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Abstract

Introduction

Glycated hemoglobin can interfere with oxygen delivery and CO₂ removal during exercise. Additionally, pancreatic insufficiency increases oxidative stress and exacerbates exercise intolerance in people with cystic fibrosis (PwCF). This investigation sought to test the hypotheses that elevated Hemoglobin A_1c (HbA_1c) can negatively affect exercise parameters in PwCF and that reductions in oxidative stress can improve tissue oxygenation in individuals with elevated HbA_1c.

Methods

Twenty four PwCF were divided into two groups; normal HbA1c <5.7% (N-HbA_1c) and elevated HbA_1c >5.7% (E-HbA_1c). A maximal exercise test was conducted to obtain peak oxygen uptake (VO₂peak), VO₂ at ventilatory threshold (VT), ventilatory parameters (V_E/VCO₂ slope and end-tidal CO₂ (petCO₂)). Near-Infrared Spectroscopy (NIRS) was used to assess muscle oxygenated/deoxygenated hemoglobin during exercise. A subset of individuals with E-HbA_1cwere given an antioxidant cocktail (AOC) for 4 weeks to determine the effects on tissue oxygenation during exercise.

Results

A negative relationship between HbA_1c and VO₂peak at VT was observed (r = −0.511; p = 0.018). In addition, a positive relationship between HbA_1c and V_E/VCO₂ slope (r = 0.587;p = 0.005) and a negative relationship between HbA_1c and petCO₂ at maximal exercise (r = −0.472;p = 0.031) was observed. N-HbA_1c had greater VO₂peak (p = 0.021), VO₂ at VT (p = 0.004), petCO₂ (p = 0.002), and lower V_E/VCO₂ slope (p = 0.004) compared with E-HbA_1c. Muscle deoxygenated hemoglobin at VT was higher in N-HbA_1c vs. E-HbA_1c and 4 weeks of AOC improved skeletal muscle utilization of oxygen.

Conclusion

Findings demonstrate that glycated hemoglobin may lead to tissue oxygenation impairment and ventilation inefficiency during exercise in PwCF. In addition, antioxidant supplementation may lead to improved tissue oxygenation during exercise.

Keywords

Cystic fibrosis exercise

Introduction

Cystic fibrosis (CF) has traditionally been characterized by pulmonary dysfunction, pancreatic insufficiency, and other systemic abnormalities. In addition, exercise intolerance is a common manifestation of CF, and a reduced exercise capacity can predict disease-related morbidity and mortality, independent of lung function.^1,2 The availability of oxygen (O₂) to the skeletal muscle and removal of metabolic carbon dioxide (CO₂) by the lungs are both critical to maintain any type of continuous activity (i.e., exercise). In fact, the assessment of the ventilatory equivalent of carbon dioxide (V_E/VCO₂) during exercise is an indicator of how adeptly the body can clear CO₂ from the lungs, with higher values being predictive of mortality in various patient populations.^3–5 Interestingly, a single report has documented that V_E/VCO₂ can increase overtime in CF without observed changes in exercise capacity.⁶ Although the mechanisms that contribute to lower exercise capacity in CF have yet to be fully elucidated, impaired oxygen extraction and utilization of oxygen by skeletal muscle may play an important role.⁷ In addition, evaluation of the ventilatory threshold (VT) can be a useful measure of aerobic fitness⁸; however, no studies have evaluated the importance of muscle oxygen extraction in relation to the VT, when aerobic respiration is the primary source of metabolism.

Oxidative stress is a common phenotype of CF and contributes to pancreatic insufficiency and progressive loss of endocrine function via destruction of insulin-producing β-cells. Indeed, 50% of adults with CF exhibit impaired glucose tolerance and eventually develop cystic fibrosis-related diabetes (CFRD), a clinical manifestation that increases disease severity and contributes to morbidity and mortality^9,10 in this patient population. It is unclear, however, whether or not CFRD is associated with exercise capacity with scant evidence to both support and refute the hypothesis.^11,12 Although treatment with antioxidants can be protective against diabetic nephropathy in people with diabetes¹³ and decrease oxidative stress in people with CF,¹⁴ mechanistic insight into the relationships among oxidative stress, impaired glucose tolerance, and exercise capacity in CF are certainly warranted.

