Diabetes is associated with increased cardiovascular risk independent of CAD or hypertension (11). Peak O2 uptake (V·O2peak) is a strong predictor of the risk of cardiovascular complications (40). Available data on the relation between type 1 diabetes and V·O2peak are contradictory: Both reduced (13,14,19,20,28,31) and similar (4,29,37,39) V·O2peak have been observed in patients with type 1 diabetes compared with that in healthy subjects. Importantly, several studies have reported that poor glycemic control reduces V·O2peak in patients with type 1 diabetes (4,13,19,29,37), albeit absence of such association has also been reported (14,20,28,31,39).
In healthy subjects, V·O2peak may be affected by limitations of pulmonary gas exchange (9), limitations of cardiac output (CO), redistribution of blood flow to active skeletal muscles, and skeletal muscle O2 extraction and use (34). In type 1 diabetes, both central and peripheral mechanisms are potential contributors to V·O2peak reduction. Reduced ventilation at peak exercise (19), impaired lung diffusion capacity (29,39), reduced HRmax (14,19), ventricular diastolic dysfunction during exercise (13), and concomitant limitations of stroke volume (SV) and CO (4,13,14,29) have been observed in patients with type 1 diabetes. In addition, our findings on faster active muscle deoxygenation in patients with type 1 diabetes (31) may also reflect limited ability to increase central and peripheral O2 delivery during increasing O2 demand. Patients with type 1 diabetes (20), similar to patients with type 2 diabetes (24), have reduced blood volume (BV), which is likely one component of their ventricular diastolic dysfunction, as BV strongly correlates with diastolic filling rate (22). Peripheral vascular function (5,15,28,32), and herewith, peripheral O2 delivery to active muscles, may also be impaired in type 1 diabetes. Reduced leg blood flow, independent of CO, has been reported in patients with type 2 diabetes during submaximal exercise (25), suggesting maldistribution of active muscle blood flow. However, no studies to date have simultaneously examined the contribution of central and peripheral mechanisms to V·O2peak in patients with type 1 diabetes.
The impedance cardiography method provides valid noninvasive evaluation of SV and CO at rest and during exercise (7,33). Near infrared spectroscopy (NIRS) is a valid noninvasive method used, for example, for monitoring active muscle deoxygenation status representing local imbalance between O2 delivery and use during exercise (8,12,27). The NIRS signal obtained can also be converted to reflect local blood flow in the active vastus lateralis muscle (Q·VL) (27). In this study, we hypothesized that men with type 1 diabetes would have lower V·O2peak than healthy control men matched for age, anthropometry, and self-reported leisure time physical activity (LTPA). To examine the contribution of central and peripheral mechanisms to the hypothetically lower V·O2peak, we simultaneously used the two noninvasive methods and compared cardiorespiratory and active leg muscle tissue responses to incremental exercise in the group with diabetes with those in the controls. We also determined BV of the subjects to examine its associations with cardiac responses to exercise.
Seventeen male volunteers participated in the study. Seven of the subjects were patients with type 1 diabetes, were normoalbuminuric, had normal glomerular filtration ratio, and had no evidence of neuropathy, retinopathy, hypertension, or chronic diseases other than their diabetes. Ten of the subjects were age-, anthropometry-, and self-reported LTPA-matched healthy controls. The subjects were not smoking, and none of them were on regular medication other than insulin (multiple daily injections) for diabetes. Every subject gave a written informed consent to participate in the study, which conformed to the Declaration of Helsinki and was approved by the ethics committee of the Hospital District of Helsinki and Uusimaa, Helsinki, Finland.
The subjects visited the laboratory three times within 7 d. Every visit was preceded by abstinence from physical exercise for at least 12 h and alcohol for at least 24 h. At the first visit, the subjects reported to the laboratory after overnight fast and their antecubital venous blood was drawn for measurement of glycosylated hemoglobin (HbA1c).
