short-term hypoxia or hyperoxia with the effects

of exercise performed under normoxic conditions. The present review also aims to discuss

possible health risks related to the use of hypoxia and hyperoxia during exercise.

Literature search strategy

To identify all relevant publications on the influence of exercise in short-term hypoxia or

hyperoxia on health variables of type 2 diabetic patients, two independent reviewers (CB and

KB) entered the following keyword combinations in Pubmed: “insulin-resistance” OR “type 2

diabetes” OR “T2DM” OR “obesity” OR “overweight” AND “exercise” OR “training” AND

“hypoxia” OR “hyperoxia”.

The articles identified (2000 - January 2017) were scanned for eligibility. Articles were

included if it was clearly stated that insulin-resistant/type 2 diabetic patients had been

enrolled in the study, that patients exercised during short-term exposure to hypoxia or

hyperoxia, a control group was included (exercise under normoxic conditions), if glycemic or

cardiovascular health variables were considered, and a full text in English was available.

In line with the narrative style of this review, further literature was searched step-by-step in

the actual contexts and added if judged relevant.

Exercise in hypoxia, glucose uptake and insulin sensitivity

Influence of exposure to hypoxia on glucose uptake and insulin sensitivity

Azevedo et al. (1995) demonstrated in their experiments that hypoxia increases glucose

uptake in skeletal muscle strips obtained from healthy and from obese insulin-resistant

subjects ex vivo.

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 It has furthermore been reported by Brooks et al. (1991) that long-term hypoxic exposure (3

weeks at an altitude of ≈ 4300 m) increases glucose turnover and reduces blood glucose
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levels in healthy subjects. In keeping with this finding, Lippl et al. (2010) have shown that

glycated hemoglobin (HbA1c) values significantly decreased in overweight/obese subjects

during a 1-week altitude stay at ≈ 2650 m. The HbA1c values remained lowered up to 4

weeks.

Obviously, hypoxia can acutely increase glucose uptake, and continuous exposure to

hypoxia can improve glycemic control in the long term.

Contrary to this assumption, Oltmanns et al. (2004) found a significant decrease in dextrose

infusion rate under the conditions of an euglycemic clamp (the rate of dextrose infusion

needed to maintain stable blood glucose levels was monitored) over a period of 150 minutes

after the start of hypoxia (75% arterial oxygen saturation) in healthy subjects.

Furthermore, it has been discussed that regular hypoxic stress in subjects suffering from

obstructive sleep apnea may contribute to the development and progression of metabolic

dysfunctions (insulin resistance) (Louis & Punjabi, 2009).

It is generally known that exercise can acutely increase peripheral glucose uptake and that

physical training can improve glycemic control in the long term (Colberg et al. 2016).

This raises the question whether exercise and hypoxia can have a positive additive effect

and whether hyperglycemic subjects in particular can benefit from acute as well as from

chronic (regular) exercise during short-term exposure to hypoxia or whether hypoxia could

even be detrimental and blunt the beneficial effects of exercise.

Influence of acute exercise during short-term hypoxia on glucose uptake and insulin

sensitivity

Mackenzie et al. (2012; 2011) analyzed the effects of acute exercise during short-term

exposure to hypoxia on the glucose homeostasis in T2DM subjects, and they demonstrated

that glucose disappearance during cycling and continuous glucose infusion was greater

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 during cycling performed in hypoxia compared with cycling in normoxia. They furthermore

found that measures of glycemic control were improved to a higher extent during glucose
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tolerance tests immediately after cycling (values were also higher compared with hypoxic

exposure only) (see study details in Table 1). Insulin sensitivity (explaining the effects of

insulin on glucose disposal rates) was elevated 24 hours and 48 hours later, but only when

exercise was performed in hypoxia. They also discovered that exercise at continuous

submaximal intensities in hypoxia was more effective for improving glucose uptake and

insulin sensitivity than intense interval training with passive recovery intervals under the

same hypoxic conditions. It can thus be concluded from their studies that acute exercise and

hypoxia have an additive effect on peripheral glucose uptake and post-exercise insulin

sensitivity in T2DM patients.

It has been considered that the increase in glucose uptake in hypoxia could be attributable to

the up-regulation of glycolytic energy pathways (accompanied by increased glucose

utilization and skeletal muscle glucose uptake), which compensate for reduced aerobic

energy production (Mackenzie et al., 2011). In this context, Katayama et al. (2010) have

demonstrated that the respiratory exchange ratio was higher during submaximal cycling

exercise (at 50% maximal (peak?) oxygen uptake) for 30 minutes at a simulated altitude of ≈

2000 m in healthy subjects compared with exercise in normoxia.

How can cells take up more glucose during acute exercise in hypoxia?

Acute exercise can increase glucose uptake via a contraction-stimulated insulin-independent

mechanism via AMPK (Santos et al. 2008), and hypoxia has been assumed to increase

glucose uptake also via AMPK (for a review, see Mackenzie & Watt, 2016). In line with this

assumption, Mu et al. (2001) showed that glucose uptake was blocked in AMPK-deficient

mice in hypoxia.

In particular, the role of the sympathoadrenal system, which is stimulated during exercise

and hypoxia, and an increase in epinephrines might contribute to the increased glucose

uptake rates observed. In the study of Katayama et al. (2010), an increased respiratory

exchange ratio -indicating that glucose utilization is increased during exercise

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 in hypoxia compared to exercise in normoxia- was accompanied by increased epinephrine

levels. Epinephrine exposure has been shown to stimulate translocation of glucose

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transporters (GLUT)-4 in rat skeletal muscle (Han & Bonen, 1998), thereby increasing

insulin-independent glucose uptake while insulin-dependent glucose uptake is inhibited.

Unfortunately, Mackenzie et al. (2012; 2011) did not measure epinephrine levels in their

studies when exercise was combined with hypoxia in T2DM patients.

