Is Physical Exercise in Hypoxia an Interesting Strategy to Prevent the Development of Type 2 Diabetes? A Narrative Review

Figures & data

Table 1 Design and Main Results from the Studies Investigating the Effects of a Single Exercise or Exercise Training in Hypoxia vs Normoxia in Subjects at Risk of Developing Diabetes

Study	Subjects	Type of Exercise	Intensity	Frequency /Duration	Main Results	Conclusions
Single exercise
Morishima et al^Citation26	Overweight men (n=8)	Rest in normoxia (FiO2 21%): N-Rest Ex in normoxia: N-Ex Rest in hypoxia (FiO2 15%): H-Rest Ex in hypoxia: H-Ex	3 sessions of 30min cycling at 60% VO2max within a 7.5-h period	4 trials	● glucose levels after ex in N-Ex and H-Ex ● glucose levels after 2nd and 3rd meal in N-Ex and H-Ex vs Rest ● insulin levels after ex in N-Ex and H-Ex % carbohydrate contribution in H-Ex > N-Ex and % fat contribution in H-Ex < N-Ex at baseline, during ex and post-ex	Carbohydrate oxidation was higher in H-Ex vs N-Ex
De Groote et al^Citation27	Healthy (H) and pre-diabetic (P) subjects (n=32)	Ex in normoxia (FiO2 21%): NE Ex in hypoxia (FiO2 14%): HE	60 min cycling at HR=55% VO2max (evaluated in NE)	1 day	● AUC blood glucose in H HE and P HE ● insulin levels at T120 of OGTT in P HE ● p-TBC1D1 at Ser^237 and in p-AMPK at Thr^172 in P NE and H HE ● p-ACC at Ser^212 in all groups	Hypoxia could alter glucose tolerance post-ex through unidentified mechanisms
Exercise training
Britto et al^Citation39	Obese adolescents (n=14)	Training in normoxia (FiO2 21%; n=7): N Training in hypoxia (FiO2 15%; n=7): H (1) 12min cycloergometer (2) resistance training	(1) session 1: 10min 70% MAP session 2: 5x1min 80% MAP session 3: start at 40% MAP and increase of 10%/2min (2) 15 reps 50% 1RM + 4×6 reps 70% 1RM (r=2min) Session duration: 50–60min	1x/week, 30 weeks	● BM, BMI, waist circumference and % fat mass in N and tendency ● in H ● fat mass similarly in N and H ● VO2max, ● MAP, ● 1RM in N and H ● systolic blood pressure in N = insulin sensitivity markers ● triglycerides plasma levels in H	Even a low dose of ex per week can induce positive health outcomes, no matter the ex conditiosn (N or H)
Mai et al^Citation37	Obese men with metabolic syndrome (n=23)	Training in normoxia (FiO2 21%; n=11): N Training in hypoxia (FiO2 15%; n=12): H	Interval training 50–60% HRmax: 15min walking + 5min break Session duration: 60min	3x/week, 6 weeks	● ISIClamp in H ● individual circulating VEGF levels in H tendency ● adipose VEGF mRNA levels in H	H training could potentiate the effects of ex on myocellular insulin sensitivity
Park et al^Citation70	Obese old Korean men (n=24)	Training in normoxia (FiO2 21%; n=12): N Training in hypoxia (FiO2 14.5%; n=12): H (1) aerobic ex (2) resistance ex	(1) 30min treadmill or cycling 60–70% HRmax (2) 30–40min elastic ex: 3×10-15 reps 60–70% 1RM (r=90s)	3x/week, 12 weeks	● BM and % body fat in N and H and ● fat-free mass in N and H H > N at improving physical fitness, pulmonary function and HR variability ● forced vital capacity and expiratory volume in 1s in H and ● max ventilation in H and N ● salivary cortisol in N and H	Compared with N training, H training is a novel and successful health promotion method in obese older populations
De Groote et al^Citation36	Obese adolescents (n=14)	Training in normoxia (FiO2 21%; n=7): N Training in hypoxia (FiO2 15%; n=7): H (1) 12min cycloergometer (2) resistance training	(1) session 1: 10min 70% MAP session 2: 5x1min 80% MAP session 3: start at 40% MAP and increase of 10%/2min (2) 15 reps 50% 1RM + 4×6 reps 70% 1RM (r=2min) Session duration: 50–60min	3x/week, 6 weeks	● AUC of plasma insulin in H ● glucose levels in H ● triglycerides levels and ● MAP, ● work capacity at 160bpm, ● carbohydrate consumption during ex in H	H training improved glucose tolerance and insulin response to a glucose challenge in adolescents with obesity