Hemoglobin A_1c (HbA_1c), a measure of glycated hemoglobin, can be used to evaluate glycemic status in people with CF. Hemoglobin A_1c values greater than 5.7%, can predict a positive glucose tolerance test that is diagnostic of CFRD.¹⁴ Glycosylation of hemoglobin allosterically inhibits the hemoglobin molecule, shifting the T-state/R-state equilibrium.¹³ Accordingly, it is plausible that glycated hemoglobin may interfere with the ability of the hemoglobin molecule to not only bind, but also release oxygen and carbon dioxide, resulting in impaired oxygen delivery to skeletal muscle and reduced emission of carbon dioxide by the lungs. Thus, the present investigation sought to test the hypotheses that elevated HbA_1c reduces both the utilization of oxygen and the removal of carbon dioxide during exercise in people with CF and that reductions in systemic oxidative stress using an antioxidant cocktail (AOC) can improve tissue oxygenation in people with CF that exhibit elevated HbA_1c.

Methods

Study participants

Twenty four people with CF (10 males and 14 females) completed the investigation at the Georgia Prevention Institute’s (GPI) Laboratory of Integrative Vascular and Exercise Physiology (LIVEP) at Augusta University. Individuals arrived to the LIVEP in a fasted state after abstaining from exercise for at least 24 h prior to testing. Individuals were instructed to adhere to their normal medications, daily pulmonary treatments, and airway clearance techniques. All protocols were approved by the Institutional Review Board at Augusta University and informed consent/assent was obtained from all individuals and parents of minors. Inclusion criteria required patients to have a clinical diagnosis of CF and be clinically stable for 2 weeks prior to testing. Individuals were excluded if they had a recent CF exacerbation or need for antibiotic treatment within 2 weeks of testing. Following enrollment, individuals were divided into groups based on HbA_1c consistent with predictive diagnostic criteria for CFRD¹³; those with an HbA_1c of <5.7% were included in the normal HbA_1c group (N-HbA_1c), while individuals with HbA_1c > 5.7% comprised the elevated HbA_1c group (E-HbA_1c).

Anthropometric assessment

Upon arrival to the LIVEP, height and weight were determined using a stadiometer and platform scale, and body mass index (BMI) was calculated. Body fat percentage, fat mass, and lean mass were determined using dual energy X-ray absorptiometry (DXA) (QDR-4500W; Hologic, Waltham, MA). Systolic and diastolic blood pressures were obtained using a sphygmomanometer. A venous blood sample was collected from the antecubital fossa to assess blood glucose and HbA_1c using standard core laboratory techniques (Laboratory Corporation of American Holdings, Burlington NC). In addition, a fasting lipid profile was obtained and included concentrations of total cholesterol (TC), high-density lipoproteins (HDL), low-density lipoproteins (LDL), triglycerides (TG). Hemoglobin and hematocrit were measured using a HemoPoint H2 analyzer (Stanbio Laboratories).

Pulmonary function test

Following the guidelines set forth by the American Thoracic Society,¹⁵ a pulmonary function assessment was performed to determine forced vital capacity (FVC), forced expiratory volume in 1 s (FEV₁), FEV₁ percent predicted, FEV₁/FVC, and forced expiratory flow at 25–75% (FEF_25-75) in all individuals as previously described.¹⁶

Cardiopulmonary exercise test

All individuals completed an exercise test to volitional fatigue on a cycle ergometer using the Godfrey protocol. During exercise, expired gases were analyzed as 30 s averages using a TruOne® 2400 metabolic cart (Parvo Medics, Sandy UT) to obtain VO₂ peak and peak minute ventilation (V_E). Additionally, hemodynamics responses were monitored non-invasively both at rest and throughout maximal exercise by patented technology of signal morphology-based impedance cardiography (PhysioFlow®, Ebersviller, France) as previously described by our group.⁷ Ventilatory threshold (VT) was calculated using the v-slope method and was used for determination of VO₂ at VT. Ventilatory parameters were obtained as a ratio of minute ventilation (V_E) to VO₂ and VCO_2, and the V_E/VCO₂ slope was calculated. End-tidal CO₂ (petCO₂) was calculated from expired CO₂. Muscle oxygen consumption (mVO₂) and concentrations of oxygenated and deoxygenated hemoglobin of the vastus lateralis were determined during exercise in a subset of 13 individuals by assessing the deoxygenated hemoglobin concentration using Near-Infrared Spectroscopy (NIRS) (Portalite, Artinis Medical Systems, Elst, The Netherlands). Near-Infrared Spectroscopy provides a novel, noninvasive assessment of skeletal muscle oxygenation during exercise as previously described in CF by our group.⁷