Mackenzie et al. (2012) report that insulin sensitivity was increased even 48 hours after

exercise in hypoxia (while it was not improved when exercise was performed in normoxia),

and it can be speculated that insulin-independent glucose uptake was replaced by an up-

regulation of insulin-dependent insulin signaling. However, underlying mechanisms must be

explored and more studies are necessary to explain this effect at a molecular level.

Influence of exercise training during short-term hypoxia on glucose uptake and insulin

sensitivity

While it seems that acute exercise during short-term exposure to hypoxia can improve

glucose uptake more than exercise in normoxia in diabetic patients, study results on the

long-term effects of exercise training in short-term hypoxia are inconclusive. Haufe et al.

(2008) demonstrated that the values of the homeostatic model assessment for the

quantification of insulin resistance (HOMA-IR) index significantly improved in healthy

subjects only when exercise was performed in hypoxia, but were not improved following

exercise training in normoxia. By contrast, Lecoultre et al. (2010) found increased glucose

and insulin concentrations and a higher insulin to glucagon ratio post- exercise training in

hypoxia compared with results from exercise training in normoxia. The studies of Haufe et al.

(2008) and Lecoultre et al. (2010) are described in detail in Table 2.

Studies involving insulin-resistant/type 2 diabetic patients exist as well. In the study of

Wiesner et al. (2010), overweigth/obese subjects (some of them were insulin-resistant) were

studied. No group-specific differences in improvements of the HOMA-IR index were found

between the group that performed exercise training in short-term hypoxia and the group

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 performing exercise training in normoxia. However, it is noteworthy that training workloads

were significantly lower in the hypoxia group. Thus, training in hypoxia led to similar
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improvements at a lower workload. Schreuder et al. (2014) did not find any improvements in

insulin sensitivity and glycemic control in T2DM patients following exercise training, neither

in normoxia nor in short-term hypoxia. Both aforementioned studies are described in detail in

Table 1.

Studies analyzing the influence of exercise training in hypoxia are generally difficult to

compare due to differences in the training programs, the subjects involved (healthy or

diseased) or in the applied oxygen availability. Furthermore, interpretations of their results

are limited due to a relatively low number of subjects.

The studies of Haufe et al. (2008) and Wiesner et al. (2010) raise the interesting point that

improvements in the HOMA-IR index coincide with body fat reductions that were higher in

the hypoxia groups. Reductions in body fat are especially relevant for improving insulin

sensitivity in diabetic patients because there are positive relationships between body fat, the

pro-inflammatory state and peripheral insulin resistance (Mancuso, 2016). The benefit of

hypoxia on body composition and its regulating mechanisms are discussed later in this

review.

Improvements in glucose metabolism have also been demonstrated in an animal study with

rats (Chiu et al. 2004). Exposure to hypoxia 12 hours per day and swim training twice daily

for 3 hours improved glucose tolerance to a higher extent after three weeks than endurance

training alone. While hypoxia exposure alone did not increase GLUT-4 protein and mRNA

after 4 weeks, hypoxia exposure combined with endurance training increased GLUT-4

protein and mRNA to a higher extent than endurance training alone. This result may be

transferable to humans. Zoll et al. (2006) have shown that GLUT-4 mRNA levels were

significantly increased in the vastus lateralis muscle of healthy endurance runners following

training in short-term hypoxia (regular training + training in hypoxia: 2*12-20 minutes at

ventilatory threshold 2 (determined during an endurance test in hypoxia prior to training),

with active recovery phases between intervals, twice a week for 6 weeks) at a simulated

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 altitude of ≈ 3200 m (normobaric hypoxia: FiO2: 14.5%), yet not after training in normoxia.

While the combination of short-term hypoxia and exercise might be beneficial, there are
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indices that continuous long-term exposure to hypoxia could decrease insulin-dependent

glucose uptake and promote insulin resistance. In this context, continuous hypoxia has been

shown to block components of the insulin signaling cascade in muscle cell experiments

(Majmundar et al., 2012).

It has recently been hypothesized (Mackenzie et al., 2016) that a metabolic switch might take

place during exposure to hypoxia, as insulin-dependent glucose uptake is down-regulated

and partly replaced with the insulin-independent glucose uptake mechanism via AMPK. It

can further be deduced from the study of Mackenzie et al. (2012) that a stress-stimulus of

acute exercise and short-term hypoxia may increase insulin sensitivity by up-regulation of

insulin-dependent pathways in the recovery period.

Nevertheless, convincing molecular evidence from human studies is still missing, and further

studies are urgently needed to clarify how exercise training in short-term hypoxia can

effectively increase insulin sensitivity more than exercise training in normoxia in the long

term.

Exercise in hypoxia and vascular health

Diabetic patients often suffer from macro- and microangiopathies with endothelial

dysfunction as well as from abnormal angiogenesis (Martin 2003). A negative correlation

between skeletal muscle capillary density and insulin concentrations has been described

indicating that reduced skeletal muscle capillarization might negatively influence glycemic

control (Marin et al., 1994).

Thus, long-term increases in skeletal muscle capillarization and improvements in vascular

function could help prevent progression of the disease and protect T2DM patients from

secondary complications.

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 Exercise in hypoxia and skeletal muscle capillarization

Regular physical exercise has been shown to be beneficial in terms of improving skeletal
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muscle capillarization (Montero & Lundby, 2016). Lundby et al. (2009) conclude in a former

review, which includes data from human biopsy studies, that long-term exposure to hypoxia

does not cause considerable alterations in capillarization in resting humans, while the

combination of exercise and hypoxia might result in accelerating structural and functional

adaptations.

In line with this assumption, Mizuno et al. (2008) found that 75 days of exposure to ≈ 5300 m

did not alter the capillary to fiber ratio. However, because a decrease in fiber size may be a

possible adaptation to exposure to hypoxia, capillaries per area were increased in some

other studies with a similar altitude (Hoppeler et al., 2001).

The systematic analysis of 21 controlled studies in the recently published meta-analysis of

Montero & Lundby (2016) revealed increased effects of exercise training under hypoxic

conditions on skeletal muscle capillarization and vascular dilator function.