At the second and third visits, the subjects reported to the laboratory 2–3 h after a meal. The second visit consisted of preexercise measurements and a cardiorespiratory exercise test. The subjects completed a preliminary questionnaire concerning personal health and medical history; LTPA was obtained from a question regarding the total average time spent performing recreational exercise weekly. The subjects’ height was measured, and body composition was determined by the bioimpedance method (InBody 720; Biospace Co., Ltd., Seoul, South Korea). Thickness of subcutaneous fat was measured with skinfold calipers at the NIRS recording site described (vide infra). Preexercise measurements at rest also included a 12-lead ECG, blood pressure, and flow–volume spirometry (Medikro Spiro 2000; Medikro Oy, Kuopio, Finland), and a physician examined the subjects to ensure suitability for exercise testing. Capillary blood was drawn from a fingertip to analyze blood glucose concentration (Glucocard X-meter; Arkray Factory, Inc., Shiga, Japan) before the exercise test; all subjects in the group with diabetes had glucose levels between 5.6 and 13.9 mM with no signs of ketosis, according to published guidelines (1). The cardiorespiratory exercise test was performed on a cycle ergometer (Monark Ergomedic 839E; Monark Exercise AB, Vansbro, Sweden). The step incremental protocol was preceded by a 5-min rest while the subjects sat relaxed on the ergometer, followed by 5-min baseline unloaded cycling. Incremental exercise (40 W per 3 min) was then initiated with a work rate of 40 W, and the subjects continued exercising until volitional fatigue.
At the third visit, BV was determined by the optimized carbon monoxide rebreathing method (SpiCO; Blood tec GbR, Bayreuth, Germany) (35). Relative BV was calculated as the quotient of absolute BV and fat-free mass (FFM). Capillary blood was drawn from a fingertip to analyze hemoglobin concentration ([Hb]) and the fraction of carboxyhemoglobin by a blood gas analyzer (ABL725; Radiometer, Copenhagen, Denmark).
Breath-by-breath ventilation was measured by a low-resistance turbine (Triple V; Jaeger Mijnhardt, Bunnik, The Netherlands) during the exercise test. Expired and inspired gases were sampled continuously at the mouth and analyzed for concentrations of O2, CO2, N2, and Ar by mass spectrometry (AMIS 2000; Innovision A/S, Odense, Denmark) after calibration with precisely analyzed gas mixtures.
HR and the electrical activity of the heart were continuously monitored by ECG (PowerLab; ADInstruments, Oxford, United Kingdom). An impedance cardiograph device (PhysioFlow; Manatec Biomedical, Paris, France) was used to evaluate cardiac function. This method has been described in detail elsewhere (7) and found valid and reliable at rest and during low- to maximal-intensity exercise in healthy, normal-weight, and overweight individuals (7,33). Briefly, the method uses changes in transthoracic impedance during cardiac ejection to calculate SV, which is multiplied by HR to provide an estimate of CO. Estimates of end-diastolic volume (EDV) and ejection fraction are also provided. Systolic and diastolic blood pressures were measured automatically (Tango+; SunTech Medical, Morrisville, NC) from the brachial artery at rest and at the end of each work rate and transferred into the impedance cardiograph device, which calculated mean arterial pressure to estimate systemic vascular resistance (SVR). The impedance cardiograph data were averaged in 15-s intervals. Arterial O2 saturation (SpO2) was monitored by fingertip pulse oximetry (Nonin 9600; Nonin Medical, Inc., Plymouth, MA), and RPE was obtained using the Borg scale (6–20) at the end of each work rate.
Arterial O2 content (CaO2) was calculated as the product of [Hb], SpO2, and the physiologic O2 binding coefficient of hemoglobin (1.34 mL·g-1), as follows: CaO2 (mL O2·L-1 blood) = [Hb] × SpO2 × 1.34. Whole body arterial–venous O2 difference (C(a–v)O2) was derived using the Fick principle, as follows: C(a–v)O2 (mL O2·L-1 blood) = V·O2/CO, where V·O2 is pulmonary O2 uptake.
For the group comparisons, EDV, SV, and CO were divided and SVR was multiplied by FFM to minimize effects of any body size differences on cardiovascular variables (38) and were referred as indices (EDVi, SVi, COi, and SVRi, respectively).
Leg muscle deoxygenation and blood flow measurements.
