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Intermittent hypoxia as a means to improve aerobic capacity in type 2 diabetes
Medical Hypotheses 100 (2017) 59–63
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Intermittent hypoxia as a means to improve aerobic capacity in type 2 diabetes R.J. Leone ⇑, S. Lalande School of Exercise and Rehabilitation Sciences, College of Health and Human Services, University of Toledo, Toledo, OH, USA
a r t i c l e
i n f o
Article history: Received 23 September 2016 Accepted 21 January 2017
a b s t r a c t Physical inactivity and a low maximal aerobic capacity (VO2max) strongly predict morbidity and mortality in patients with type 2 diabetes (T2D). Patients with T2D have a reduced VO2max when compared with healthy individuals of similar age, weight, and physical activity levels, and this lower aerobic capacity is usually attributed to a reduced oxygen delivery to the working muscles. The oxygen carrying capacity of the blood, as well as increases in cardiac output and blood flow, contribute to the delivery of oxygen to the active muscles during exercise. Hemoglobin mass (Hb mass), a key determinant of oxygen carrying capacity, is suggested to be reduced in patients with T2D following the observation of a lower blood volume (BV) in combination with normal hematocrit levels in this population. Therefore, a lower Hb mass, in addition to a reported lower BV and impaired cardiovascular response to exercise, likely contributes to the reduced oxygen delivery and VO2max in patients with T2D. While exercise training increases Hb mass, BV, and consequently VO2max, the majority of patients with T2D are not physically active, highlighting the need for alternative methods to improve VO2max in this population. Exposure to hypoxia triggers the release of erythropoietin, the hormone regulating red blood cell production, which increases Hb mass and consequently BV. Exposure to mild intermittent hypoxia (IH), characterized by few and short episodes of hypoxia at a fraction of inspired oxygen ranging between 10 and 14% interspersed with cycles of normoxia, increased red blood cell volume, Hb mass, and plasma volume in patients with coronary artery disease or chronic obstructive pulmonary disease, which resulted in an improved VO2max in both populations. We hypothesize that 12 exposures to mild IH over a period of 4 weeks will increase Hb mass, BV, cardiac function, and VO2max in patients with T2D. Therefore, exposures to mild IH may increase oxygen delivery and VO2max without the need to perform exercise in patients with T2D. Ó 2017 Elsevier Ltd. All rights reserved.
Introduction Physical inactivity and a low maximal aerobic capacity (VO2max) are strong independent predictors of cardiovascular and all-cause mortality in patients with type 2 diabetes (T2D) [1,2]. This relationship is alarming as patients with T2D generally exhibit a 20% lower VO2max than healthy individuals matched for age, weight, and physical activity levels (Fig. 1) [3–10]. The reduced VO2max in patients with T2D is mainly attributed to deficiencies in oxygen delivery to the active tissues [11–14], and occasionally associated with impairments in oxygen extraction by the tissues [15]. Attenuated increases in exercising cardiac output and muscle blood flow contribute to the impaired oxygen delivery and reduced VO2max in patients with T2D [6,12–15]. ⇑ Corresponding author at: School of Exercise and Rehabilitation Sciences, College of Health and Human Services, Health and Human Services Building, Room 2503 MS 119, 2801 W Bancroft St, University of Toledo, Toledo, OH 43606, USA. E-mail address: [email protected] (R.J. Leone). http://dx.doi.org/10.1016/j.mehy.2017.01.010 0306-9877/Ó 2017 Elsevier Ltd. All rights reserved.
Hemoglobin (Hb), a component of red blood cells, transports practically all oxygen within the blood. A greater Hb mass results in a greater oxygen carrying capacity and Hb mass strongly correlates with VO2max [16]. Increases in Hb mass lead to an expansion of plasma volume which results in a greater total blood volume (BV) while maintaining normal hematocrit levels. A larger BV contributes to a greater left ventricular filling pressure and enddiastolic volume which, in accordance with the Frank-Starling mechanism, results in a greater stroke volume (SV). The strong influence of BV on SV and VO2max has been clearly demonstrated following manipulation of BV in both untrained and endurancetrained individuals. An acute 500 mL expansion of BV immediately augmented resting and exercising SV and VO2max in untrained individuals [17]. Conversely, an acute 500 mL reduction in BV resulted in an immediate reduction in exercising SV and VO2max in endurance-trained individuals [17]. Moreover, Hb mass and BV were the strongest predictors of unexpectedly high VO2max (62.9–67.0 mL/kg/min) in individuals with no history of exercise training [18]. Together, these findings support a synergistic effect
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R.J. Leone, S. Lalande / Medical Hypotheses 100 (2017) 59–63
Fig. 1. Patients with T2D (gray bars) have a reduced VO2max when compared with healthy individuals (black bars) matched for age, weight, and physical activity levels. T2D: type 2 diabetes [3–10].