Camacho-Cardenosa et al^Citation67	Overweight/ obese woman (n=59)	(1) aerobic interval training in normoxia (FiO2 21%; n=15): AitN (2) aerobic interval training in hypoxia (FiO2 17.2%; n=13): AitH (3) sprint interval training in normoxia (FiO2 21%; n=18): SitN (4) sprint interval training in hypoxia (FiO2 17.2%; n=15): SitH	(1)-(2): 3min 90% Wmax + 3min 55–65% Wmax (3)-(4) 30s 130% Wmax + 3min 55–65% Wmax Session duration: Ait = 41.5min Sit = 29.6min	3x/week, 12 weeks T1: pre; T2: after 18 sessions; T3: 7 days post; T4: 4 weeks post	● % fat mass from T1 to T3/T4 in SitH and AitH ● muscle mass from T1 to T4 in SitH and AitH ● basal metabolic rate at T4in AitH ● fat and ● carbohydrate oxidation from T1 to T4 in AitN tendency ● fat and ● carbohydrate oxidation from T1 to T4 in AitH	SitH seems promising for reducing body fat content with a concomitant increase in muscle mass
González-Muniesa et al^Citation41	Obese men with sleep apnea syndrome (n=41)	(1) control (FiO2 21%; n=15): C (2) training in normoxia (FiO2 21%; n=12): N (3) training in hypoxia (FiO2: first 2 weeks 16.0% and rest 13.7–14.8%; n=14): H	(1) healthy diet (2) 15min cycling + 15min lifting 4kg (3) 15min cycling + 15min lifting 4kg Session duration: 60min	2x/week, 8 weeks	● body weight, fat-free mass (C > N), waist circumference in all groups ● hip circumference in H and N ● RERmax in H and N ● exertion time in H ● diastolic blood pressure in H = blood glucose in all groups	Specific benefits of H training on cardiometabolic-related measurements with a therapeutical potential in obese individuals
Kong et al^Citation69	Obese young adults (n=18)	(1) training in normoxia (FiO2 21%; n=8): N (2) training in hypoxia (FiO2 16.4–14.5%; n=10): H	(1) 22h normoxia/week (2) 16h normoxia and 6h hypoxia/week aerobic: running, stepping or cycling 50–70% HRmax strength: 3×15 repetitions 40–50% 1RM or light dumbbells	22h/week, 4 weeks	● body weight in H > N ● systolic blood pressure in H and ● in N ● resting HR in N	H training coupled to low caloric diet might be a promising method to lose weight and to treat obesity
Wiesner et al^Citation38	Overweight to obese subjects (n=45)	Training in normoxia (FiO2 21%; n=21): N Training in hypoxia (FiO2 15%; n=24): H	60min treadmill HR=65% VO2max (evaluated in N)	3x/week, 4 weeks	training workload in H < N ● VO2max and time to exhaustion in N and H ● RER and lactate levels at the anaerobic threshold in H ● body fat in H > N ● fat free mass in H ● fasting insulin and HOMA index in N and H	In obese subjects, H training elicits similar or better effects on physical fitness, metabolic risk markers, and body composition at a lower workload
Netzer et al^Citation71	Obese subjects (n=20)	Training in normoxia (FiO2 21%; n=10): N Training in hypoxia (FiO2 15.2%; n=10): H	90min HR=60% VO2max on stepper, treadmill and cycloergometer	3x/week, 8 weeks	● weight H > N training workload in H < N	Even moderate H, if combined with ex, leads to weight loss
Camacho-Cardenosa et al^Citation74	Overweight/ obese woman (n=59)	(1) aerobic interval training in hypoxia (FiO2 17.2%; n=13): AitH (2) aerobic interval training in normoxia (FiO2 21%; n=15): AitN (3) sprint interval training in hypoxia (FiO2 17.2%; n=15): SitH (4) sprint interval training in normoxia (FiO2 21%; n=18): SitN	(1)-(2): 3min 90% Wmax + 3min 55–65% Wmax (3)-(4) 30s 130% Wmax + 3min 55–65% Wmax Session duration: Ait = 41.5 min Sit = 29.6 min	3x/week, 12 weeks	● waist circumference in hypoxic conditions ● waist:hip ratio in hypoxic conditions ● % trunk fat mass in hypoxic conditions	H, not N, training improves the % of fat mass located in the trunk.