Exercise-induced changes in active leg muscle deoxygenation and Q· VL were examined using a continuous wave NIRS system (Oxymon Mk III near infrared spectrophotometer; Artinis Medical Systems, Zetten, The Netherlands). The NIRS probe consisted of one receiving and three transmitting optodes operating at wavelengths of 765 and 860 nm, and it was placed over the vastus lateralis muscle of the right leg at midthigh level and parallel to the long axis of the muscle. The optodes were housed in an optically dense plastic holder, attached to the skin by a double-sided adhesive tape, and covered by an elastic tape. The interoptode distance was set to 35 or 40 mm to reach good signal quality before the measurements.
Leg muscle deoxygenation status representing local imbalance between O2 delivery and use was estimated by recording deoxyhemoglobin ([DELTA][HHb]) (8,12,27). The theory of NIRS and its use in exercise measurements have been described in detail elsewhere (12). Briefly, the intensity of incident and transmitted light is recorded continuously and, along with the specific optical path length and extinction coefficients, used for online estimation and display of concentration changes from the resting baseline of [DELTA][HHb]. The differential path length factor value used was 5.51 (10), and a sampling frequency of 10 Hz was used for collecting NIRS data. The obtained NIRS data were averaged to give values in 1-s intervals and time-aligned with the cardiorespiratory data. The averaged [DELTA][HHb] responses were then normalized (%[DELTA][HHb]), such that 0% represents the mean steady-state value of the last 30 s of the unloaded cycling and 100% represents the highest mean value of the last 30 s of any work rate. The rationale for this, instead of comparing values with the values at rest, was that muscle pump activation expels blood from the muscles toward the heart at the onset of exercise, which is expected to induce rapid temporary changes in NIRS measurements (8).
The determination of Q·VL was performed as previously described (27). Peripheral arterial–venous O2 difference ((a–v)O2) was estimated from the pattern of %[DELTA][HHb] using published values for muscle (a–v)O2 (17,18), which was thus assumed to equal 10 mL per 100 mL of blood during unloaded cycling (18) and 18 mL per 100 mL of blood at peak exercise (17). The following formula was then used to convert the normalized change in %[DELTA][HHb] to peripheral (a–v)O2:
where 10 corresponds to the assumed (a–v)O2 during unloaded cycling and 8 corresponds to the assumed change in (a–v)O2 from unloaded cycling to peak exercise. Thus, second-by-second Q·VL was calculated (Fick principle) for each subject as the quotient of V·O2 (measured) and peripheral (a–v)O2 (as described immediately in a previous section). The V·O2 values used in this context were time-aligned with %[DELTA][HHb] by left-shifting the V·O2 signal by 20 s to account for the circulatory transit delay between the muscle and lung (27). Although the 20-s value may not precisely match the circulatory time delay in every subject, it represents a reasonable estimate for the subjects tested (26).
The mean values of the last 30 s at rest, during unloaded cycling, at each work rate, and at peak exercise were chosen for further analyses. V·O2peak was determined as the highest value of a 60-s moving averaging interval. V·O2peak provided the major determinant of sample size; a priori calculation of statistical power for V·O2peak was based on <5% risk of type I error, 80% statistical power, and expected 19% difference between the subject groups with 16% SD (31). Thus, at least seven subjects were required in both subject groups. The Shapiro–Wilk test was used to check for normality. Two-tailed independent samples t-test was used to compare the subject groups. Relations between key variables were determined by the Pearson correlation coefficient. Repeated-measures ANOVA with Sidak post hoc analysis was used to compare %[DELTA][HHb] and Q·VL values at each work rate with those during unloaded cycling. Statistical significance was defined at P < 0.05, and all data are expressed as mean ± SD. The results were computed with PASW Statistics 18.0 (IBM Corporation, Somers, NY).
Descriptive characteristics of the subjects.
The anthropometric, physical activity, hematologic, and spirometric data of the subjects are presented in Table 1. The group with diabetes had higher HbA1c than controls. The difference of absolute BV between the groups missed significance, whereas the group with diabetes had significantly lower relative BV. The groups had similar [Hb]. No defects or differences between the groups were observed in the flow–volume spirometry measurements. In addition to the data in Table 1, a similar thickness in subcutaneous fat of the vastus lateralis muscle (8 ± 3 vs 8 ± 3 mm, P = 0.984) was observed in the group with diabetes and controls, respectively, and similar systolic (126 ± 19 vs 120 ± 19 mm Hg, P = 0.484) and diastolic (77 ± 7 vs 81 ± 12 mm Hg, P = 0.420) resting blood pressures were also observed in the group with diabetes and controls, respectively.