As regards skeletal muscle capillarization, Montero & Lundby (2016) analyzed studies in

which the capillary to fiber ratio as well as capillary length density (CLD), which is calculated

by dividing the length of capillaries per unit volume of muscle fibers, were considered.

Of note, they observed higher increases in skeletal muscle capillarization in their meta-

analysis based on studies determining CLD, while no overall significant effects were

reported for studies evaluating the capillary to fiber ratio (Montero & Lundby, 2016). While

changes in CLD could also be explained by changes in muscle fiber sizes, and considering

the fact that it has been shown that exposure to hypoxia can induce decreases in muscle

fiber size (as mentioned earlier), it could be speculated that CLD did not increase as a result

of higher capillarization but due to decreased muscle fiber sizes. However, no training study

included reported decreased muscle fiber sizes. Thus, increased capillarization can be

assumed and other factors, such as baseline fitness levels of the tested subjects or varying

durations and intensities of the training programs, might explain the divergence between

CLD and the capillary to fiber ratio results in this meta-study. Studies with exercise during

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 short-term exposure to hypoxia, which were included in the analysis, are described in detail

in Table 1 or Table 2.
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To shed more light on adaptations induced by training in hypoxia, it might also be worthwhile

to look at what happens following acute exercise in short-term hypoxia. Acute exercise-

induced transient increases in pro-angiogenic factors are deemed to be responsible for the

initiation and control of angiogenesis, that is, a multi-stage process (Colville-Nash et al.,

1997). We recently demonstrated in a pilot study that acute exercise in hypoxia can induce a

more reliable up-regulation of serum pro-angiogenic regulators (e.g., vascular endothelial

growth factor (VEGF), matrix metalloproteinases (MMPs)) than exercise in normoxia in type

2 diabetic patients (Brinkmann et al., 2017, study details in Table 1). Although these results

need to be confirmed in future studies involving a higher number of subjects, they highlight

the assumption that regular exercise in hypoxia could be particularily beneficial in promoting

angiogenesis in the long term.

Different mechanisms can be discussed as being responsible for the increased release of

pro-angiogenic regulators following exercise in hypoxia. First, tissue hypoxia, which can

occur during exercise, can be intensified by environmental hypoxic conditions and the

activation of the hypoxia-inducible-factor (HIF)-1α transcription factor, which initiates protein

expression of angiogenic regulators, can be increased (Forsythe et al., 1996). However, the

response to hypoxia has been shown to be impaired in diabetic conditions and

hyperglycemia appears to be the critical event in HIF-1α regulation (Bento & Pereira 2011).

Second, sympathetic nerve activity and an increase in skeletal muscle blood flow and shear

stress at the vessel wall could induce intracellular signaling through the mechanical

stimulation of capillaries, resulting in an increased release of angiogenic regulators from the

vasculature (Brown et al., 2003).

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 Exercise in hypoxia and vascular function

In their meta-analysis, Montero & Lundby (2016) also analyzed whether vascular dilator
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function can improve more through exercise training in hypoxia than in normoxia. While

several studies reported major improvements in healthy subjects (Nishiwaki et al., 2011;

Wang et al., 2010) (Table 2), Schreuder et al. (2014) did not find any effect of their training

on the vascular dilator function in T2DM patients, neither when exercise was performed in

normoxia nor when it was performed in hypoxia. The divergent results can be explained by

the different training protocols or oxygen concentrations used as well as possible different

adaptation mechanisms in T2DM and healthy subjects (in this regard, lower responses in

heart rate and cardiac output in T2DM patients have been observed, which are associated

with possible autonomic neuropathies (Tesfaye et al., 2010)).

Specific mechanisms that could lead to additive effects of hypoxia remain to be determined,

but an increased expression/activation of the endothelial nitrix oxide synthase (eNOS) and

release of nitric oxide (NO) as a potent vasodilator may be responsible in this regard, since it

has been demonstrated that hypoxic exposure of endothelial cells leads to increased eNOS

contents and NO generation (Presley et al., 2008).

To summarize, it can be concluded that exercise in hypoxia has a high potential for

increasing vascular health. However, long-term studies are urgently needed to ascertain

whether exercise in short-term hypoxia can increase skeletal muscle capillarization to a

higher extent than exercise in normoxia in T2DM patients. Such studies could also

eventually demonstrate how training protocols must be modified to induce such adaptation

effectively. While there is little doubt based on the study of Schreuder et al. (2014) that the

vascular dilator function in T2DM patients can be positively influenced through exercise

training in short-term hypoxia, additional studies applying different training protocols and

oxygen concentrations should be conducted.

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 Exercise in hypoxia and further possible benefits for T2DM patients

Weight loss
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Since appetite is suppressed and energy expenditure is increased, body mass loss occurs at

very high altitudes (Westerterp et al. (1994) reported a loss of body fat mass during a 21 day

sojourn in ≈ 6500 m in non-overweight/obese subjects), a phenomenon also known as

“altitude anorexia” (Millet et al. 2016), it can be speculated that exercise in hypoxia may be

particularly beneficial for reducing body weight in type 2 diabetic patients as well, who are

usually overweight/obese.

Since there are positive rleationships between increased body fat and chronic inflammation,

insulin resistance and cardiovascular complications (Mancuso, 2016), body fat reduction is,

of course, an important objective in the treatment of overweight/obese T2DM patients.

Wiesner et al. (2010) showed that body composition improved more in the hypoxia training

group compared with the normoxia training group, which both included obese non-diabetic

and insulin-resistant subjects. Kong et al. (2014) demonstrated that training (combined

endurance training (aerobics) and strength training, 60-70% maximal heart rate (HRmax)/40-

50% 1-repetition maximum (1-RM), 11 sessions per week, 4 weeks) caused more weigh loss

in obese young adults when it was performed in hypoxia (6 hours of exposure to hypoxia per

week (3 sessions in hypoxia, 8 sessions in normoxia), normobaric hypoxia: FiO2: 14.5-

16.5%, simulated altitude: ≈ 2100-3200 m) compared with training in normoxia (all training

sessions in normoxia). Alterations in hormones which regulate appetite might be relevant.

