1 Introduction
2 Methods
2.1 Search strategy
2.2 Selection criteria
3 Results
3.1 Literature search
3.2 The effects of hypoxia exposure on glucose homeostasis
3.2.1 The effects of hypoxia exposure on circulating glucose and insulin concentrations
Authors | Characteristics of study participants | Hypoxia exposure protocol | Main outcome parameters | Study outcomes* |
---|---|---|---|---|
Duennwald et al. 2013 [18] | T2DM patients (n = 14; 3 females); age 59.3 ± 1.5 yrs; BMI 29.4 ± 1.0 kg/m2. | Single-blind, placebo-controlled study. 1h intermittent hypoxia (5 x 6 min at FiO2 13%, interspersed with 5 x 6 min at FiO2 21%) or normoxia (continuous FiO2 21%) exposure. Blood glucose concentration was measured at t=0, 3h and 6h following the 1h-exposure. Wash-out period: 3–5 days. | Plasma glucose values (mmol/L) | Δ fasting plasma glucose (mmol/L) (post-baseline): • Hypoxia group: -2.1 P < 0.01 • Placebo group: -0.8 P = N.S Hypoxia versus normoxia: P = 0.037 |
Serebrovska et al. 2017 [19] | Individuals with IFG (5.6-6.9 mmol/L) and/or IGT (2h plasma glucose 7.8-11.0 mmol/L) (n = 11; 6 females); age 66.4 ± 5.2 yrs; BMI 33.2 ± 5.6 kg/m2). | Measurements were performed at baseline, one day (acute normobaric hypoxic test: 12% O2 for 20 min) and one month after intermittent hypoxia exposure. Participants wore a mask during hypoxia exposure, 3x/wk for 3 weeks. Each session consisted of 4 x 5-min normobaric hypoxia (FiO2 12%) followed by 5-min normoxia (room air breathing). | Fasting and post-glucose ingestion serum glucose (mmol/L) concentration pre and one month post intermittent hypoxic training. | Δ fasting serum glucose (mmol/L) (post-pre): • -0.4 P < 0.05 Δ 2h OGTT serum glucose concentration (mmol/L) (post-pre): • -1.5 P < 0.01 |
LeCoultre et al. 2013 [20] | Obese men (n = 8; 4 Caucasians, 3 African Americans, and 1 Hispanic); age 28 ± 1 yrs; BMI 32.7 ± 1.3 kg/m2 | Hypoxia exposure (FiO2 15%) for 10 consecutive nights (±10 hours/night in hypoxic tent). Insulin sensitivity was measured by a two-step hyperinsulinemic-euglycemic clamp at baseline and on day 12. | Fasting insulin (mU/L), fasting glucose (mg/dL) and glucose disposal rate (mg/kg/min) | Δ fasting glucose (mg/dL) (post-pre): • -3.0 P < 0.05 Δ glucose disposal rate (mg/kg/min) (post-pre): • 0.9 P < 0.05 Δ fasting insulin (mU/L) (post-pre): • -0.8 P = N.S. |
Mackenzie et al. 2011 [21] | Sedentary men (n = 8) with recently-diagnosed (<5 yrs) T2DM (age 58 ± 4 yrs, BMI 29.2 ± 6.7 kg/m2). | Following an overnight fast (∼12 h), subjects completed four trials: 60 min of 1) normoxic rest (FiO2 21%), 2) hypoxic rest (FiO2 14.6%), 3) normoxic exercise (FiO2 21%) and 4) hypoxic exercise (FiO2 14.6%). Dietary intake was controlled 48 h prior to each condition. Five subjects were diet treated, and three subjects were treated with metformin. Subjects were asked to abstain from medication 48 h the before experimental trials. | Insulin sensitivity (Si2*), AUC for arterialized blood glucose (mmol/L/4h) and AUC for plasma insulin (μU/mL/4h) during a 4-h intravenous glucose tolerance test | Δ Insulin sensitivity (Si2*, ∙104 μU/ml) (normoxic – hypoxic): • Rest: -0.86 P < 0.05 • Exercise: -1.13 P < 0.05 Δ AUC for plasma insulin (μU/mL/4h) (normoxic-hypoxic): • Rest: 1861 P < 0.05 • Exercise: 1303 P < 0.01 Δ AUC for arterialized blood glucose (mmol/L/4h) (normoxic-hypoxic): • Rest: 204 P = N.S. • Exercise: 120 P = N.S. |