Antioxidant supplementation

A subset of individuals with elevated HbA_1c (n = 7) volunteered to ingest an oral AOC (vitamin C 1000 mg, vitamin E 600 IU, and alpha lipoic acid 600 mg) for 4 weeks to determine the role of oxidative stress on tissue oxygenation during exercise; these data were obtained as part of a clinical trial studying the impacts of antioxidant therapy on people with CF (#NCT02690064). We have previously reported the efficacy of this AOC to improve markers of oxidative stress in people with CF.¹⁷

Statistical analysis

All analyses were performed using SPSS Statistics Version 27. To determine differences in participant characteristics and exercise outcomes between the normal HbA_1c and elevated HbA_1c groups, an analysis of covariance (ANCOVA) was utilized controlling for age, sex, BMI, and percent predicted FEV₁. To determine if changes in deoxygenated Hgb during exercise were different between N-HbA_1c, E-HbA_1c, and individuals taking antioxidants, a two-way (group by time) repeated measures analysis of variance (ANOVA) with a Bonferroni correction was performed. Pearson correlations were performed to assess the relationships between HbA_1c (on a continuum with values ranging from 5.1–6.7) and exercise capacity, ventilatory parameters, and hemoglobin desaturation. Effect sizes for differences in VO₂ peak, VO₂ at VT, VE/VCO₂, and petCO2 are reported as Cohen’s d values to represent small (Cohen’s d = 0.2), medium (Cohen’s d = 0.5), and large (Cohen’s d = 0.8) effect sizes.¹⁸ All group data are reported as mean ± standard deviation (SD) unless otherwise noted. All correlative data are reported as the coefficient of determination (r) and significance was set at p < 0.05.

Results

Patient comorbidities, demographics, laboratory values, and pulmonary function testing

Patient demographics, laboratory values, measures of pulmonary function, and indices of exercise capacity are presented in Table 1. Only four patients had a clinical diagnosis of CFRD and one patient had hypertension. There were four participants under the age of 18 (the youngest was 16 years old) and they were split equally into the two groups. Forty-seven percent of patients were on oral antibiotics and 29% were on an inhaled antibiotic regimen. Hemoglobin A_1c was significantly different between groups. In addition, absolute FEV₁ was lower in the E-HbA_1c group (p = 0.019); however, no significant difference in percent predicted FEV₁ was observed. Furthermore, hemoglobin concentration was lower in the E-HbA_1c group (p = 0.026). No other differences for any other demographic or pulmonary function values were observed between groups. Cardiopulmonary values at baseline and during maximal exercise in both groups are presented in Table 2. The cardiopulmonary responses to exercise were similar (all variables p > 0.05); however, absolute VO₂ (l/min) was different between groups.

Table 1.

Patient demographics and pulmonary function values.

Variable	All individuals (n = 24)	N-HbA_1c (n = 11)	E-HbA_1c (n = 13)	p-value
Sex (M/F)	10/14	6/5	4/9	n/a
Age (y)	28.3 ± 12.6	23.5 ± 6.4	32.5 ± 15.2	0.258
HbA_1c (%)	6.0 ± 1.3	5.3 ± 0.16	6.6 ± 1.5	0.015*
BMI (kg/m²)	22.7 ± 2.8	22.8 ± 2.6	22.7 ± 3.1	0.952
Body fat (%)	30.2 ± 7.4	29.0 ± 7.6	31.3 ± 7.3	0.473
Lean Mass (kg)	40.8 ± 10.8	42.8 ± 11.8	38.9 ± 10.0	0.406
SBP (mmHg)	114 ± 12	111 ± 10	118 ± 13	0.199
DBP (mmHg)	72 ± 9	70 ± 7	73 ± 11	0.557
O₂ saturation (%)	98 ± 1	97 ± 1	98 ± 1	0.498
Hgb (g/dL)	14.2 ± 2.0	15.0 ± 1.6	13.5 ± 2.1	0.072
FEV₁ (L/min)	2.74 ± 0.93	3.04 ± 1.21	2.46 ± 0.52	0.183
FEV₁ (% predicted)	73 ± 17	76 ± 16	70 ± 17	0.385
FVC (L/min)	3.37 ± 0.96	3.14 ± 1.13	3.68 ± 0.76	0.508
FEV₁/FVC (%)	71 ± 12	69 ± 17	73 ± 7	0.552
FEF_25-75% (L/s)	2.22 ± 0.98	2.55 ± 1.14	1.92 ± 0.74	0.164

Notes: Values are mean ± SD. BMI, body mass index, SBP, systolic blood pressure, DBP, diastolic blood pressure, GLU, fasting blood glucose, Hgb, hemoglobin, FEV₁, forced expiratory volume in 1 s, FVC, forced vital capacity, FEF_25-75%, forced expiratory flow over the middle one-half of the FVC. *Significant difference between groups (p < 0.05).