Short-term hypoxic exposure has been shown to increase serotonin levels in rats and it has

further been shown that serotonin administration to rats leads to anorexia (Gonzales et al.,

1980).

On the contrary, exposure to hypoxia (simulated altitude: ≈ 4300 m) for 120 minutes has

been demonstrated to reduce the leptin response to glucose ingestion (leptin is known to

suppress appetite) in healthy humans (Kelly et al., 2010). In this context, it should be

considered that T2DM patients often have leptin resistance (Sainz et al. 2015), and that the

acute effect of hypoxia on leptin and appetite has not yet been proven in diabetic patients.

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 A study by Debevec et al. (2014 a) recently revealed that performing daily moderate intensity

exercise (2*60 minutes of cycling, HR corresponded to HR measured at 50% of the altitude

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specific peak power output) during continuous exposure to hypoxia (normobaric hypoxia:

FiO2: 13.9%, simulated altitude: ≈ 3500 m) for 10 days does not alter hormonal appetite

regulation in healthy young adults, suggesting that appetite regulation is most likely not the

crucial factor for weight reduction in hypoxia. However, it might also be possible that 10 days

of exposure to hypoxia simply did not suffice or that the hypoxia was too mild to have an

effect on appetite regulation. Future research on regulatory mechanisms is needed.

Lipid profile improvements

Another interesting point is whether regular exercise in hypoxia can affect lipid profiles. In a

well-controlled crossover study, Simpson et al. (2016) investigated how 16 days of bed rest

in normoxia and continuous normobaric hypoxia (FiO2: 14%, simulated altitude: ≈ 3400 m),

as well as confinement in hypoxia + daily moderate exercise (2* 30 minutes of cycling,

stepping or dancing, HR corresponded to that achieved at 50 % of the peak power output

determined during a hypoxic graded exercise test) affect total cholesterol, low-density

lipoprotein (LDL) and high-density lipoprotein (HDL) in healthy subjects. Total cholesterol

significantly decreased in the two experimental runs applied during hypoxic exposure. LDL

significantly decreased only in the hypoxia-exercise-intervention. HDL was reduced following

all three interventions (reductions were significantly higher in the subjects following the

hypoxia bed rest intervention than in the two other interventions). Although this study

provides little evidence for a possible influence of hypoxia and exercise on blood lipids, the

studies of Schreuder et al. (2014) and Wiesner et al. (2009) did not show any beneficial

effects of exercise training during short-term hypoxic exposure on the blood lipid profile of

overweight/obese (insulin-resistant/type 2 diabetic) patients.

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 Oxidative stress reduction

Type 2 diabetic patients exhibit increased oxidative stress with an increased amount of free
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radicals, which can further promote insulin resistance or trigger cardiovascular complications

(Watson, 2014). Belikova & Asanov (2006) have reported that training under short-term

hypoxic conditions reduced lipid peroxidation products in tissues of elderly subjects at

baseline (note: this article is not available in English and thus no further details can be

provided in this review). Whether exercise training in short-term hypoxia can decrease

oxidative stress in diabetic patients as well and protect them from free radical-induced

secondary complications more than exercise training in normoxia is highly likely, but requires

further research.

Improvements in autonomic regulation

Duennwald et al. (2013) showed that a single exposure to intermittent normobaric hypoxia

(60 minutes, FiO2: 13%, simulated altitude: ≈ 4000 m, intervals: 5 minutes of hypoxia and 6

minutes of recovery) improved ventilatory responses in T2DM patients. This might be

another benefit for diabetic patients, especially for those suffering from autonomic

imbalances. Future studies should evaluate whether exercise under short-term hypoxia can

enhance this effect.

Exercise, hyperoxia and possible benefits for T2DM patients

Breathing hyperoxic air (with increased oxygen availability) is a common method for the

treatment of diabetic foot infections (Chen et al., 2010; Karadurmus et al., 2010), and it has

been demonstrated that oxygen therapy can also improve glycemic control and insulin

resistance in diabetic patients. For example, HbA1c and the HOMA-IR index decreased

significantly in T2DM patients following 30 sessions of hyperbaric oxygen therapy (FiO2:

100% at 2.4 absolute atmosphere, 105 minutes per session, 5 sessions per week)

(Karadurmus et al., 2010).

Another study has shown that (controlled) breathing of hyperoxic air (5l/minute oxygen) can

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 improve baroreflex sensitivity in T2DM patients with cardiovascular autonomic dysfunction

more than breathing of normoxic air (Esposito et al., 2016).

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Compared to exercise in hypoxia, exercise in hyperoxia remains less extensively

investigated. Breathing hyperoxic air can enhance endurance performance in healthy

subjects (3-30% higher absolute power output) as recently reviewed by Sperlich et al. (2016),

while there is no consensus yet on the best level of oxygen that ought to be applied for this

purpose (in normobaric hyperoxia: FiO2: 30-100%).

Looking at underlying mechanisms, arterial oxygen saturation can drop considerably during

exercise and arterial oxygen concentration can be elevated when breathing hyperoxic air

(Richardson et al., 1999). This can induce numerous metabolic, hormonal or central

responses as demonstrated in several studies (Sperlich et al., 2016). For example, it has

been shown that exercise-induced lactate concentrations were attenuated and that time to

exhaustion was higher in healthy subjects following performance tests in hyperoxia (FiO2:

60%) compared with results from normoxic testing (Linossier et al., 2000). In addition,

subjective ratings of perceived exertion have been shown to be lower in healthy subjects

following treadmill running at 80% VO2max when exercise was performed in normobaric

hyperoxia (FiO2: 80%) (Allen & Pandolf 1977). Central regulation might play a role in this

regard. An analysis of prefrontal cortex oxygenation in untrained subjects showed that

breathing hyperoxic air (normobaric hyperoxia: FiO2: 30%) helped maintain cerebral

oxygenation during an exhaustive ramp test on a cycle ergometer at higher output compared

with normoxia (Oussaidene et al., 2013).