of Hb mass on VO2max through increases in both oxygen carrying capacity and in the cardiac response to exercise [16]. Normal hematocrit levels and lower BVs were reported in patients with T2D when compared to healthy individuals [11], suggesting a reduced Hb mass and oxygen carrying capacity in this population. The lower BV likely contributes to the smaller exercising SV reported in patients with T2D [6,12], ultimately resulting in an impaired oxygen delivery and reduced VO2max in these patients. Aerobic exercise increases Hb mass and plasma volume by triggering the production of red blood cells and increasing fluid retention through increases in plasma proteins and oncotic pressure, resulting in an increased BV [19,20]. However, only 20% of Americans meet the American College of Sports Medicine’s physical activity recommendations [21] and patients with T2D are even less likely to be physically active [22,23]. These discouraging statistics underscore the need for alternative methods, such as exposure to intermittent hypoxia, to improve the aerobic capacity of patients with T2D. Hypothesis Twelve brief exposures to mild intermittent hypoxia over a period of 4 weeks will increase Hb mass, BV, SV, and VO2max in patients with T2D. Hematological adaptations to hypoxia Hypoxia, defined as a reduced partial pressure of oxygen, presents a physiological challenge resulting in several adaptations in an effort to preserve adequate oxygen delivery to the tissues. An increase in red blood cell production contributes to the maintenance of a sufficient oxygen delivery during hypoxia. Low systemic oxygen levels prevent the rapid degradation of hypoxia-inducible factor 2a (HIF-2a) usually occurring under normoxic conditions [24]. The greater HIF-2a levels facilitate dimerization with HIF-b, forming HIF-2. HIF-2 then stimulates the synthesis and release of the hormone erythropoietin (EPO) from the kidneys, which results in the production of red blood cells [24]. Serum EPO increases
within 1.5 h of sustained hypoxic exposure [25] while reticulocytosis, an increase in immature red blood cells, occurs 3–4 days following an increase in plasma EPO [26]. Increases in Hb mass and red blood cell volume can be observed within 7 days of continuous hypoxic exposure [27], therefore, hypoxia has the ability to improve the oxygen carrying capacity of the blood. Physiological adaptations to intermittent hypoxia Intermittent hypoxia (IH) consists of short hypoxic exposures interspersed with periods of normoxia [28]. IH is a distinguishing characteristic of obstructive sleep apnea and has often been used as an experimental model of sleep-disordered breathing. Experimental models of ‘‘severe” IH, usually consisting of 48–2400 short exposures at a fraction of inspired oxygen (FiO2) of 2–8%, result in detrimental outcomes such as increases in blood pressure and impaired glucose tolerance [29–31]. However, increasing evidence supports the notion that ‘‘mild” IH elicits beneficial physiological outcomes in various clinical populations [32–34]. Indeed, exposure to mild IH, characterized by <10 episodes ranging from 15 s to 4 min and totaling <60 min hypoxia at an FiO2 between 10 and 14%, improved blood pressure in patients with hypertension [34] and improved performance on behavioral cognitive tests in elderly individuals, possibly due to angiogenesis [35]. Exposure to three to five cycles lasting 3–5 min at an FiO2 ranging from 10 to 14% interspersed with 3 min of normoxia five times per week for 3 weeks increased red blood cell count by 4% and VO2max by 6% in patients with coronary artery disease [36]. In addition, exposure to the same protocol performed at an FiO2 ranging from 12 to 15% increased Hb mass by 4%, plasma volume by 6%, and VO2max by 8% in patients with chronic obstructive pulmonary disease [37]. Few studies examined the effect of mild IH in patients with prediabetes and T2D and have primarily focused on glucose regulation [38,39]. Duennwald et al. [38] reported that a single, 1-h IH exposure alternating between 6 min at an FiO2 of 13% and 6 min of normoxia attenuated the increase in plasma glucose following a meal challenge performed immediately after the IH exposure, potentially due to an increased glucose transport in the muscles [40]. Additionally, daily exposure to 60 min of IH for 4 weeks
R.J. Leone, S. Lalande / Medical Hypotheses 100 (2017) 59–63
Fig. 2. Repeated exposure to mild intermittent hypoxia will increase hemoglobin mass, blood volume, stroke volume, and, subsequently, VO2max. Hemoglobin mass independently and indirectly contributes to VO2max through its influence on total blood volume.