The V·O2 and cardiovascular responses are presented in Figure 1. The work rates and cardiorespiratory responses at peak exercise are presented in Table 2. The group with diabetes attained lower peak work rate and V·O2peak than controls. Ventilation, RER (1.20 ± 0.06 vs 1.16 ± 0.03, P = 0.072), partial pressure of end-tidal CO2 (35.4 ± 5.5 vs 34.3 ± 5.9 mm Hg, P = 0.693), and RPE (20 ± 1 vs 19 ± 1, P = 0.698) were similar between the group with diabetes and controls, respectively, at peak exercise, indicating that both groups made their maximal effort during the exercise test. No subject was hypoglycemic or near hypoglycemia immediately before the exercise test or at its termination.
SpO2 and CaO2 were similarly maintained in the groups throughout the exercise. At peak exercise, the group with diabetes had lower SVi and COi and higher SVRi than controls. The differences of peak EDVi, peak EDV (161 ± 30 vs 166 ± 23 mL, P = 0.684), peak SV (112 ± 14 vs 121 ± 19 mL, P = 0.313), peak ejection fraction (69% ± 8% vs 73% ± 9%, P = 0.345), HRmax, peak CO (19.8 ± 2.5 vs 22.3 ± 4.4 L·min-1, P = 0.216), and peak systolic and diastolic blood pressures between the group with diabetes and controls, respectively, missed significance. Similar hyperbolic responses of C(a–v)O2 were seen in the groups throughout the exercise.
Absolute BV correlated with peak EDV (r = 0.45, P < 0.05), peak SV (r = 0.85, P < 0.001), and peak CO (r = 0.78, P < 0.001) in all subjects. The peak EDV/BV (24 ± 5 vs 23 ± 3 mL·L-1, P = 0.709) and peak SV/BV (16 ± 2 vs 17 ± 1 mL·L-1, P = 0.816) quotients were similar for the group with diabetes and controls, respectively. In the group with diabetes, HbA1c inversely correlated with peak SVi (r = -0.80, P < 0.05) and peak COi (r = -0.68, P < 0.05) whereas the association between HbA1c and V·O2peak (mL·min-1·kg-1 FFM) missed significance (r = -0.54, P = 0.107) and no association was observed between HbA1c and relative BV (r = 0.08, P = 0.433).
Leg Muscle Deoxygenation and Blood Flow
The patterns of leg muscle deoxygenation and Q·VL are presented in Figure 2. Leg muscle %[DELTA][HHb] rose from unloaded cycling toward high work rates, where it reached a plateau, except for one patient with diabetes and four controls. All subjects attained their highest %[DELTA][HHb] value (100%) at peak exercise. The values of %[DELTA][HHb] tended to be higher in the group with diabetes than that in controls at moderate work rates, but no significant differences between the groups were observed for %[DELTA][HHb] at any work rate. A significant rise in Q·VL was observed in both groups from unloaded cycling toward high work rates, and Q·VL was similar at submaximal work rates but lower in the group with diabetes than that in controls at peak exercise (0.19 ± 0.02 vs 0.22 ± 0.02, respectively, P < 0.05).
Peak Q·VL correlated positively with peak CO in controls (r = 0.74, P < 0.01) but not in the group with diabetes (r = 0.27, P = 0.281). In addition, HbA1c tended to correlate inversely with peak Q·VL (r = -0.62, P = 0.070) in the group with diabetes.
The novelty of this study resided in the purpose to simultaneously examine the contribution of central and peripheral mechanisms to V·O2peak in patients with type 1 diabetes. This was also the first study to examine associations between BV and cardiac responses to incremental exercise in patients with type 1 diabetes. Physically active adult men with type 1 diabetes had lower relative BV and lower SVi and COi at peak exercise than healthy controls matched for age, anthropometry, and self-reported LTPA. In addition, Q·VL was reduced independently of CO in the group with diabetes at peak exercise and SVRi was higher in the group with diabetes than that in controls. Thus, the group with diabetes attained lower V·O2peak than controls despite physically active lifestyles and absence of clinically overt micro- or macrovascular diseases. Importantly, peak SVi and peak COi correlated and peak Q·VL tended to correlate inversely with HbA1c in the group with diabetes.