Ploutz-Snyder et al. (1996) found that submaximal cycling exercise at 70% HRmax in

normoxia led to greater adaptations in mitochondrial oxidative capacity than in hyperoxia

(FiO2: 70%), suggesting that hyperoxia at the same relative workload provides a less

metabolic stimulus. It would thus be necessary to increase training intensities to achieve

better stimuli and adaptations when exercise training is performed in hyperoxia.

A novel strategy that could be implemented in the training therapy of type 2 diabetic patients

is to combine hypoxic and hyperoxic intervals. We have recently carried out a study using

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 alternating 5-minute intervals of hypoxia and hyperoxia during cycling at constant workload

(Brinkmann et al., 2017). The patients exhibited similar post-exercise lactate levels
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compared with lactate levels in normoxia, and significantly reduced post-exercise lactate

levels compared with values when exercise was performed in hypoxia only. Whether this

strategy can induce long-term adaptations more efficiently or similar to exercise under short-

term hypoxic conditions without hyperoxic intervals should be investigated in future studies.

Exercise in hyperoxia only might also be another strategy in the treatment of diabetes in so

far that exercise in hyperoxia could result in increased performance/exercise tolerance

against higher workloads and in increased exercise adaptations.

Furthermore, long-term additive effects of hyperoxia during exercise on glycemic control or

autonomic regulation can be assumed. Nevertheless, to date, no training studies have been

conducted which investigated the effects of regular exercise during short-term exposure to

hyperoxia among this particular patient group; whether this strategy really works should be

investigated in future studies as well.

Possible health risks

Several health risks relating to exercise in hypoxia or hyperoxia and in particular for T2DM

patients are mentioned in the literature. In general, the question is raised in which range of

oxygen availability exercise can be performed without posing health risks. In the studies

already mentioned, short-term hypoxic conditions were used, which were equivalent to a

simulated altitude of up to ≈ 4000 m in healthy subjects and ≈ 3400 m in diabetic patients.

While these conditions seemed to be well tolerable and no health problems were reported by

the authors, breathing air with strongly diminished oxygen levels or a prolonged stay in very

high altitudes has been discussed as increasing the risk for myocardial infarction,

neurocognitive deficits and stroke, especially in patients with cardiovascular disorders (Mol

de et al., 2014). It has been shown that T2DM patients react to hypoxia with a lower

ventilatory response, although the clinical implications are not entirely clear (Weisbrod et al.,

2005). Furthermore, it can be assumed that responses in heart rate and cardiac output are

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 also altered in T2DM patients (Tesfaye et al., 2010). Especially T2DM patients suffering from

neuropathies might face certain risks during exercise (e.g., silent myocardial ischemia,
Accepted Article
hypoglycemia unawareness in insulin-dependent patients), which could be increased during

exposure to hypoxia.

Although exposure to hypoxia may help reduce body weight and fat mass in the long term,

the study of Wagner (2010) indicates that exposure to extreme altitude (>5000 m) has an

adverse effect on fat-free muscle mass.

Regarding the possible effect of an increased capillarization in skeletal muscle following

exercise training in hypoxia, it remains to be determined whether there is also an increased

capillarization in tissues that can show abnormal excessive angiogenesis in diabetes (e.g.

retinal tissue in diabetic patients suffering from retinopathy), and to clarify the clinicial

relevance (Martin et al., 2003).

Both intense and long duration exercise elicit oxidative stress, that is exacerbated at hypoxic

conditions (for a review, see Quindry et al. 2015). The actual protocols of hypoxia exposure

vary markedly in cycle length, number of hypoxic episodes per day and number of exposure

days. Transient strong hypoxic stimulation may be similar to the model of

ischemia/reperfusion induced in some animal studies, likely to trigger an acute excessive

release of free radicals and a reduction in antioxidative capacity (e.g., Dong et al., 2014).

While oxidative stress can be detrimental, on the one hand, and result in cell and tissue

damage, changes in redox balance can serve as potent stimuli for long-term exercise

adaptations, on the other (Sachdev & Davies, 2008).

However, there is evidence that regular moderate physical activity can attenuate hypoxia-

related oxidative stress (Debevec et al., 2017; Debevec et al., 2016; Debevec et al., 2014 b).

Hyperoxia (normobaric hyperoxia) in previous studies has varied between FiO2: 30% and

FiO2: 100%. The use of hyperoxia should also be handled with caution because long-term

exposure to hyperoxia may also cause severe health problems as a result of increased free

radicals, inflammation, cell damage and dysfunction (Gonzalez-Muniesa et al., 2015;

Sperlich et al., 2016).

This article is protected by copyright. All rights reserved.

 Perspective

Exercise during short-term exposure to hypoxia can increase glucose uptake in T2DM
Accepted Article
patients during exercise and improve post-exercise insulin sensitivity to a higher extent than

exercise in normoxia. Furthermore, regular exercise in short-term hypoxia can help increase

insulin sensitivity in the long term. This might be associated with increased weight loss in

overweight/obese (insulin- resistant) patients. However, while several studies imply positive

effects of exercise training in hypoxia, no studies exist that have investigated the additive

effects of exposure to hypoxia during exercise training on vascular health in T2DM patients

in the long term.

As indicated in studies involving healthy humans, exercise during short-term exposure to

hyperoxia might be beneficial in increasing exercise tolerance and regeneration. Future

studies are necessary to further evaluate the potential of breathing hypoxic or hyperoxic air

during exercise for T2DM patients, and novel training strategies (e.g., combining hypoxic-

hyperoxic intervals during exercise sessions) should be considered. In this regard, it should

be acknowledged that normobaric versus hypobaric/hyperbaric hypoxia/hyperoxia could

produce different results.

All in all, the primary rationale for clinical use of hypoxia or hyperoxia during exercise in

T2DM patients is the potential value of adaptation to an additive stress stimulus, which can

then provide protection against other stresses and the pathophysiology of diabetes.