reduced fasting blood glucose levels, which led to the remission of prediabetes in a 49 year-old female, potentially due to an increase in glycolytic enzyme activity [39]. However, the effect of mild IH on hematological variables and cardiac function has not been studied in patients with T2D. Mild IH has the potential to increase Hb mass, which would directly and indirectly increase VO2max through a greater BV and SV (Fig. 2). Thus, mild IH represents a promising intervention to improve VO2max through increases in both oxygen carrying capacity and oxygen delivery in patients with T2D. Effect of mild IH on autonomic cardiovascular control Any detrimental effect of IH on the autonomic control of the cardiovascular system would outweigh the potential benefit of an enhanced aerobic capacity in patients with T2D. While severe IH increases blood pressure [29,31,41], mild IH does not change or reduces blood pressure in healthy individuals and clinical populations [37,42–45]. Zhang et al. [42] reported that 14 consecutive days of IH exposure, consisting of five cycles alternating between 5 min of hypoxia (FiO2 of 10%) and 4 min of normoxia, did not alter mean arterial pressure in young, healthy individuals. Moreover, 10 consecutive days of IH exposure to four cycles of 5 min at an FiO2 of 12% interspersed with 5 min of normoxia did not affect blood pressure in healthy older men [43]. While mild IH does not affect blood pressure in healthy individuals, varying responses to mild IH have been observed in clinical populations. Fifteen IH exposures over a period of 3 weeks, with each IH exposure consisting of three to five cycles lasting 3–5 min at an FiO2 ranging from 12 to 15% interspersed with 3 min of normoxia, did not affect blood pressure in normotensive patients with chronic obstructive pulmonary disease [45]. In a group of pre-hypertensive patients with chronic obstructive pulmonary disease, mild IH decreased blood pressure by 17 mmHg, although blood pressure decreased to a similar extent in the control group exposed to a sham protocol, suggesting that the reduction was not caused by the hypoxic exposure [37]. Although several patients from these clinical studies were taking anti-hypertensive medications [37,45], medication use was similar between patients exposed to IH and patients exposed to a sham protocol, and there was no reported change in prescribed medication during the course of the study. However, twenty consecutive daily exposures ranging between 4 and 10 cycles alternating between 3 min at an FiO2 of 10% and 3 min of normoxia reduced systolic blood pressure by 22 mmHg in young, hypertensive men, presumably due to increased nitric oxide production [44]. Together, these findings suggest that mild IH does not change or even reduces blood pressure in healthy individuals and clinical populations. The commonly observed autonomic dysfunction in patients with T2D contributes to the attenuated increase in exercising cardiac output [12]. Normal autonomic control represents a balance between sympathetic and vagal activity, with increases in sympathetic activity and decreases in vagal activity being associated with
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T2D and an increased mortality in these patients [12,46–49]. Measures of heart rate variability (HRV), a marker of the autonomic control of the heart, and baroreflex sensitivity, the heart rate response to changes in blood pressure, provide an assessment of sympathovagal balance. Reduced HRV and baroreflex sensitivity have been reported in patients with T2D, further suggesting a reduced vagal activity in these patients [12,49–52]. Mild IH improved HRV and baroreflex sensitivity in both healthy individuals and clinical populations [42,45]. Indeed, fourteen consecutive days of mild IH exposure increased HRV in healthy individuals, while repeated mild IH exposures increased baroreflex sensitivity in patients with chronic obstructive pulmonary disease and early autonomic dysfunction, suggesting an enhanced vagal-cardiac function [42,45]. Although a single exposure to mild IH did not alter HRV or baroreflex