Klug et al^Citation43	Men with metabolic-syndrome (n=23)	Training in normoxia (FiO2 21%; n=11): N Training in hypoxia (FiO2 15%; n=12): H	60min 60% VO2max: 3x15min intervals walking + 5min rest	3x/week, 6 weeks	● waist circumference in N and H shifting to a more lipolytic state for adipose tissue metabolism in H ● postprandial energy expenditure in H ● activity energy expenditure in N ● adipose tissue triglyceride lipase, leptin, and HIF1α expression in N	H added little to N. Training counts, far less the FiO2
Camacho-Cardenosa et al^Citation45	Overweight/ obese woman(n=60)	(1) interval training in hypoxia (FiO2 17.2%; n=13): IHT (2) interval training in normoxia (FiO2 21%; n=15): INT (3) repeated-sprint training in hypoxia (FiO2 17.2%; n=15): RSH (4) repeated-sprint training in normoxia (FiO2 21%; n=17): RSN	(1)-(2): 3min 90% Wmax + 3min 55–65% Wmax Session duration: from 24min 1st week to 42min last week (3)-(4): 30s 130% Wmax + 3min 55–65% Wmax Session duration: from 6min30s 1st week to 27min last week	3x/week, 12weeks A: baseline B: after 36 training sessions C: after 4 weeks of detraining	● waist circumference at both B and C in IHT and RSH ● % trunk fat in IHT and RSH ● cholesterol at B and C in RSN ● triglycerides at B in all groups tendency ● glucose at B in all groups	RSH could be a time-metabolic alternative for those subjects with less time available, by causing beneficial effects on metabolism with time sparing intervention
Chobanyan-Jürgens et al^Citation40	Older sedentary subjects (n=25) age: 62y BMI: 28.4kg⋅m^−2	Training in normoxia (n=15; FiO2 21%): N Training in hypoxia (n=14; FiO2 15%): H	30–40 min HR=60–70% VO2max	3x/week, 8 weeks	● glucose infusion rate in both group ● carbohydrate oxidation in both group ● Glut4 in fasting condition in both group	H training did not enhance metabolic effects in older people beyond N training
Morishima et al^Citation34	Sedentary men (n=21) BMI: 25.5kg⋅m^−2	Training in hypoxia: FiO2 15% 2-week group (n=11) 4-week group (n = 10)	60min cycling 65% VO2max (evaluated in H)	6x/week, 2 weeks 3x/week, 4 weeks	● VO2max in both groups ● mean blood pressure in both groups ● AUC insulin after glucose ingestion in 4-week group	H training for 4 vs 2 weeks might be better for improving insulin sensitivity
Chacaroun et al^Citation42	Overweight/ obese subjects (n=23)	Training in normoxia (FiO2 21%; n=7): N Training in hypoxia (FiO2 13%; n=7): H	45min cycling 75% HRmax	3x/week, 8 weeks	● diastolic blood pressure in N and H ● VO2max, ● MAP in H ● HRmax in N and H ● VE in H ● SOD activity in H	H training may provide some additional benefits to standard N training for obese individual health status
Morishima et al^Citation35	Sedentary men (n=20) BMI: 25.6kg⋅m^−2	Training in normoxia (FiO2 21%; n=11): N Training in hypoxia (FiO2 15%; n=9): H	60min cycling at 55% VO2max (measured in each condition)	3x/week, 4 weeks	● blood glucose in N and H ● AUC blood glucose in H > N ● insulin after a meal: Pre > Post ● VO2max in N and H ● AUC leptin in N and H	Greater improvement in postprandial glucose tolerance in H vs N training
Gatterer et al^Citation72	Obese men (n=32)	Training in normoxia (FiO2 21%; n=16): N Training in hypoxia (FiO2 14%; n=16): H	90min cycling, running or cross training at 65–70% VO2max	2x/weeks, 8 months	improvements in body weight, BMI, waist and hip circumference and VO2max in N and H ● systolic blood pressure in N and H	Beneficial effects of training but no difference between N and H