From an applied perspective, the use of short-term hypoxia during exercise (at a simulated

altitude of ≈ 3000 m) seems to be promising for improving health in diabetic patients.

However, further studies are needed to develop evidence-based recommendations for the

use of short-term hypoxia/hyperoxia during exercise for T2DM patients.

The use of hypoxia or hyperoxia during exercise should be administered with care, and

patients should seek medical advice before using any devices that can generate hypoxic or

hyperoxic air.

This article is protected by copyright. All rights reserved.

 The authors declare that there is no conflict of interest.
Accepted Article
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Accepted Article
Tables

Table 1. Controlled studies investigating the effects of acute and chronic exercise in short-

term hypoxia or/and hyperoxia versus normoxia in insulin-resistant/type 2 diabetic patients

(systematic literature search)

Table 2. Controlled studies investigating the effects of chronic exercise in short-term hypoxia

versus normoxia in non-diabetic study participants (studies investigating the effects on

glycemic control or vascular health (skeletal muscle capillarization or endothelial function)

selected from the reviews of Montero & Lundby (2016) and Wee & Climstein (2015))

This article is protected by copyright. All rights reserved.

ccepted Articl
Study
Table 1. Controlled studies investigating the effects of acute and chronic exercise in short-term hypoxia or/and hyperoxia versus normoxia in insulin-
resistant/type 2 diabetic patients (systematic literature search)
Type 2 Type of exercise/exercise details Intensity Important outcomes (selected variables)
diabetic
patients
Acute exercise in hypoxia
Mackenzie et al.(2011) n=8 Each subject performed in a randomized 3)-4) 90% lactate -Blood lactate did not differ significantly between 1) and 2), increased significantly during
order: threshold exercise, but did not differ significantly between 3) and 4)
determined in an -Blood glucose was reduced significantly during 2) but not during 1) and it was reduced
1) 60 min rest in normoxia endurance test in significantly during 3) and 4) with significant greater decreases observed in 4). The magnitude of
2) 60 min rest in hypoxia (normobaric normoxia performed decreases was greatest in 4).
hypoxia: FiO2:14.6%, simulated altitude: prior to the trials -Insulin sensitivity determined during glucose tolerance test was significantly higher following 2)
≈3100 m) compared with 1) and higher following 4) compared with 3). It was highest in 4).
3) 60 min cycling in normoxia
4) 60 min cycling in hypoxia (normobaric
hypoxia: FiO2:14.6%)

followed by glucose tolerance tests

Mackenzie et al.(2012) n=8 Each subject performed in a randomized 1) 90% lactate -Heart rate and blood lactate increased significantly in all trials and the magnitude of increases did
order: threshold not differ significantly between trials
2) 120% lactate -Magnitude of decreases in blood glucose from pre- to post-exercise was significantly greater in 1)
1) 60 min continuous cycling in hypoxia threshold compared with 2)
(normobaric hypoxia: FiO2: 14.7%, 3) 120% lactate -Glucose disappearance was increased significantly 24 h later in 1), but not in 2) and 3)
simulated altitude: ≈3100 m) threshold -The HOMA-IR index was improved significantly in 1) 24 h and 48 h later, and in 2) 24 h later,
2) 60 min interval training with passive determined in an while no significant changes were observed in 3).
recovery periods (5:5 min) in hypoxia endurance test in
(normobaric hypoxia: FiO2: 14.7%) normoxia performed
3) 60 min interval training with passive prior to the trials
recovery periods (5:5 min) in normoxia

All trials during continuous glucose

infusion
Acute exercise in hyperoxia
Rozenberg et al. (2016) n=11 Each subject performed in the same 1) – 5) 20% Wmax -Blood lactate increased significantly during exercise, but did not differ significantly between
order: determined in an conditions
endurance test in -Heart rate and blood pressure increased significantly with exercise, but did not differ significantly
30 min cycling while breathing air with normoxia performed at different supplemental oxygen flows
different supplemental oxygen flows prior to the trials

1) 0 l/min (10 min)

Acute exercise in hypoxia/hyperoxia
Brinkmann et al. (2017) n=9
2) 5 l/min (5 min)
3) 10 l/min (5 min)
4) 15 l/min (5 min)
5) 0 l/min (5 min)
Each subject performed in a randomized 1)-3) Workload -Pro-angiogenic factors:
order: corresponded to the -VEGF increased significantly in 2) and 3)
workload at 2.5 -MMP-2 increased significantly in 1)-3)

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ccepted Articl 40 min cycling while breathing air with
different oxygen availability:

1) normoxia
mmol/l blood lactate
during an endurance
test in normoxia
performed prior to
-MMP-9 increased significantly in 2) and 3)
-Anti-angiogenic factor endostatin increased significantly in 1) and 2)
However, delta values did not differ significantly between groups.
-Blood lactate (post-exercise) was significantly lower in 3) compared with 2)
2) hypoxia (normobaric hypoxia: FiO2: the experimental -BORG RPE did not differ significantly between trials
14%, simulated altitude: ≈3400 m) trials
3) hypoxia (normobaric hypoxia: FiO2: 14%
O2) – hyperoxia (normobaric hyperoxia:
FiO2: 30%) intervals (5:5 min)

Study Type 2 Type of exercise/training Intensity Frequency and Important

diabetic duration outcome measures (selected variables)
patients
Chronic exercise (exercise training) in hypoxia

Schreuder et al. (2014) n=19 Randomization: 70-75% HRReserve 3 times per week, - VO2max in normoxia increased significantly through training in both
determined with 8 weeks groups, no group-specific differences
n=9: training in normoxia values from an -BMI, blood pressure, fasting glucose, HbA1c, the HOMA-IR index, HDL
n=10: training in hypoxia (normobaric endurance test in cholesterol, LDL cholesterol, total cholesterol and triglycerides did not
hypoxia: FiO2: 16.5%, simulated altitude: normoxia prior to change significantly
≈2100 m) training -Vascular dilator function (FMD) did not change significantly through training