sensitivity in patients with T2D [38], repeated exposures to mild IH may improve autonomic function by increasing vagal activity in this population. Evaluation of the hypothesis The hypothesis will be tested by studying the effects of mild IH exposures on blood pressure, HRV, Hb mass, BV, SV, and VO2max in patients with T2D. The mild IH protocol will last a total of 40 min and will consist of five cycles of 5 min of hypoxia at an FiO2 of 14% interspersed with 3 min of normoxia (Fig. 3). Participants will be exposed to three IH sessions per week over a period of 4 weeks totaling 300 min of hypoxic exposure. While the optimal protocol to elicit erythropoiesis remains to be identified [33], exposure to a higher FiO2 (14.8–16.2%) was enough to trigger an increase in red blood cell production in healthy individuals [53]. Our proposed protocol is also similar to the mild IH protocol consisting of 5 exposures per week over 3 weeks for a total of 270 min of hypoxic exposure resulting in an increased red blood cell count in patients with coronary artery disease and an increased Hb mass in patients with chronic obstructive pulmonary disease [36,37]. Pre- and postintervention measures will take place on two separate visits. On the first visit, VO2max will be measured by gas exchange during a graded exercise test to exhaustion and exercising SV will be derived from an arterial waveform obtained by finger plethysmography. The second visit will take place at least 48 h later to allow for the transient, exercise-induced increases in plasma volume to subside. During this visit, resting SV and beat-by-beat blood pressure will be obtained by finger plethysmography, HRV will be derived from a 5-min recording of a 3-lead electrocardiogram, and Hb mass and BV will be assessed via the optimized carbon monoxide rebreathing method [54]. The carbon monoxide rebreathing method has similar accuracy, sensitivity, and variability as radioactive methods and is commonly used to measure Hb mass and BV [55]. Resting SV and blood pressure, Hb mass, and BV will be measured 24–72 h after the final hypoxic exposure and exercising SV and VO2max will be measured 24–48 h later. Additionally, all measures besides VO2max will be performed halfway into the mild IH intervention. VO2max will not be measured to prevent any increase in plasma volume triggered by one bout of high-intensity exercise, which could affect the hematological response to mild IH.
Fig. 3. Intermittent hypoxia protocol. Total protocol time: 40 min; total hypoxic time: 25 min.
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Consequences of the hypothesis T2D affects roughly 28 million Americans [56] and is considered one of the seven controllable risk factors for cardiovascular disease [57]. Indeed, patients with T2D have a 2–4-fold greater risk of heart disease or stroke than individuals without T2D [57]. Physical activity is widely recommended for the prevention and treatment of T2D, however, the majority of patients with T2D do not perform regular exercise [22]. It has been reported that patients with T2D experience greater rates of perceived effort during exercise, even when adjusting for relative intensity, than healthy individuals matched for age, weight, and physical activity levels, which may preclude adherence of patients with T2D to regular physical activity [58,59]. Impairments in exercise tolerance may result from the reduced BV reported in patients with T2D [11], which would affect oxygen delivery to the working muscles. Mild IH could increase Hb mass and expand BV in patients with T2D, ultimately leading to improvements in VO2max without the need to perform exercise. These physiological adaptations may reduce the greater perceived exertion during exercise in this population, and potentially improve the physical activity habits in patients with T2D [23,59]. Thus, the proposed study will investigate the potential beneficial effects of mild IH on Hb mass, BV, and cardiac function which, coupled with previously observed improvements in blood glucose control [38], may improve overall health in individuals with T2D.