Abbreviations: Ex, exercise; F_iO₂, fraction of inspired oxygen; MAP, maximal aerobic power; 1RM, 1-repetition maximum; reps, repetitions; r, rest; BM, body mass; BMI, body mass index; VO₂max, maximal oxygen uptake, HR, heart rate; ISI, insulin sensitivity index; VEGF, vascular endothelial growth factor; Wmax, maximal workload; RER, respiratory exchange ratio; HOMA, homeostatic model assessment; HIF1α, hypoxia-inducible factor 1 alpha; AUC, area under the curve.

Figure 1 Regulation of glucose transport by exercise and hypoxia in human skeletal muscle. Proposed model for the underlying mechanisms mediating exercise- and hypoxia-induced skeletal muscle GLUT4 translocation. F_iO₂, inspired oxygen fraction; AMP/ATP, adenosine monophosphate/adenosine triphosphate; AMPK, AMP-activated protein kinase; TBC1D1, Tre-2/BUB2/cdc 1 domain family 1; TBC1D4, Tre-2/BUB2/cdc 1 domain family 4; CaMKII, Ca²⁺/calmodulin-dependent protein kinase II; p38MAPK, p38 mitogen-activated protein kinase; GLUT4, glucose transporter 4; HIF1α, hypoxia-inducible factor 1 alpha; PFK, phosphofructokinase; GLUT1, glucose transporter 1; Rab-GDP, guanosine-diphosphate Rab; Rab-GTP, guanosine-triphosphate Rab. Filled arrows represent exercise signaling and dotted arrows represent hypoxia signaling; ^?Indicate probable but not proven pathways.

Morishima T , Mori A , Sasaki H , Goto K . Impact of exercise and moderate hypoxia on glycemic regulation and substrate oxidation pattern. PLoS One . 2014;9(10):e108629. doi:10.1371/journal.pone.0108629 25329405

 PubMed Web of Science ®Google Scholar

De Groote E , Britto FA , Balan E , et al. Effect of hypoxic exercise on glucose tolerance in healthy and pre-diabetic adults. Am J Physiol Endocrinol Metab . 2020;320(1):E43–E54 33103453

 PubMed Web of Science ®Google Scholar

Britto FA , De Groote E , Aranda J , Bullock L , Nielens H , Deldicque L . Effects of a 30-week combined training program in normoxia and in hypoxia on exercise performance and health-related parameters in obese adolescents: a pilot study. J Sports Med Phys Fitness . 2020;60(4):601–609. doi:10.23736/S0022-4707.20.10190-7

 Web of Science ®Google Scholar

Mai K , Klug L , Rakova N , et al. Hypoxia and exercise interactions on skeletal muscle insulin sensitivity in obese subjects with metabolic syndrome: results of a randomized controlled trial. Int J Obes . 2019;44(5):1119–1128

 Web of Science ®Google Scholar

Park H-Y , Jung W-S , Kim J , Lim K . Twelve weeks of exercise modality in hypoxia enhances health-related function in obese older Korean men: a randomized controlled trial. Geriatr Gerontol Int . 2019;19(4):311–316.30788892

 PubMed Web of Science ®Google Scholar

De Groote E , Britto FA , Bullock L , et al. Hypoxic training improves normoxic glucose tolerance in adolescents with obesity. Med Sci Sports Exerc . 2018;50(11):2200–2208. doi:10.1249/MSS.0000000000001694 29923910

 PubMed Web of Science ®Google Scholar

Camacho-Cardenosa A , Camacho-Cardenosa M , Burtscher M , et al. High-intensity interval training in normobaric hypoxia leads to greater body fat loss in overweight/obese women than high-intensity interval training in normoxia. Front Physiol . 2018;9:60. doi:10.3389/fphys.2018.00060 29472870