Table 2.

Cardiopulmonary measures at baseline and maximal exercise between groups.

Variable	N-HbA1c		E-HbA1c
	Baseline (n = 11)	Maximal (n = 11)	Baseline (n = 13)	Maximal (n = 13)	Interaction p-value
	Baseline (n = 11)	Maximal (n = 11)	Baseline (n = 13)	Maximal (n = 13)	Interaction p-value	HR (bpm)	83 ± 11	153 ± 57	88 ± 18	152 ± 41	0.955
SV (mL)	72 ± 15	95 ± 32	68 ± 21	90 ± 35	0.843
CO (L/min)	6.2 ± 1.1	16.6 ± 5.2	5.7 ± 1.5	13.4 ± 3.8	0.114
MAP (mmhg)	55 ± 39	111 ± 14	67 ± 36	105 ± 17	0.229
VO₂ peak (L/min)		1.71 ± 0.46		1.34 ± 0.52	0.045

Notes: Values are mean ± SD. HR, heart rate, SV, stroke volume, CO, cardiac output, MAP, mean arterial pressure.

Exercise capacity, ventilatory parameters, and hemoglobin desaturation at VT

Figure 1 illustrates the differences in VO₂ peak, ventilatory parameters, and deoxygenated hemoglobin between groups, controlling for lung function, age, and BMI. Exercise capacity (Figure 1(a); p = 0.021, Cohen’s d = 0.796) and exercise capacity at VT (Figure 1(b); p = 0.004, Cohen’s d = 0.783) were both significantly higher in the N-HbA_1c group compared with the E-HbA_1c group. In addition, V_E/VCO₂ slope was significantly (Figure 1(c); p = 0.004, Cohen’s d = −0.559) lower and petCO₂ (Figure 1(d); p = 0.002, Cohen’s d = 0.754) was higher in the N-HbA_1c group compared with the E-HbA_1c group. In contrast, no significant difference between ventilation was observed between groups. Figure 2 illustrates the associations between exercise indices and HbA_1c corrected for age and BMI. Negative relationships between HbA_1c and both VO₂ peak (r = −0.411; p = 0.064; Figure 2(a)) and VO₂ peak at VT (r = −0.511; p = 0.018; Figure 2(b)) were observed. V_E/VCO₂ slope was positively correlated (r = 0.587; p = 0.005) with HbA_1c (Figure 2(c)) and petCO₂ was inversely proportional (r = −0.473; p = 0.031) to HbA_1c (Figure 2(d)).

Figure 1.

Differences in indices of exercise capacity (a–b) and ventilatory parameters (c–d) between individuals in the N-HbA_1c and E-HbA_1c groups.

Figure 2.

Associations between exercise variables and HbA_1c (%).

Hemoglobin desaturation during maximal exercise

The change in deoxygenated hemoglobin throughout maximal exercise in patients with normal and elevated HbA_1c is presented in Figure 3. A significant interaction (p = 0.046) was observed for the deoxygenated hemoglobin response between groups. Specifically, deoxygenated hemoglobin during exercise was greater at 60% (p = 0.007), 80% (p = 0.026), and 100% (p = 0.089) of VO₂ max in the N-HbA_1c group compared to the E-HbA_1c. In addition, Figure 3 illustrates that treatment with 4 weeks of antioxidants in a subgroup of patients (n = 7) with E-HbA_1c is able to restore the deoxygenated hemoglobin response to exercise to similar values observed in the N-HbA_1c group. In addition, a significant negative association (r = −0.625; p = 0.004) between concentrations of deoxygenated hemoglobin of the vastus lateralis at VT and HbA_1c was observed.

Figure 3.

Deoxygenated hemoglobin concentration by percent VO₂ in the N-HbA_1c (n = 11) and E-HbA_1c (n = 13) groups, and a subset of individuals (n = 7) with an average elevated HbA_1c (average HbA_1c = 5.8%) following 4-weeks of antioxidant supplementation. *Significant from N-HbA_1c and AOC.

Discussion

Exercise intolerance can predict morbidity and mortality in people with CF, independent of lung function.^19,20 Although the mechanisms for exercise intolerance in CF have yet to be fully elucidated, adequate tissue oxygenation and efficient removal of metabolically produced carbon dioxide from the body are critical to maintain exercise capacity. Previous research shows that poor glucose control is associated with reduced exercise capacity in children with CF¹¹; however, findings from the present investigation have identified that glycemic status can affect exercise physiology in people with CF. Specifically, individuals in the N-HbA_1c group had higher exercise capacity, greater hemoglobin desaturation, decreased CO₂ retention, and decreased V_E/VCO₂ slope compared to individuals in the E-HbA_1c group. In addition, present findings demonstrate that supplementation with an AOC for 4 weeks can improve skeletal muscle oxygen utilization during exercise in a subset of individuals with elevated HbA_1c.