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Intermittent hypoxia increases exercise tolerance in elderly men with and without coronary artery disease. Int J Cardiol 2004;96(2):247–54. [37] Burtscher M, Haider T, Domej W, et al. Intermittent hypoxia increases exercise tolerance in patients at risk for or with mild COPD. Respir Physiol Neurobiol 2009;165(1):97–103. [38] Duennwald T, Gatterer H, Groop PH, et al. Effects of a single bout of interval hypoxia on cardiorespiratory control and blood glucose in patients with type 2 diabetes. Diabetes Care 2013;36(8):2183–9. [39] Fuller NR, Courtney R. A case of remission from pre-diabetes following intermittent hypoxic training. Obes Res Clin Pract 2016;10(4):487–91. [40] Azevedo Jr JL, Carey JO, Pories WJ, et al. Hypoxia stimulates glucose transport in insulin-resistant human skeletal muscle. Diabetes 1995;44(6): 695–8. [41] Gilmartin GS, Lynch M, Tamisier R, et al. 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[55] Burge CM, Skinner SL. Determination of hemoglobin mass and blood volume with Co: evaluation and application of a method. J Appl Physiol (1985) 1995;79(2):623–31. [56] Centers for Disease Control and Prevention. 2014 national diabetes statistics report Retrieved from http://www.cdc.gov/diabetes/data/statistics/ 2014statisticsreport.html; 2015. [57] American Heart Association. Cardiovascular disease & diabetes Retrieved from http://www.heart.org/HEARTORG/Conditions/Diabetes/WhyDiabetesMatters/ Cardiovascular-Disease-Diabetes_UCM_313865_Article.jsp-.VtWc5vkrK70; 2015. [58] Huebschmann AG, Kohrt WM, Herlache L, et al. Type 2 diabetes exaggerates exercise effort and impairs exercise performance in older women. BMJ Open Diabetes Res Care 2015;3(1):e000124. [59] Huebschmann AG, Reis EN, Emsermann C, et al. Women with type 2 diabetes perceive harder effort during exercise than nondiabetic women. Appl Physiol Nutr Metab 2009;34(5):851–7.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Intermittent hypoxia as a means to improve aerobic capacity in type 2 diabetes R.J. Leone ⇑, S. Lalande School of Exercise and Rehabilitation Sciences, College of Health and Human Services, University of Toledo, Toledo, OH, USA
a r t i c l e
i n f o
Article history: Received 23 September 2016 Accepted 21 January 2017
a b s t r a c t Physical inactivity and a low maximal aerobic capacity (VO2max) strongly predict morbidity and mortality in patients with type 2 diabetes (T2D). Patients with T2D have a reduced VO2max when compared with healthy individuals of similar age, weight, and physical activity levels, and this lower aerobic capacity is usually attributed to a reduced oxygen delivery to the working muscles. The oxygen carrying capacity of the blood, as well as increases in cardiac output and blood flow, contribute to the delivery of oxygen to the active muscles during exercise. Hemoglobin mass (Hb mass), a key determinant of oxygen carrying capacity, is suggested to be reduced in patients with T2D following the observation of a lower blood volume (BV) in combination with normal hematocrit levels in this population. Therefore, a lower Hb mass, in addition to a reported lower BV and impaired cardiovascular response to exercise, likely contributes to the reduced oxygen delivery and VO2max in patients with T2D. While exercise training increases Hb mass, BV, and consequently VO2max, the majority of patients with T2D are not physically active, highlighting the need for alternative methods to improve VO2max in this population. Exposure to hypoxia triggers the release of erythropoietin, the hormone regulating red blood cell production, which increases Hb mass and consequently BV. Exposure to mild intermittent hypoxia (IH), characterized by few and short episodes of hypoxia at a fraction of inspired oxygen ranging between 10 and 14% interspersed with cycles of normoxia, increased red blood cell volume, Hb mass, and plasma volume in patients with coronary artery disease or chronic obstructive pulmonary disease, which resulted in an improved VO2max in both populations. We hypothesize that 12 exposures to mild IH over a period of 4 weeks will increase Hb mass, BV, cardiac function, and VO2max in patients with T2D. Therefore, exposures to mild IH may increase oxygen delivery and VO2max without the need to perform exercise in patients with T2D. Ó 2017 Elsevier Ltd. All rights reserved.
Introduction Physical inactivity and a low maximal aerobic capacity (VO2max) are strong independent predictors of cardiovascular and all-cause mortality in patients with type 2 diabetes (T2D) [1,2]. This relationship is alarming as patients with T2D generally exhibit a 20% lower VO2max than healthy individuals matched for age, weight, and physical activity levels (Fig. 1) [3–10]. The reduced VO2max in patients with T2D is mainly attributed to deficiencies in oxygen delivery to the active tissues [11–14], and occasionally associated with impairments in oxygen extraction by the tissues [15]. Attenuated increases in exercising cardiac output and muscle blood flow contribute to the impaired oxygen delivery and reduced VO2max in patients with T2D [6,12–15]. ⇑ Corresponding author at: School of Exercise and Rehabilitation Sciences, College of Health and Human Services, Health and Human Services Building, Room 2503 MS 119, 2801 W Bancroft St, University of Toledo, Toledo, OH 43606, USA. E-mail address: [email protected] (R.J. Leone). http://dx.doi.org/10.1016/j.mehy.2017.01.010 0306-9877/Ó 2017 Elsevier Ltd. All rights reserved.