Mackenzie et al. 2012 [22] | Sedentary males (n = 8), with recently diagnosed T2DM; age 57.5 ± 2.3 yrs, BMI 29.2 ± 2.9 kg/m2). | Subjects performed 3 acute exercise sessions (60, 40 and 20 minutes at 90% of predetermined lactate threshold) under hypoxia (FiO2 14.7±0.2%) separated by at least 7 days. After each exercise trial (day 1), fasting glucose and HOMA-IR were determined after 24 hours (day 2) and 48 hours (day 3). No normoxic exercise control group was included. | Fasting glucose (mmol/L), fasting insulin (μU/ml), HOMA-IR. | Δ fasting glucose (mmol/L) (day 3-day 1): • 20 minutes: -0.46 P = N.S. vs day 1 • 40 minutes: -0.87 P < 0.05 vs day 1 • 60 minutes: -1.01 P < 0.05 vs day 1 Δ fasting insulin (μU/ml) (day 3-day 1): • 20 minutes: -0.20 P = N.S. vs day 1 • 40 minutes: -2.40 P = N.S. vs day 1 • 60 minutes: -2.67 P < 0.05 vs day 1 Δ HOMA-IR (day 3-day 1): • 20 minutes: -0.18 P = N.S. vs day 1 • 40 minutes: -1.47 P < 0.05 vs day 1 • 60 minutes: -1.96 P < 0.05 vs day 1 |
Marlatt et al. 2020 [23] | Adults with confirmed T2DM (n = 8, 3 females) Age 49 ± 10 yrs; BMI 39.6 ± 5.8 kg/m2. | Participants were required to sleep for 14 consecutive nights (7–12 h per night) at home in a hypoxic tent maintained at ~15% O2 (range 14.5– 15.5% O2). Participants completed inpatient visits at day 0 (baseline, pre-intervention) and day 14 (end of intervention). | 2-h plasma glucose AUC (in mg/dL × h), 2- h plasma insulin AUC (in μU/mL × h), and insulin sensitivity as estimated by the Matsuda Index and Disposition Index | Δ 2-h plasma glucose AUC (in mg/dL × h) (post-pre): • -62 P < 0.05 Δ insulin sensitivity (estimated by Matsuda Index) (post-pre): • 0.5 P = N.S. Δ insulin sensitivity (estimated by Disposition Index) (post-pre): • 0.5 P = N.S. |
De Groote et al. 2018 [24] | Adolescents (n = 14, 8 females), aged 12–15 yrs; BMI >30 kg/m2. | 8 week, randomized, single-blind study, including 6 weeks of exercise training where three times per week, adolescents were trained for 50– 60 min, including 12 min on a cycle ergometer - Session 1: 2 min at 50% MAP and 10 min at 70% MAP - Session 2: 2 min at 50% MAP and 5 repetitions of 1 min 80%–1 min 50% MAP; - Session 3: incremental training started at 40% MAP with an increase of 10% MAP each 2 min and resistance training of the abdominal, quadriceps, and biceps muscles (15 repetitions at 50% 1RM + 4 sets of 6 repetitions at 70% 1RM; resting time: 2 min). The normoxic exercise group (n = 7, 4 females) was exposed to ambient conditions, while the normobaric hypoxic exercise group (n = 7; 4 females) was exposed to a FiO2 15%. | HOMA-IR, HOMA-β, QUICKI, AUC plasma insulin (µU/ml) and glucose (mg/dl). | Δ AUC plasma insulin (%) (post-pre): • Hypoxia group: -49 P < 0.01 • Normoxia group: -21 P = N.S. Δ AUC glucose levels (%) (post-pre): • Hypoxia group: -14 P < 0.01 • Normoxia group: -7 P = N.S. Δ HOMA-IR (%) (post-pre): • Hypoxia group: -37 P = 0.08 • Normoxia group: -45 P < 0.05 Δ HOMA-β (%) (post-pre): • Hypoxia group: -30 P < 0.05 • Normoxia group: -29 P < 0.05 Δ QUICKI (%) (post-pre) • Hypoxia group: 7 P < 0.01 Normoxia group: 6 P < 0.01 |
Wiesner et al. 2009 [25] | Sedentary, nondiabetic or insulin resistant, overweight/obese men and women (n = 45, 27 females). Age 42 ± 7.1 yrs; BMI: 30.2 ± 3.6 kg/m2. | Subjects were submitted to a training program (60 min/day, 3x/week) for 4 weeks at a heart rate corresponding to 65% of maximum oxygen consumption under normobaric normoxia (FiO2 21.0%) or hypoxia (FiO2 15%). Both groups trained at the same relative exercise intensity. | HOMA-IR, fasting insulin (µU/ml). | Δ HOMA-IR (post-pre): • Hypoxia group: -0.8 P < 0.05 • Normoxia group: -0.7 P < 0.05 Δ fasting insulin (µU/ml) (post-pre): • Hypoxia group: -3.1 P < 0.05 • Normoxia group: -3.2 P < 0.05 |