Hemoglobin A_1c and exercise capacity

Findings from the present study demonstrate that higher HbA_1c can negatively impact exercise capacity in people with CF. For decades, the conventional wisdom was that poor lung function limits exercise ability in people with CF; however, recent data support that lung dysfunction is not the primary driver for exercise intolerance among people with mild to moderate CF.^1,21 Decreased exercise capacity and skeletal muscle dysfunction have been observed in people with Type 2 diabetes and is likely due, in part, to fat infiltration and metabolic dysregulation of the functional muscle.²² In addition, poor glycemic control, a strong predictor of increased morbidity and mortality, can contribute to worsening of exercise capacity among individuals with Type 2 diabetes.²³ Limited data support the association between CFRD and exercise intolerance in children with CF.¹¹ However, more recently, no association between CFRD and maximal aerobic capacity was observed in physically active people with CF.¹² Individuals with poor glycemic control in the present study not only had lower exercise capacity compared to those in the N-HbA_1c group, but exercise capacity at VT was also lower in the E-HbA_1c group. Impairment in exercise capacity at VT is particularly revealing, as this variable is a direct measure of submaximal aerobic exercise tolerance. The body primarily relies on oxygen to produce cellular energy during aerobic exercise; therefore, VO₂ at VT is indicative of the body’s availability of oxygen while performing aerobic respiration.⁸ These findings suggest that elevated glycosylated hemoglobin can impair oxidative metabolism during exercise in individuals with CF. It is important to note that individuals in the E-HbA_1c group had lower FEV₁ compared to those in the N-HbA_1c group; however, percent predicted FEV₁ was similar. Accordingly, the difference in absolute lung function is likely due to the sex differences between groups, as more females were in the E-HbA_1c group. Additionally, sex, age, and BMI can contribute to the differences in exercise capacity^24–26 reported in people with CF. Accordingly, percent predicted FEV₁, sex, age, and BMI were used as covariates in analyses. Indeed, it is important to note that controlling for these variables did not change the overall findings that glycosylated hemoglobin can affect exercise parameters in CF. In general, there are also sex differences between exercise capacity, with men having an overall higher exercise performance than women.^27,28 The low number of patients with CF in our area prevented our group from obtaining an equal representation of sex within groups. Furthermore, there was no data on physical activity status in this cohort; however, we understand that physical activity may influence VO₂ max in individuals with CF.

Hemoglobin A_1c and ventilation efficiency

The mechanism by which oxygen and carbon dioxide are carried in the blood is complex. Briefly, the hemoglobin molecule moves between the T-state/deoxygenated state and the R-state/oxygenated state²⁹ dependent upon the body’s demand to maintain physiologic homeostasis. As described by the Bohr effect, the presence of excess CO₂ in the blood generally decreases the molecule’s affinity for oxygen and promotes release of oxygen to the tissue, while the lack of CO₂ increases the molecule’s affinity for oxygen. Similarly, the Haldane effect describes that oxygen-rich hemoglobin has a decreased affinity for carbon dioxide while oxygen-depleted hemoglobin has an increased affinity for carbon dioxide.³⁰ Therefore, the allostery of the hemoglobin molecule is responsible for oxygen delivery to the tissue as well as transporting carbon dioxide to the lungs for removal. Paradoxically, individuals within the E-HbA_1c group had increased carbon dioxide retention but decreased hemoglobin desaturation and subsequent impairment of tissue oxygenation during exercise. It is therefore probable that glycated hemoglobin disrupts the T-state/R-state equilibrium in people with CF. In individuals without CF, studies demonstrate that people with increased HbA_1c have decreased tissue oxygen utilization which contributes to increased oxygenated venous blood.³¹ Additionally, glucose can alter the quaternary structure of the T-state, leading to higher affinity for oxygen and less tissue oxygenation during physiologic stress. The present investigation demonstrates that HbA_1c is associated with not only decreased hemoglobin desaturation, but also abnormal ventilatory parameters during exercise in people with CF. Specifically, these findings demonstrate that individuals within the E-HbA_1c group have lower concentrations of muscle deoxygenated hemoglobin during exercise, higher V_E/VCO₂ slope, and lower petCO₂ during exercise compared with those in the N-HbA_1c group, independent of changes in ventilation. These data support our hypothesis in people with CF, that impaired glycemic control can contribute to decreases in the (1) unloading oxygen to the skeletal muscle, and (2) expiring carbon dioxide by the lungs during exercise, with both leading to this paradox of the Bohr and Haldane effect.