45 min endurance training (cycling) +

series of strength training exercises
Wiesner et al. (2010) n=45 Randomization: Workload 3 times per week, -Lactate values at the anaerobic threshold during an endurance test in
overweight/ corresponded to 4 weeks normoxia were decreased significantly post-training only in the hypoxia
obese n=21: training in normoxia 65% of VO2peak of an group
subjects, n=24: training in hypoxia (normobaric endurance test in -Fasting insulin and the HOMA-IR index were decreased significantly post-
some were hypoxia: simulated altitude: ≈2740 m) normoxia or hypoxia training in both groups, no group-specific effects
insulin- performed prior to -Reductions in body fat were significantly higher in the hypoxia group
resistant, 60 min running on a treadmill the experimental -Blood pressure and LDL cholesterol did not change significantly
some were trials.
non-
diabetics Absolute training
workloads were
significantly lower in
the hypoxia group,
while training heart
rates (relative
intensity) did not
differ

1-RM= 1-repetition maximum, BMI= body mass index, BORG RPE= BORG rating of perceived exertion, FiO2= fraction of inspired oxygen, FMD=flow-
mediated dilatation, HDL= high-density lipoprotein, HbA1c= glycated hemoglobin, HIT= high-intensity training, HOMA-IR=homeostatic model assessment
for the quantification of insulin resistance , HRmax= maximal (peak?) heart rate, HRReserve= heart rate reserve, LDL= low-density lipoprotein, MMP-2/9=matrix

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ccepted Articlmetalloproteinase-2/9, OGTT= oral glucose tolerance test, VEGF= vascular endothelial growth factor, VO2max= maximal (peak?) oxygen uptake , Wmax
=maximal workload.

Table 2. Controlled studies investigating the effects of chronic exercise in short-term hypoxia versus normoxia in non-diabetic study participants (studies
investigating the effects on glycemic control or vascular health (skeletal muscle capillarization or endothelial function) were selected from the reviews of
Montero & Lundby (2016) and Wee & Climstein (2015))
Study Participants Exercise training Intensity Frequency and Important outcomes (selected variables)
duration
Exercise training (chronic exercise) in hypoxia

Desplanches et al. n=12 Randomization: 65% Wmax 30 training - VO2max in normoxia was increased significantly post-training in both groups,
(2014) determined in an sessions no group specific effects
n=6: training in normoxia endurance test in -No significant group effect (interaction effect) for changes in skeletal muscle
n=6: training in hypoxia (normobaric normoxia or hypoxia capillary density/ capillaries per fiber
hypoxia: simulated altitude: ≈4000 m) performed prior to
training
30 min cycling
Geiser et al. n=33 Randomization: 1) ,2): Heart rates 5 times per week, -VO2max in normoxia increased significantly through training in all groups
(2001) corresponded to 6 weeks without group effects
1) n=8: high-intensity training in normoxia 85% HRmax -Hypoxia training resulted in significantly higher increases in VO2max in hypoxia
2) n=10: high-intensity training in hypoxia 3), 4): Heart rates - No significant changes for reticulocytes or hemoglobin concentrations
(normobaric hypoxia: simulated altitude: ≈ corresponded to -Capillary length density in skeletal muscle was increased significantly post-
3850 m) 77% HRmax. training only in group 2)
3) n=7: low-intensity training in normoxia
4) n=8: low-intensity training in hypoxia The low intensity
(normobaric hypoxia: simulated altitude: normoxia group
≈3850 m) trained at the same
absolute workload
30 min cycling as the high-intensity
hypoxia group.

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ccepted Articl
Haufe et al. (2008) n=20 Randomization:

n=10: training in normoxia

n=10: training in hypoxia (normobaric
Workload
corresponded to the
workload at 3.0
mmol/l blood lactate
3 times per week,
4 weeks
-Lactate values at the anaerobic threshold during endurance testing in
normoxia decreased significantly from pre- to post-training in both groups, no
group-specific difference
-The HOMA-IR index decreased significantly only in the hypoxia group
hypoxia: FiO2: 15%, simulated altitude: during an endurance -Insulin response to OGTT was significantly lower post-training in the hypoxia
≈2800 m) test in normoxia or group than in the normoxia group
hypoxia performed -Reductions in body fat and triglycerides were significantly higher in the
60 min running on a treadmill prior to the hypoxia group
experimental trials. -Leptin concentration decreased significantly through training in both groups,
no group-specific differences
Absolute training -Adiponectin, resistin retinol binding protein 4, total cholersterol, HDL
workloads were cholesterol, LDL cholesterol and blood pressure did not change significantly
significantly lower in
the hypoxia group,
while training heart
rates (relative
intensity) did not
differ
Kon et al (2015) n=16 Randomization: 70% 1-RM Twice a week, -1-RMs increased significantly through training in both groups, no group
8 weeks specific differences
n=7: training in normoxia -Cross sectional area of muscle fibers increased significantly in both groups,
n=9: training in hypoxia (normobaric no group specific differences
hypoxia: FiO2: 14.4%, simulated altitude: -Circulating VEGF levels increased significantly through training only in the
≈3200 m) hypoxia group
-VEGF-B levels in skeletal muscle increased significantly in both groups, no
Strength training: bench and leg press, group-specific effects
5*10 repetitions -Capillary to fiber ratio increased significantly through training only in the
hypoxia group
Lecoultre et al. Competitive Randomization: 3 different sessions 3 times per week, -VO2max in normoxia increased significantly through training in both groups, no
(2010) cyclists and per week: 4 weeks group-specific differences
triathletes n=7: training in normoxia 1.HIT: 6-8* 2 min + regular -Plasma glucose and insulin concentrations increased significantly
n=14 n=7: training in hypoxia (normobaric cycling at 100% endurance and the glucose metabolic clearance rate was reduced significantly during a
hypoxia: simulated altitude: ≈3000 m) maximal aerobic training as lactate turnover test (exercise with endogenous lactate infusion) following
power + 6-8* 1 min performed before hypoxia training
Cycling cycling at 110% the study -Hemoglobin concentrations did not change significantly through training
maximal aerobic intervention
power (+ 8*30 sec
cycling at 120%
maximal aerobic
power in the fourth
week)
2.HIT: 3-5*6-12min
cycling at ventilator
threshold 2
3. Continuous
cycling: 100 min at
80-90% ventilatory
threshold 1.