Lippl et al. 2010 [26] | Obese men with the metabolic syndrome (n = 20); Age 55.7 ± 4.1 yrs, BMI 33.7 ± 1.0 kg/m2). | Baseline (day 1) and follow-up investigations (day 42) were performed at an altitude of 530m. High-altitude measurements (day 7 and day 14) were performed at an altitude of 2,650m. Activity was restricted to slow walks. The selection and amount of foods was similar at the different locations. Testing was performed at the same time of day for each patient after a minimum fast of 8h. | Fasting glucose (mg/dl), insulin values (μU/ml), HbA1c (%) and HOMA. | Δ HbA1c (%) (day 14-day 1): • -0.1 P < 0.05 Δ fasting blood glucose (mg/dl) (day 14-day 1): • -1.9 P = N.S. Δ insulin (μU/ml) (day 14-day 1): • 3.5 P = N.S. Δ HOMA-IR (day 14-day 1): • 1.3 P = N.S. |
Morishima et al. 2015 [27] | Sedentary men (n = 21); Age 24.3 ± 1.12 yrs; BMI 25.5 ± 0.7 kg/m2). | Subjects were randomly assigned to either the 2-week hypoxic training group (n = 11; 6 sessions/week) or the 4-week hypoxic training group (n = 10; 3 sessions/week). Each training session consisted of 60-min cycling at 65% of maximal oxygen uptake (VO2max) evaluated under hypoxic conditions (FiO2 15.0%). | Fasting glucose (mg/dl) and insulin values (μU/ml) | Δ fasting glucose (mg/dl) (post-pre): • 2-week group: -1.0 P = N.S. • 4-week group: -1.0 P = N.S. Δ fasting insulin (μU/ml) (post-pre): • 2-week group: -2.0 P = N.S. • 4-week group: -2.5 P = N.S. |
Morishima et al. 2014 [28] | Sedentary, overweight men (n = 8); Age 27 ± 3 yrs; BMI 28.6 ± 0.8 kg/m2). | Maximal oxygen uptake (VO2max) was assessed using a graded power test on an ergometer under normoxic (first visit) and hypoxic (second visit) conditions. Four acute experimental studies were carried out in a randomized crossover design (sessions separated by ± 7 days) in an environmental chamber following an overnight fast: both a 1) rest and 2) exercise trial under normoxic conditions (FiO2 = 20.9%), and a 3) rest and 4) exercise trial under hypoxic conditions (FiO2 = 15.0%). In the rest trials subjects rested on a chair. In the exercise trials, subjects conducted 3x30 min pedaling exercise at 60% of VO2max at 8:00, 10:30, and 13:00, and rested during the remaining periods. Standard meals were provided at 8:30, 11:00, and 13:30. | AUC for glucose (mg/dL ∙7.5h) and AUC for serum insulin (μIU/∙7.5h), including intake of meals with or without exercise sessions. | Δ AUC for blood glucose (mg/dL∙7.5h ) (normoxic-hypoxic) (data not shown in text but in figures): • Rest : P = N.S. • Exercise: P = N.S. Δ AUC for serum insulin (μIU/mL∙7.5h ) (normoxic-hypoxic): • Rest: P = N.S. • Exercise: P = N.S. |
Gutwenger et al. 2015 [29] | Individuals with the metabolic syndrome (n = 14; 8 females); high altitude: Age: 39 – 60 yrs; BMI 31.1 ± 5.3 kg/m2 Low altitude: Age 55 – 69 yrs; BMI 32.3 ±4.2 kg/m2. | Participants were assigned to two groups: exercise under mild hypobaric hypoxic conditions at 1,900 m altitude for 2 weeks (n = 8), or exercise under normobaric normoxic conditions at 300 m altitude (n = 6) for 2 weeks. Both groups participated in the supervised training program (hiking; 3h/day, 4x/week; total training time of 24 hours) at an intensity of 55–65% of the individual maximal heart rate. | Insulin values (mU/L) and glucose values (mg/dl). | Δ blood insulin values (mU/L) (post-pre): • Moderate altitude: 1.0 • Low altitude: 1.5 Moderate versus low altitude: P = N.S. Δ blood glucose values (mg/dl) (post-pre): • Moderate altitude: -1.6 • Low altitude: -1.5 Moderate versus low altitude: P = N.S. |