Our finding of 16% lower V·O2peak (mL·min-1·kg-1 FFM) in the group with diabetes compared with that in controls is rather consistent with approximately 20% lower V·O2peak reported previously in adults with type 1 diabetes (20,31). V·O2peak similar to that seen in healthy subjects has also been reported in adults with type 1 diabetes (4,29,37,39), but poor glycemic control has been associated with reduced V·O2peak in patients with type 1 diabetes in three of those studies (4,29,37). In this study, a moderately high but nonsignificant negative correlation coefficient between HbA1c and V·O2peak was observed in the group with diabetes. Thus, as previously concluded (3), patients with type 1 diabetes are likely capable of attaining V·O2peak similar to that of healthy subjects, but this may depend on them maintaining good glycemic control.
Central O2 delivery may limit V·O2peak in type 1 diabetes because of limitations of pulmonary (19,29,39) and/or cardiac function (4,13,14,19,29). In this study, the levels of SpO2 and CaO2 were well maintained in both groups throughout the exercise, suggesting that pulmonary function set no limitation to V·O2peak. Previous studies have reported reduced SV and CO in patients with type 1 diabetes during both submaximal (13,14) and maximal exercise (4,29). Accordingly, we also observed lower SVi and, herewith, COi in the group with diabetes at peak exercise, indicating decreased cardiac performance. Importantly, HbA1c inversely correlated with peak SVi and peak COi in the group with diabetes, supporting previous findings (4,13,29) of association between glycemic control and cardiac performance during exercise in type 1 diabetes.
The diabetes-specific reductions in SV are primarily due to diastolic, but possibly also systolic, dysfunction (11). The mechanisms behind the diastolic dysfunction in diabetes include reductions of early ventricular relaxation (2,24), ventricular preload (24), and ventricular compliance (30). In this study, the mean EDVi of the group with diabetes was 9% lower at rest and, on average, 10% lower during exercise, which agrees with previous findings in adolescents with type 1 diabetes (13). However, the differences in EDVi between the groups missed statistical significance, which is discussed later in this article. Reduced diastolic function, associated with reduced BV, has been observed in adults with type 2 diabetes (24). We observed a 9% lower relative BV in the group with diabetes compared with controls, which is congruent with our previous finding (20). Thus, because BV also correlated positively with peak EDV, peak SV, and peak CO, we suggest that lower BV reduces ventricular preload, SV, and CO capacities in patients with type 1 diabetes. This emphasis on the reduced preload is supported by the observed similar peak EDV/BV and peak SV/BV quotients in the groups. However, no association between HbA1c and relative BV in the group with diabetes was observed, which is in accordance with our previous finding (20) and indicates that some HbA1c-related components of SV (e.g., reduced ventricular relaxation and/or compliance) were also present in the group with diabetes and led to the strong inverse association between HbA1c and cardiac performance. Strict interpretation of our data would suggest that the combination of nonsignificantly reduced peak EDVi but significantly reduced peak SVi implies impaired systolic function in the group with diabetes at peak exercise. However, ejection fraction was rather similar between groups at peak exercise and no evidence of impaired systolic function in the group with diabetes was thus provided by this study.
The difference in EDVi between the groups missed statistical significance at rest and during exercise. This likely is due to the “derived nature” of the impedance cardiography method and, thus, relatively high SD of EDVi values but also deserves further interpretation. The amount of diastolic filling is affected by HR. Lower HRmax has occasionally been reported in patients with type 1 diabetes (14,19), which might be explained by hypoglycemia-associated reduction of catecholamine sensitivity (21) or autonomic neuropathy (37). No patient with diabetes was hypoglycemic or had evidence of neuropathy in this study. However, only two patients with diabetes, but six controls, attained age-predicted (36) HRmax, leading to statistically nonsignificant 6 bpm lower HRmax in the group with diabetes.