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ccepted Articl Maximal aerobic
power and
ventilatory
thresholds were
determined during
an endurance test in
normoxia or hypoxia
prior to training.

Absolute training
workloads were
significantly lower in
the hypoxia group,
while the relative
intensity did not
differ.

Masuda et n=14 Randomization: 60-70% VO2max 28 training -VO2max in normoxia increased significantly through training in both groups, no
al.(2001) determined in an sessions within group-specific effects
n=7: training in normoxia endurance test in 8 weeks -Skeletal muscle myoglobin concentrations did not differ significantly pre- vs.
n=7: training in hypoxia (hypobaric normoxia or hypoxia post-training in any group
hypoxia: simulated altitude: ≈2500 m) prior to training -Skeletal muscle citrate synthase activity increased significantly in both
groups, no group-specific effects
1 h cycling -Capillary to fiber ratio increased significantly through training in both groups,
no group-specific effects
Melissa et al. n=10 One-leg cycling in 75% Wmax 3 times per week, -VO2max increased significantly from pre- to post-training (for both legs)
(1997) determined in an 8 weeks -Skeletal muscle capillary density did not change significantly through training
a) normoxia endurance test in -Increases in citrate synthase activity were significantly greater post-training in
b) hypoxia (normobaric hypoxia: normoxia prior to the leg trained in hypoxia
FiO2:13.5%, simulated altitude: ≈3800 m) training

2*30 min cycling (1* each leg)

The order (in which the legs were trained)

was alternated each training session
Messonnier et al. n=13 Randomization: 60-80% Wmax 6 times per week, -Lactate curves were positively influenced during incremental exercise tests in
(2001) determined in an 4 weeks normoxia post-training in both groups, no group-specific effects
n=8: training in normoxia endurance test in -Training increased skeletal muscle citrate synthase activity significantly, no
n=5: training in hypoxia (normobaric normoxia or hypoxia group-specific effects
hypoxia: FiO2: 13.2%,simulated altitude: prior to training -Training increased capillary density significantly, no group-specific effects
≈3800 m)

2 h cycling
Nishiwaki et al. n=16 Randomization: Heart rates in both 3-4 times per -VO2max in normoxia was not increased significantly post-training, no group-
(2011) groups week, specific effects
n=8: training in normoxia (high-intensity) corresponded to 8 weeks -FMD increased significantly through training only in the hypoxia group

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ccepted Articl n=8: training in hypoxia (hypobaric
hypoxia: simulated altitude: ≈2000 m) *

30 min aquatic exercise

50% VO2max
determined in an
endurance test in
normoxia prior to
training
*2 h hypoxic conditions per exercise
session
Terrados et al. n=10 One-leg cycling during 65% Wmax 4 times per week, -Time to fatigue increased significantly during endurance testing from pre- to
(1990) determined during 4 weeks post-training, but significantly more in the leg trained in hypoxia
a) normoxia an endurance test in -Skeletal muscle citrate synthase activity increased significantly in both legs,
b) hypoxia (hypobaric hypoxia: simulated normoxia prior to but significantly more in the leg trained in hypoxia
altitude: ≈2300m) training -Number of capillaries in skeletal muscle did not change significantly through
training
2*30 min cycling (1* each leg)

The order (in which the legs were trained)

was alternated each training session
Vogt et al. (2001) n=30 Randomization: Training blood 5 times per week, -VO2max in normoxia was increased significantly post-training in all groups
lactate levels: 6 weeks -VO2max in hypoxia was increased significantly post-training in 2)-4), but not in
1) n=8: training in normoxia, low intensity 1)
2) n=8: training in normoxia, high intensity 1), 3): 2-4 mmol/l -Capillary length density in skeletal muscle was increased significantly post-
3) n=7: training in hypoxia (normobaric 2), 4); 4-6 mmol/l training only in 4)
hypoxia: simulated altitude: ≈3850 m), low -Volume density of skeletal muscle mitochondria increased significantly in 2)-
intensity 4), but not in 1)
4) n=7: training in hypoxia (normobaric
hypoxia: simulated altitude: ≈3850 m), high
intensity

30 min cycling
Wang et al. (2010) n=60 Randomization: 3) 50% Wmax 5 times per week, -VO2max increased significantly through training in all training groups,
4) 50% HRReserve 4 weeks significantly higher increases in 5) compared with 3)
1) n=12: rest in normoxia 5) 50% Wmax - All interventions increased muscle perfusion (Δ total hemoglobin in the
2) n=12: rest in hypoxia (normobaric determined in an vastus lateralis muscle) during continuous exercise in normoxia significantly,
hypoxia: FiO2: 15%, simulated altitude: endurance test in while only the hypoxia interventions increased muscle perfusion during
≈2730 m) normoxia prior to continuous exercise in hypoxia significantly
3) n=12: training in normoxia traininig
4) n=12: training in hypoxia (normobaric
hypoxia: FiO2: 15%)
5) n=12: training in hypoxia (normobaric
hypoxia: FiO2: 15%)

30 min rest or cycling

1-RM= 1-repetition maximum, FiO2= fraction of inspired oxygen, FMD=flow-mediated dilatation, HDL= high-density lipoprotein, HIT= high-intensity training,
HOMA-IR=homeostatic model assessment for the quantification of insulin resistance , HRmax= maximal (peak?) heart rate, LDL= low-density lipoprotein, NA=
data not available, but estimated, OGTT= oral glucose tolerance test, VEGF= vascular endothelial growth factor, VO2max= maximal (peak?) oxygen uptake,
Wmax =maximal workload.

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