Hemoglobin (Hb), a component of red blood cells, transports practically all oxygen within the blood. A greater Hb mass results in a greater oxygen carrying capacity and Hb mass strongly correlates with VO2max [16]. Increases in Hb mass lead to an expansion of plasma volume which results in a greater total blood volume (BV) while maintaining normal hematocrit levels. A larger BV contributes to a greater left ventricular filling pressure and enddiastolic volume which, in accordance with the Frank-Starling mechanism, results in a greater stroke volume (SV). The strong influence of BV on SV and VO2max has been clearly demonstrated following manipulation of BV in both untrained and endurancetrained individuals. An acute 500 mL expansion of BV immediately augmented resting and exercising SV and VO2max in untrained individuals [17]. Conversely, an acute 500 mL reduction in BV resulted in an immediate reduction in exercising SV and VO2max in endurance-trained individuals [17]. Moreover, Hb mass and BV were the strongest predictors of unexpectedly high VO2max (62.9–67.0 mL/kg/min) in individuals with no history of exercise training [18]. Together, these findings support a synergistic effect
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Fig. 1. Patients with T2D (gray bars) have a reduced VO2max when compared with healthy individuals (black bars) matched for age, weight, and physical activity levels. T2D: type 2 diabetes [3–10].
of Hb mass on VO2max through increases in both oxygen carrying capacity and in the cardiac response to exercise [16]. Normal hematocrit levels and lower BVs were reported in patients with T2D when compared to healthy individuals [11], suggesting a reduced Hb mass and oxygen carrying capacity in this population. The lower BV likely contributes to the smaller exercising SV reported in patients with T2D [6,12], ultimately resulting in an impaired oxygen delivery and reduced VO2max in these patients. Aerobic exercise increases Hb mass and plasma volume by triggering the production of red blood cells and increasing fluid retention through increases in plasma proteins and oncotic pressure, resulting in an increased BV [19,20]. However, only 20% of Americans meet the American College of Sports Medicine’s physical activity recommendations [21] and patients with T2D are even less likely to be physically active [22,23]. These discouraging statistics underscore the need for alternative methods, such as exposure to intermittent hypoxia, to improve the aerobic capacity of patients with T2D. Hypothesis Twelve brief exposures to mild intermittent hypoxia over a period of 4 weeks will increase Hb mass, BV, SV, and VO2max in patients with T2D. Hematological adaptations to hypoxia Hypoxia, defined as a reduced partial pressure of oxygen, presents a physiological challenge resulting in several adaptations in an effort to preserve adequate oxygen delivery to the tissues. An increase in red blood cell production contributes to the maintenance of a sufficient oxygen delivery during hypoxia. Low systemic oxygen levels prevent the rapid degradation of hypoxia-inducible factor 2a (HIF-2a) usually occurring under normoxic conditions [24]. The greater HIF-2a levels facilitate dimerization with HIF-b, forming HIF-2. HIF-2 then stimulates the synthesis and release of the hormone erythropoietin (EPO) from the kidneys, which results in the production of red blood cells [24]. Serum EPO increases
within 1.5 h of sustained hypoxic exposure [25] while reticulocytosis, an increase in immature red blood cells, occurs 3–4 days following an increase in plasma EPO [26]. Increases in Hb mass and red blood cell volume can be observed within 7 days of continuous hypoxic exposure [27], therefore, hypoxia has the ability to improve the oxygen carrying capacity of the blood. Physiological adaptations to intermittent hypoxia Intermittent hypoxia (IH) consists of short hypoxic exposures interspersed with periods of normoxia [28]. IH is a distinguishing characteristic of obstructive sleep apnea and has often been used as an experimental model of sleep-disordered breathing. Experimental models of ‘‘severe” IH, usually consisting of 48–2400 short exposures at a fraction of inspired oxygen (FiO2) of 2–8%, result in detrimental outcomes such as increases in blood pressure and impaired glucose tolerance [29–31]. However, increasing evidence supports the notion that ‘‘mild” IH elicits beneficial physiological outcomes in various clinical populations [32–34]. Indeed, exposure to mild IH, characterized by <10 episodes ranging from 15 s to 4 min and totaling <60 min hypoxia at an FiO2 between 10 and 14%, improved blood pressure in patients with hypertension [34] and improved performance on behavioral cognitive tests in elderly individuals, possibly due to