Exercise intervention under hypoxic condition as a new therapeutic paradigm for type 2 diabetes mellitus: A narrative review

Table 1 Effects of acute exercise under hypoxia vs under normoxia in patients with type 2 diabetes mellitus

Ref.	Participants	Design and protocol	Exercise intensity	Main results
Mackenzie et al[63] (2011)1	n = 8; sex: Male; age: 58 ± 4.0 yr; BMI: 29.2 ± 6.7 kg/m2	(1) 60 min rest in normoxia; (2) 60 min rest in hypoxia normobaric hypoxia (FiO2: 14.6%, simulated altitude: ca.3100 m); (3) 60 min cycling in normoxia; and (4) 60 min cycling in hypoxia (normobaric hypoxia: FiO2: 14.6%)	(3) and (4): 90% lactate threshold	Blood lactate: ↔ (1), (2); ↑ (3), (4). Blood glucose: ↔ (1); ↓ (2), (3), (4). Insulin sensitivity (during glucose tolerance test): (4) > (3) > (2) > (1)
Mackenzie et al[46] (2012)1	n = 8; sex: Male; age: 58.7 ± 2.2 yr; BMI: 28.3 ± 2.1 kg/m2	(1) 60 min continuous cycling in hypoxia (normobaric hypoxia: FiO2: 14.7%, simulated altitude: ca.3100 m); (2) 60 min interval training with passive recovery (5:5 min) in hypoxia (normobaric hypoxia: FiO2: 14.7%); and (3) 60 min interval training with passive recovery (5:5 min) in normoxia	(1): 90% lactate threshold; (2): 120% lactate threshold; (3): 120% lactate threshold	HR and blood lactate: ↑ (1), (2), (3). Blood glucose decrease (pre- to post-exercise): (1) > (2). Glucose disappearance: ↑ (1); ↔ (2), (3). HOMA-IR index improved after 24 h: ↑ (1), (2); ↔ (3); after 48 h: ↑ (1); ↔ (3)
Brinkmann et al[76] (2017)2	n = 8; sex: Male; age: 58.0 ± 15.0 yr; BMI: 33.0 ± 6.0 kg/m2	40 min cycling: (1) Normoxia; (2) Hypoxia (normobaric hypoxia: FiO2: 14%, simulated altitude: ca. 3400 m); and (3) Hypoxia (normobaric hypoxia: FiO2: 14%) + hyperoxia (normobaric hyperoxia: FiO2: 30%) intervals (5:5 min)	Blood lactate: 2.5 mmol/L	Blood lactate (post-exercise lower): (3) > (2). BORG RPE: ↔ (1), (2), (3). Pro-angiogenic factors: VEGF: ↑ (2), (3). Anti-angiogenic factor: endostatin: ↑ (2), (3)

¹Data are presented as mean ± SE.

²Data are presented as mean ± SD. BMI: Body mass index; HR: Heart rate; BORG RPE: BORG rating of perceived exertion; FiO₂: Fraction of inspired oxygen; HOMA-IR: Homeostatic model assessment for the quantification of insulin-resistance; VEGF: Vascular endothelial growth factor.

Table 2 Effects of hypoxia vs normoxia chronic exercise in patients with type 2 diabetes mellitus or insulin-resistance

Ref.	Participants	Intervention	Intensity	Frequency and duration	Main results
Wiesner et al[69] (2010)1	n = 45. NTG: sex: 8 male, 13 females; age: 42.1 ± 1.7yr; BMI: 32.5 ± 0.8. HTG: sex: 10 male, 14 females; age: 42.2 ± 1.2 yr; BMI: 33.1 ± 0.3	60 min running on a treadmill; normobaric hypoxia: simulated altitude: ca. 2740 m	VO2peak: 65%	3 d/wk, 4 wk	Lactate levels at the anaerobic threshold: ↓ HTG; fasting insulin, HOMA-IR: ↓ NTG, HTG; body fat decreased: HTG > NTG; BP, LDL-c: ↔ NTG, HTG
Schreuder et al[66] (2014)2	n = 19. NTG: sex: 5 male, 4 females; age: 52.0 ± 8.0 yr; BMI: 36.0 ± 6.5 kg/m2. HTG: sex: 9 male, 1 female; age: 57.0 ± 6.0 yr; BMI: 30.9 ± 4.1 kg/m2	45 min endurance training (cycling) + series of strength training exercises; normobaric hypoxia: FiO2: 16.5%: simulated altitude: ca. 2100 m	HRR: 70%-75%	3 d/wk, 8 wk	VO2max: ↑ NTG, HTG; BMI, BP, HOMA-IR, HDL-c, LDL-c, TC, TG, fasting glucose, HbA1c: ↔ NTG, HTG; Vasodilatory function: ↔ NTG, HTG

¹Data are presented as mean ± SE.

²Data are presented as mean ± SD. NTG: Normoxia training group; HTG: Hypoxia training group; BMI: Body mass index; Fi₂: Fraction of inspired oxygen; HDL-c: High-density lipoprotein cholesterol; HbA1c: Glycated hemoglobin; HOMA-IR: Homeostatic model assessment for the quantification of insulin-resistance; HRR: Heart rate reserve; LDL-c: Low-density lipoprotein cholesterol; VO₂peak: Peak oxygen uptake; VO₂max: Maximal oxygen uptake; BP: Blood pressure; TC: Total cholesterol; TG: Triglyceride.