 PubMed Web of Science ®Google Scholar

Gonzalez-Muniesa P , Lopez-Pascual A , de Andres J , et al. Impact of intermittent hypoxia and exercise on blood pressure and metabolic features from obese subjects suffering sleep apnea-hypopnea syndrome. J Physiol Biochem . 2015;71(3):589–599. doi:10.1007/s13105-015-0410-3 25913417

 PubMed Web of Science ®Google Scholar

Kong Z , Zang Y , Hu Y . Normobaric hypoxia training causes more weight loss than normoxia training after a 4-week residential camp for obese young adults. Sleep Breath . 2014;18(3):591–597. doi:10.1007/s11325-013-0922-4 24318688

 PubMed Web of Science ®Google Scholar

Wiesner S , Haufe S , Engeli S , et al. Influences of normobaric hypoxia training on physical fitness and metabolic risk markers in overweight to obese subjects. Obesity . 2010;18(1):116–120. doi:10.1038/oby.2009.193 19543214

 PubMed Web of Science ®Google Scholar

Netzer NC , Chytra R , Kupper T . Low intense physical exercise in normobaric hypoxia leads to more weight loss in obese people than low intense physical exercise in normobaric sham hypoxia. Sleep Breath . 2008;12(2):129–134. doi:10.1007/s11325-007-0149-3 18057976

 PubMed Web of Science ®Google Scholar

Camacho-Cardenosa A , Camacho-Cardenosa M , Olcina G , Timon R , Brazo-Sayavera J . Detraining effect on overweight/obese women after high-intensity interval training in hypoxia. Scand J Med Sci Sports . 2019;29(4):535–543. doi:10.1111/sms.13380 30615248

 PubMed Web of Science ®Google Scholar

Klug L , Mahler A , Rakova N , et al. Normobaric hypoxic conditioning in men with metabolic syndrome. Physiol Rep . 2018;6(24):e13949. doi:10.14814/phy2.13949 30565412

 PubMed Web of Science ®Google Scholar

Camacho-Cardenosa A , Camacho-Cardenosa M , Brazo-Sayavera J , Burtscher M , Timon R , Olcina G . Effects of high-intensity interval training under normobaric hypoxia on cardiometabolic risk markers in overweight/obese women. High Alt Med Biol . 2018;19(4):356–366. doi:10.1089/ham.2018.0059 30204493

 PubMed Web of Science ®Google Scholar

Chobanyan-Jurgens K , Scheibe RJ , Potthast AB , et al. Influences of hypoxia exercise on whole-body insulin sensitivity and oxidative metabolism in older individuals. J Clin Endocrinol Metab . 2019;104(11):5238–5248. doi:10.1210/jc.2019-00411 30942862

 PubMed Web of Science ®Google Scholar

Morishima T , Hasegawa Y , Sasaki H , Kurihara T , Hamaoka T , Goto K . Effects of different periods of hypoxic training on glucose metabolism and insulin sensitivity. Clin Physiol Funct Imaging . 2015;35(2):104–109. doi:10.1111/cpf.12133 24494790

 PubMed Web of Science ®Google Scholar

Chacaroun S , Borowik A , Ygi V-E , et al. Hypoxic exercise training to improve exercise capacity in obese individuals. Med Sci Sports Exerc . 2020;52(8):1641–1649. doi:10.1249/MSS.0000000000002322 32102058

 PubMed Web of Science ®Google Scholar

Morishima T , Kurihara T , Hamaoka T , Goto K . Whole body, regional fat accumulation, and appetite-related hormonal response after hypoxic training. Clin Physiol Funct Imaging . 2014;34(2):90–97. doi:10.1111/cpf.12069 23879294

 PubMed Web of Science ®Google Scholar

Gatterer H , Haacke S , Burtscher M , et al. Normobaric intermittent hypoxia over 8 months does not reduce body weight and metabolic risk factors-a randomized, single blind, placebo-controlled study in normobaric hypoxia and normobaric sham hypoxia. Obes Facts . 2015;8(3):200–209. doi:10.1159/000431157 26008855

 PubMed Web of Science ®Google Scholar