angiogenesis [35]. Exposure to three to five cycles lasting 3–5 min at an FiO2 ranging from 10 to 14% interspersed with 3 min of normoxia five times per week for 3 weeks increased red blood cell count by 4% and VO2max by 6% in patients with coronary artery disease [36]. In addition, exposure to the same protocol performed at an FiO2 ranging from 12 to 15% increased Hb mass by 4%, plasma volume by 6%, and VO2max by 8% in patients with chronic obstructive pulmonary disease [37]. Few studies examined the effect of mild IH in patients with prediabetes and T2D and have primarily focused on glucose regulation [38,39]. Duennwald et al. [38] reported that a single, 1-h IH exposure alternating between 6 min at an FiO2 of 13% and 6 min of normoxia attenuated the increase in plasma glucose following a meal challenge performed immediately after the IH exposure, potentially due to an increased glucose transport in the muscles [40]. Additionally, daily exposure to 60 min of IH for 4 weeks
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Fig. 2. Repeated exposure to mild intermittent hypoxia will increase hemoglobin mass, blood volume, stroke volume, and, subsequently, VO2max. Hemoglobin mass independently and indirectly contributes to VO2max through its influence on total blood volume.
reduced fasting blood glucose levels, which led to the remission of prediabetes in a 49 year-old female, potentially due to an increase in glycolytic enzyme activity [39]. However, the effect of mild IH on hematological variables and cardiac function has not been studied in patients with T2D. Mild IH has the potential to increase Hb mass, which would directly and indirectly increase VO2max through a greater BV and SV (Fig. 2). Thus, mild IH represents a promising intervention to improve VO2max through increases in both oxygen carrying capacity and oxygen delivery in patients with T2D. Effect of mild IH on autonomic cardiovascular control Any detrimental effect of IH on the autonomic control of the cardiovascular system would outweigh the potential benefit of an enhanced aerobic capacity in patients with T2D. While severe IH increases blood pressure [29,31,41], mild IH does not change or reduces blood pressure in healthy individuals and clinical populations [37,42–45]. Zhang et al. [42] reported that 14 consecutive days of IH exposure, consisting of five cycles alternating between 5 min of hypoxia (FiO2 of 10%) and 4 min of normoxia, did not alter mean arterial pressure in young, healthy individuals. Moreover, 10 consecutive days of IH exposure to four cycles of 5 min at an FiO2 of 12% interspersed with 5 min of normoxia did not affect blood pressure in healthy older men [43]. While mild IH does not affect blood pressure in healthy individuals, varying responses to mild IH have been observed in clinical populations. Fifteen IH exposures over a period of 3 weeks, with each IH exposure consisting of three to five cycles lasting 3–5 min at an FiO2 ranging from 12 to 15% interspersed with 3 min of normoxia, did not affect blood pressure in normotensive patients with chronic obstructive pulmonary disease [45]. In a group of pre-hypertensive patients with chronic obstructive pulmonary disease, mild IH decreased blood pressure by 17 mmHg, although blood pressure decreased to a similar extent in the control group exposed to a sham protocol, suggesting that the reduction was not caused by the hypoxic exposure [37]. Although several patients from these clinical studies were taking anti-hypertensive medications [37,45], medication use was similar between patients exposed to IH and patients exposed to a sham protocol, and there was no reported change in prescribed medication during the course of the study. However, twenty consecutive daily exposures ranging between 4 and 10 cycles alternating between 3 min at an FiO2 of 10% and 3 min of normoxia reduced systolic blood pressure by 22 mmHg in young, hypertensive men, presumably due to increased nitric oxide production [44]. Together, these findings suggest that mild IH does not change or even reduces blood pressure in healthy individuals and clinical populations. The commonly observed autonomic dysfunction in patients with T2D contributes to the attenuated increase in exercising cardiac output [12]. Normal autonomic control represents a balance between sympathetic and vagal activity, with increases in sympathetic activity and decreases in vagal activity being associated with