Reduced Q·VL, independent of CO, was observed in the group with diabetes at peak exercise. Reduced leg blood flow, independent of CO, has also been observed in patients with type 2 diabetes during submaximal exercise (25). In our study, the group with diabetes also had higher SVRi and tended to have higher systolic blood pressure at peak exercise than controls. On the basis of these findings, we suggest that previously (5,15,28,32) demonstrated peripheral vascular dysfunction of patients with type 1 diabetes limits blood flow to their active muscles at peak exercise. Importantly, peak Q·VL tended to correlate inversely with HbA1c in the group with diabetes and may thus depend on glycemic control.
Although peak blood flow, and herewith peripheral O2 delivery to active muscles, were limited in the group with diabetes, the C(a–v)O2 response was similar in the groups throughout the exercise. This accords with previous findings in adolescents with type 1 diabetes (14) and indicates that O2 extraction was not limited at the whole body level for the group with diabetes. This combination of reduced peak Q·VL but preserved peak C(a–v)O2 in the group with diabetes might be explained by the following mechanism: impaired microvascular blood flow (16) and reduced muscle microvascular O2 partial pressure (PmvO2) (6) have been observed in rats with type 1 diabetes at rest, suggesting that fractional O2 extraction from the flowing blood could be higher in the group with diabetes. In addition, before attaining a similar steady-state level, PmvO2 has been observed to fall more rapidly and to far lower levels during 3-min electrical muscle stimulation (1 Hz) in rats with type 1 diabetes than that in healthy rats (6). These findings (6,16) suggest that if fractional O2 extraction from the flowing blood was significantly higher in the group with diabetes in our study, it conceivably was so at rest and immediately after each transition from the previous to the next work rate but not after attaining steady state. Because we used a step incremental protocol (40 W per 3 min), which enables attaining steady state at each submaximal work rate, it can be concluded that fractional O2 extraction likely was similar in the groups during the last 30 s of each submaximal work rate. Thus, diabetes hardly affected the used method to estimate Q·VL at submaximal work rates. If diabetes affected the method at peak exercise (i.e., if fractional O2 extraction was higher in the group with diabetes because of not attaining steady state before volitional fatigue), it only led to underestimating the difference of peak Q·VL between the groups but not to incorrect conclusions. Thus, reduced peak Q·VL but preserved peak C(a–v)O2 in the group with diabetes might be explained by higher local fractional O2 extraction from the flowing blood in the group with diabetes at peak exercise.
The main limitation of this study is the use of the assumed values of muscle (a–v)O2 (17,18) when estimating Q·VL. Accepting this limitation, the actual profiles of Q·VL should remain similar to those presented here, unless large deviations occurred between the actual muscle (a–v)O2 and the published values (17,18) used. In addition, the use of this method to estimate Q·VL in patients with type 1 diabetes can be regarded as appropriate, as previously discussed in this article. Another limitation is that we monitored only the vastus lateralis muscle, while there is heterogeneity in blood flow distribution and metabolism within muscle groups during exercise (23). A fairly small sample size also limits this study by weakening the statistical power of the results, highlighted in correlation analyses (e.g., peak Q·VL vs HbA1c in the group with diabetes). However, we had statistical power of 91.5% (P < 0.05) to detect the difference in V·O2peak between the group with diabetes and controls, indicating that the difference was not a result of Type I error.
In summary, the physically active adults with type 1 diabetes had lower V·O2peak than the age-, anthropometry-, and LTPA-matched healthy controls because of both central and peripheral cardiovascular limitations of O2 delivery. Centrally, lower BV reduces ventricular preload, SV, and CO capacities and is herewith limiting O2 delivery. Peripherally, peak blood flow to active muscles is limited also independently of cardiac function, probably explained by vascular dysfunction. Importantly, central limitations, and probably peripheral limitations as well, are associated with glycemic control in patients with type 1 diabetes.
This study was funded by Tekes—the Finnish Funding Agency for Technology and Innovation (40043/07) and Ministry of Education and Culture (Finland).
The authors declare no conflicts of interest.
The results of this study do not constitute endorsement by the American College of Sports Medicine.
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Keywords:© 2015 American College of Sports Medicine
BLOOD VOLUME; CARDIAC OUTPUT; GLYCEMIC CONTROL; IMPEDANCE CARDIOGRAPHY; NEAR INFRARED SPECTROSCOPY; OXYGEN DELIVERY