Hemoglobin A_1c and deoxygenated hemoglobin saturation: Role of oxidative stress

Oxidative stress is a common phenotype in both CF and diabetes and can contribute to heightened inflammation and microvascular dysfunction.^32,33 Findings from the present investigation have identified that individuals in the E-HbA_1c group not only have a lower muscle deoxygenated hemoglobin at VT compared with individuals in the N-HbA_1c group, but that the change in deoxygenated hemoglobin throughout exercise was lower in the E-HbA_1c group. This finding indicates that skeletal muscle dysfunction may exist even during aerobic exercise when oxygen is the major source of cellular respiration. Interestingly, 4 weeks of treatment with an AOC in individuals with E-HbA_1c was able to restore the concentration of deoxygenated hemoglobin during exercise to the levels observed in the N-HbA_1c group (Figure 3). Our group has previously published the efficacy of the AOC used in the present study to reduce the characteristic “triplet of doublets” EPR signal, which is proportional to the concentration of O₂ centered alkoxyl free radical species.³⁴ In addition, treatment with the AOC contributes to improvement in vascular endothelial function mediated in people with CF that is mediated by an increase in nitric oxide bioavailability.¹⁷ While no significant relationships were found between concentrations of deoxygenated hemoglobin and HbA_1c and the impact of treatment with AOC on deoxygenated hemoglobin, the small sample size of this sub-group analysis likely contributed to this analysis being underpowered. Nonetheless, findings from the present study demonstrate that glycosylated hemoglobin in individuals with CF negatively affects tissue oxygenation during exercise. In addition, the present investigation has provided provocative proof-of-concept data to support that antioxidant supplementation and a subsequent reduction in oxidative stress may improve tissue saturation during exercise. It is plausible to expect that increases in skeletal muscle oxygen utilization, likely influenced by decreased oxidative stress, can increase exercise capacity, and likely explains the differences in VO₂ peak between groups. Future studies are certainly needed to provide mechanistic insight into how reducing oxidative stress in these individuals can increase exercise capacity.

Experimental considerations

The present investigation is the first to provide mechanistic insight into how glycated hemoglobin can affect exercise capacity and ventilatory efficiencies in people with cystic fibrosis (PwCF). However, given the nature of this preliminary investigation, there are some limitations to consider when interpreting the data. First, the sample size and open label experimental design to test the hypothesis that reductions in oxidative stress can improve tissue oxygenation during exercise in CF should be considered. Importantly, the effect sizes for the between group comparisons are robust; however, we are unable to determine the impact that sex or genotype may have on the differences between groups. In addition, although the present investigation presents experimental data following antioxidant supplementation in only seven PwCF who exhibit E-HbA_1c, the results are extremely compelling. Nonetheless, larger, multi-center, randomized, placebo-controlled clinical trials over a longer period of time are needed to fully exploit this hypothesis and determine whether antioxidant supplementation can also reduce glycated hemoglobin and improve exercise capacity. Second, the present investigation supports that increased glycated hemoglobin can impair exercise capacity in PwCF; however, it is still unclear if exercise capacity is actually impacted in PwCF who have CFRD. It is important to note that only four patients in the present investigation had a clinical diagnosis of CFRD and the use of HbA_1c as a diagnostic tool for CFRD has been a matter of debate.^35–37 Given the accelerated disease severity in CFRD and the fact that exercise capacity can predict survival in CF, independent of lung function, future studies are needed to understand if and how CFRD affects exercise tolerance in CF. Third, NIRS represents a novel, non-invasive methodology to investigate skeletal muscle O₂ delivery and extraction. However, this technique is dependent on the placement and penetration depth of the signal and only provides a global surrogate of tissue perfusion and utilization. The placement of the NIRS on the vastus lateralis muscle was carefully chosen and ultrasound was used to assess the adipose tissue thickness to ensure adequate penetration of the NIRS device. However, molecular and more invasive studies to investigate skeletal muscle perfusion and skeletal muscle oxidative metabolism are needed to identify the specific level of skeletal muscle dysregulation.