Chacaroun et al. 2020 [30] | Overweight or obese, sedentary subjects (n = 23, 4 females); Age 54 ± 11 yrs; BMI 31.5 ± 2.8 kg/m2). | Subjects performed 3x45-min exercise sessions/week for 8 weeks. Measurements were performed before and after the 8-week training period. During cycling, workload was continuously adjusted to obtain a heart rate of 75% of individual maximal heart rate. For the hypoxic exercise training group (11 males and 1 female), FiO2 was individually and continuously adjusted to reach a target SpO2 of 80% under normobaric conditions. The normoxic exercise training group (8 males and 3 females) inhaled normoxic ambient air (FiO2 21%). | HOMA2-IR, plasma insulin (μU/ml). | Δ HOMA2-IR (post-pre): • Hypoxia group: -0.03 P = N.S. • Normoxia group: -0.05 P = N.S. Δ plasma insulin (μU/ml) (post-pre): • Hypoxia group: -0.4 P = N.S. • Normoxia group: -0.4 P = N.S. |
Klug et al. 2018 [31] | Men with metabolic syndrome (n = 23); Age 18-70 yrs; BMI hypoxic group 34.1±0.9, BMI normoxic group 35.5±1.4 kg/m2. | Patients completed a 6-week moderate, aerobic exercise program (3x/wk at 50–60% of maximal heart rate). One training session lasted 60 min with 3x15 min intervals of walking on the treadmill and a 5 min break in between for recovery. The hypoxic exercise group was exposed to normobaric hypoxia (FiO2 15%), while the normoxic exercise group was exposed to normobaric normoxia (FiO2 21%) | Glucose (mmol/L) and insulin levels (μU/ml), HbA1c (%). | Δ fasting insulin (μU/ml) ( post-pre): • Hypoxia group: 3 P = N.S. • Normoxia group: -2 P = N.S. Hypoxia versus normoxia: P = N.S. Δ blood glucose (mmol/L) (post-pre): • Hypoxia group: -0.2 P = N.S. • Normoxia group: 0 P = N.S. Hypoxia versus normoxia: P = N.S. Δ HbA1c (%) (post-pre): • Hypoxia group: -0.2 P = N.S. • Normoxia group: -0.1 P = N.S. Hypoxia versus normoxia: P = N.S. |
Chobanyan-Jürgens et al. 2019 [32] | Older sedentary individuals (n = 29, 14 females), Hypoxic group: Age 60.4±5.1 yrs; BMI 28.6±3.0 kg/m2. Normoxic group: Age 63.8±5.8 yrs; BMI 28.3±1.9 kg/m2. | Participants trained on a bicycle ergometer 3 days per week for 8 weeks under normobaric hypoxia (FiO2 15%) or normoxia. Subjects trained at a heart rate corresponding to 60% of pre-training VO2-peak for 30 minutes for the first 4 weeks. After 4 weeks, exercise intensity was increased to 70% of pre-training VO2-peak and exercise duration to 40 minutes. Pre-training VO2-peak was determined by performing an incremental exercise test on a bicycle ergometer. | Glucose infusion rate (mg/min), HOMA-IR and the insulin sensitivity index (μg/kg/min/(mM∙pM)) | Δ glucose infusion rate (mg/min) (post-pre): • Hypoxia group: 74 P < 0.01 • Normoxia group: 54 P < 0.05 Hypoxia versus normoxia: P = N.S. Δ HOMA-IR (post-pre): • Hypoxia group: -0.5 P = N.S. • Normoxia group: -0.2 P = N.S. Hypoxia versus normoxia: P = N.S. Δ insulin sensitivity index ((μg/kg/min/(mM∙pM)) (post-pre): • Hypoxia group: 0.17 P < 0.05 • Normoxia group: 0.16 P < 0.05 Hypoxia versus normoxia: P = N.S. |
Shin et al. 2018 [33] | Japanese men (n = 41), Hypoxic group: Age 45.6±20.9 yrs; BMI 26.8±2.3 kg/m2. Normoxic group: Age 46±20.5 yrs; BMI 27±3 kg/m2. | Subjects trained on a treadmill 3 days per week for 4 weeks, for 50 min (including 5-minute warm-up and cool-down periods). A 30-minute rest period preceded and followed each exercise session. Exercise was performed at an intensity corresponding to 60% of the maximum heart rate, which was calculated from the age and heart rate at rest. Exercise was performed at either normobaric hypoxic (15.4% O2) conditions (equivalent to an altitude of 2500 m), or normobaric normoxic (20.9% O2) conditions (equivalent to sea level). | HOMA-IR, fasting insulin (μU/ml) and glucose (mmol/L). | Δ HOMA-IR (post-pre): • Hypoxia group: -1.13 P < 0.05 • Normoxia group: -0.22 P < 0.05 Δ fasting insulin (μU/ml) (post-pre): • Hypoxia group: -5.43 P = N.S. • Normoxia group: -0.85 P = N.S. Δ blood glucose (mmol/L) (post-pre): • Hypoxia group: -3.25 P = N.S. • Normoxia group: -4.14 P < 0.01 |