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T2D and an increased mortality in these patients [12,46–49]. Measures of heart rate variability (HRV), a marker of the autonomic control of the heart, and baroreflex sensitivity, the heart rate response to changes in blood pressure, provide an assessment of sympathovagal balance. Reduced HRV and baroreflex sensitivity have been reported in patients with T2D, further suggesting a reduced vagal activity in these patients [12,49–52]. Mild IH improved HRV and baroreflex sensitivity in both healthy individuals and clinical populations [42,45]. Indeed, fourteen consecutive days of mild IH exposure increased HRV in healthy individuals, while repeated mild IH exposures increased baroreflex sensitivity in patients with chronic obstructive pulmonary disease and early autonomic dysfunction, suggesting an enhanced vagal-cardiac function [42,45]. Although a single exposure to mild IH did not alter HRV or baroreflex sensitivity in patients with T2D [38], repeated exposures to mild IH may improve autonomic function by increasing vagal activity in this population. Evaluation of the hypothesis The hypothesis will be tested by studying the effects of mild IH exposures on blood pressure, HRV, Hb mass, BV, SV, and VO2max in patients with T2D. The mild IH protocol will last a total of 40 min and will consist of five cycles of 5 min of hypoxia at an FiO2 of 14% interspersed with 3 min of normoxia (Fig. 3). Participants will be exposed to three IH sessions per week over a period of 4 weeks totaling 300 min of hypoxic exposure. While the optimal protocol to elicit erythropoiesis remains to be identified [33], exposure to a higher FiO2 (14.8–16.2%) was enough to trigger an increase in red blood cell production in healthy individuals [53]. Our proposed protocol is also similar to the mild IH protocol consisting of 5 exposures per week over 3 weeks for a total of 270 min of hypoxic exposure resulting in an increased red blood cell count in patients with coronary artery disease and an increased Hb mass in patients with chronic obstructive pulmonary disease [36,37]. Pre- and postintervention measures will take place on two separate visits. On the first visit, VO2max will be measured by gas exchange during a graded exercise test to exhaustion and exercising SV will be derived from an arterial waveform obtained by finger plethysmography. The second visit will take place at least 48 h later to allow for the transient, exercise-induced increases in plasma volume to subside. During this visit, resting SV and beat-by-beat blood pressure will be obtained by finger plethysmography, HRV will be derived from a 5-min recording of a 3-lead electrocardiogram, and Hb mass and BV will be assessed via the optimized carbon monoxide rebreathing method [54]. The carbon monoxide rebreathing method has similar accuracy, sensitivity, and variability as radioactive methods and is commonly used to measure Hb mass and BV [55]. Resting SV and blood pressure, Hb mass, and BV will be measured 24–72 h after the final hypoxic exposure and exercising SV and VO2max will be measured 24–48 h later. Additionally, all measures besides VO2max will be performed halfway into the mild IH intervention. VO2max will not be measured to prevent any increase in plasma volume triggered by one bout of high-intensity exercise, which could affect the hematological response to mild IH.
Fig. 3. Intermittent hypoxia protocol. Total protocol time: 40 min; total hypoxic time: 25 min.
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Consequences of the hypothesis T2D affects roughly 28 million Americans [56] and is considered one of the seven controllable risk factors for cardiovascular disease [57]. Indeed, patients with T2D have a 2–4-fold greater risk of heart disease or stroke than individuals without T2D [57]. Physical activity is widely recommended for the prevention and treatment of T2D, however, the majority of patients with T2D do not perform regular exercise [22]. It has been reported that patients with T2D experience greater rates of perceived effort during exercise, even when adjusting for relative intensity, than healthy individuals matched for age, weight, and physical activity levels, which may preclude adherence of patients with T2D to regular physical activity [58,59]. Impairments in exercise tolerance may result from the reduced BV reported in patients with T2D [11], which would affect oxygen delivery to the working muscles. Mild IH could increase Hb mass and expand BV in patients with T2D, ultimately leading to improvements in VO2max without the need to perform exercise. These physiological adaptations may reduce the greater perceived exertion during exercise in this population, and potentially improve the physical activity habits in patients with T2D [23,59]. Thus, the proposed study will investigate the potential beneficial effects of mild IH on Hb mass, BV, and cardiac function which, coupled with previously observed improvements in blood glucose control [38], may improve overall health in individuals with T2D.
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