Conclusion

The present study has demonstrated that elevated glycosylated hemoglobin plays a negative role in exercise capacity and ventilatory equivalents in both children and adults with CF. An increased concentration of glycated hemoglobin may impair muscle oxygenation, ventilation efficiency, and CO₂ elimination during exercise in people with CF. Based on the present findings, it is possible that glycosylation inhibits the ability of the hemoglobin molecule to not only release oxygen to the working muscle but also to unload the carbon dioxide at the lungs. Impaired allostery can lead to decreased utilization of oxygen and increased retention of carbon dioxide, both of which contribute to exercise intolerance in people with CF. Our data also support that reducing oxidative stress can improve oxygen unloading at the muscle during exercise. Decreasing oxidative stress through antioxidant supplementation in people with CFRD may improve exercise capacity, thereby, decreasing their risk for disease-related morbidity and mortality.

Footnotes

Acknowledgments

The authors would like to thank all of the participants and their families for their contribution to this study and dedication to continuing CF research. Results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. Results of the present study do not constitute endorsement by ACSM.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was supported by CF Foundation Therapeutics (Harris14A0 and Harris19A0) and NIH (R21DK100783) to RAH.

ORCID iD

Ryan A Harris

References

Nixon

Orenstein

Kelsey

, et al. The prognostic value of exercise testing in patients with cystic fibrosis. N Engl J Med 1992; 327(25): 1785–1788.

Moorcroft

Dodd

Webb

. Long-term change in exercise capacity, body mass, and pulmonary function in adults with cystic fibrosis. Chest 1997; 111(2): 338–343.

Brunelli

. Ventilatory efficiency slope: an additional prognosticator after lung cancer surgery. Eur J Cardiothorac Surg 2016; 50(4): 780–781.

Brunelli

Belardinelli

Pompili

, et al. Minute ventilation-to-carbon dioxide output (VE/VCO2) slope is the strongest predictor of respiratory complications and death after pulmonary resection. Ann Thorac Surg 2012; 93(6): 1802–1806.

Poggio

Arazi

Giorgi

, et al. Prediction of severe cardiovascular events by VE/VCO2 slope versus peak VO2 in systolic heart failure: a meta-analysis of the published literature. Am Heart J 2010; 160(6): 1004–1014.

Tucker

Lee

Rodriguez-Miguelez

, et al. Exercise testing in patients with cystic fibrosis-importance of ventilatory parameters. Eur J Appl Physiol 2019; 119(1): 227–234.

Rodriguez-Miguelez

Seigler

Ishii

, et al. Exercise intolerance in cystic fibrosis: importance of skeletal muscle. Med Sci Sports Exerc 2021; 53(4): 684–693.

Hebestreit

Staschen

Hebestreit

. Ventilatory threshold: a useful method to determine aerobic fitness in children? Med Sci Sports Exerc 2000; 32(11): 1964–1969.

Hwang

. CFTR: a missing link between exocrine and endocrine pancreas? Sci China Life Sci 2014; 57(10): 1044–1045.

10.

Sandouk

Khan

Khare

, et al. Cystic fibrosis related diabetes (CFRD) prognosis. J Clin Transl Endocrinol 2021; 26: 100278.

11.

Foster

Huang

Zhang

, et al. Relationship between exercise capacity and glucose tolerance in cystic fibrosis. Pediatr Pulmonol 2018; 53(2): 154–161.

12.

Radtke

Kriemler

Stein

, et al. Cystic fibrosis related diabetes is not associated with maximal aerobic exercise capacity in cystic fibrosis: a cross-sectional analysis of an international multicenter trial. J Cyst Fibros 2023; 22(1): 31–38.

13.

De Rosa

Sanna

Messana

, et al. Glycated human hemoglobin (HbA1c): functional characteristics and molecular modeling studies. Biophys Chem 1998; 72(3): 323–335.

14.

Burgess

Bridges

Banya

, et al. HbA1c as a screening tool for cystic fibrosis related diabetes. J Cyst Fibros 2016; 15(2): 251–257.

15.

Culver

Graham

Coates

, et al Recommendations for a standardized pulmonary function report. An official American thoracic society technical statement. Am J Respir Crit Care Med 2017; 196(11): 1463–1472.

16.

Tucker

Crandall

Seigler

, et al. A single bout of maximal exercise improves lung function in patients with cystic fibrosis. J Cyst Fibros 2017; 16(6): 752–758.

17.

Tucker

Fox

Seigler

, et al. Endothelial dysfunction in cystic fibrosis: role of oxidative stress. Oxid Med Cell Longev 2019; 2019: 1629638.

18.

Cohen

. Eta-squared and partial Eta-squared in fixed factor anova designs. Educ Psychol Measurement 1973; 33(1): 107–112.

19.

Radtke

Nolan

Hebestreit

, et al. Physical exercise training for cystic fibrosis. Cochrane Database Syst Rev 2015; 6: CD002768.

20.

Perez

Groeneveld

Santana-Sosa

, et al. Aerobic fitness is associated with lower risk of hospitalization in children with cystic fibrosis. Pediatr Pulmonol 2014; 49(7): 641–649.

21.

Pianosi

Leblanc

Almudevar

. Peak oxygen uptake and mortality in children with cystic fibrosis. Thorax 2005; 60(1): 50–54.

22.

Fang

Sharman

Prins

, et al. Determinants of exercise capacity in patients with type 2 diabetes. Diabetes Care 2005; 28(7): 1643–1648.

23.

Bianchi

Volpato

. Muscle dysfunction in type 2 diabetes: a major threat to patient's mobility and independence. Acta Diabetol 2016; 53(6): 879–889.

24.

Shei

Mackintosh

Peabody Lever

, et al. Exercise physiology across the lifespan in cystic fibrosis. Front Physiol 2019; 10: 1382.

25.

Fomin

Ahlstrand

Schill

, et al. Sex differences in response to maximal exercise stress test in trained adolescents. BMC Pediatr 2012; 12: 127.

26.

Ribisl

Lang

Jaramillo

, et al. Exercise capacity and cardiovascular/metabolic characteristics of overweight and obese individuals with type 2 diabetes: the Look AHEAD clinical trial. Diabetes Care 2007; 30(10): 2679–2684.

27.

Thomas

West

Browning

, et al. Why women are not small men: sex-related differences in perioperative cardiopulmonary exercise testing. Perioper Med (Lond) 2020; 9: 18.

28.

Flammer

Anderson

Celermajer

, et al. The assessment of endothelial function: from research into clinical practice. Circulation 2012; 126(6): 753–767.

29.

Ahmed

Ghatge

Safo

. Hemoglobin: structure, function and allostery. Subcell Biochem 2020; 94: 345–382.

30.

Teboul

Scheeren

. Understanding the Haldane effect. Intensive Care Med 2017; 43(1): 91–93.

31.

Hammer

Vilser

Riemer

, et al. Diabetic patients with retinopathy show increased retinal venous oxygen saturation. Graefes Arch Clin Exp Ophthalmol 2009; 247(8): 1025–1030.

32.

Rodriguez-Miguelez

Thomas

Seigler

, et al. Evidence of microvascular dysfunction in patients with cystic fibrosis. Am J Physiol Heart Circ Physiol 2016; 310(11): H1479–H1485.

33.

Vithian

Hurel

. Microvascular complications: pathophysiology and management. Clin Med 2010; 10(5): 505–509.

34.

Harris

Nishiyama

Wray

, et al. The effect of oral antioxidants on brachial artery flow-mediated dilation following 5 and 10 min of ischemia. Eur J Appl Physiol 2009; 107(4): 445–453.

35.

Kilpatrick

Bloomgarden

Zimmet

. Is haemoglobin A1c a step forward for diagnosing diabetes? BMJ 2009; 339: b4432.

36.

Chan

Hope

Thurston

, et al. Hemoglobin A(1c) accurately predicts continuous glucose monitoring-derived average glucose in youth and young adults with cystic fibrosis. Diabetes Care 2018; 41(7): 1406–1413.

37.

Lanng

Hansen

Thorsteinsson

, et al. Glucose tolerance in patients with cystic fibrosis: five year prospective study. BMJ 1995; 311(7006): 655–659.

Muscle oxygen utilization and ventilatory parameters during exercise in people with cystic fibrosis: Role of HbA 1c

Abstract

Introduction

Methods

Results

Conclusion

Keywords

Introduction

Methods

Study participants

Anthropometric assessment

Pulmonary function test

Cardiopulmonary exercise test

Antioxidant supplementation

Statistical analysis

Results

Patient comorbidities, demographics, laboratory values, and pulmonary function testing

Exercise capacity, ventilatory parameters, and hemoglobin desaturation at VT

Hemoglobin desaturation during maximal exercise

Discussion

Hemoglobin A1c and exercise capacity

Hemoglobin A1c and ventilation efficiency

Hemoglobin A1c and deoxygenated hemoglobin saturation: Role of oxidative stress

Experimental considerations

Conclusion

Footnotes

Acknowledgments

Declaration of conflicting interests

Funding

ORCID iD

References

Hemoglobin A_1c and exercise capacity

Hemoglobin A_1c and ventilation efficiency

Hemoglobin A_1c and deoxygenated hemoglobin saturation: Role of oxidative stress