Faster Heart Rate and Muscular Oxygen Uptake Kinetics in Type 2 Diabetes Patients Followin

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For personal use only. This Just-IN manuscript is the accepted manuscript prior to copy editing and page composition. It may differ from the final official version of record.
Faster Heart Rate and Muscular Oxygen Uptake Kinetics in Type 2 Diabetes
Patients following Endurance Training
Jessica Koschate1, Uwe Drescher1, Christian Brinkmann2, Klaus Baum1, Thorsten Schiffer3,
Joachim Latsch4, Klara Brixius2, Uwe Hoffmann1

Appl. Physiol. Nutr. Metab. Downloaded from www.nrcresearchpress.com by MICHIGAN STATE UNIV on 10/28/16
1
Institute of Physiology and Anatomy, German Sport University Cologne, Germany
2
Institute of Cardiovascular Research and Sport Medicine, Department of Molecular
and Cellular Sport Medicine, German Sport University Cologne, Germany

3
Outpatient Clinic for Sports Traumatology and Public Health Consultation, German
Sport University Cologne, Germany

4
Institute of Cardiovascular Research and Sport Medicine, Department of Preventive
and Rehabilitative Sport Medicine, German Sport University Cologne, Germany
Corresponding author:
Jessica Koschate
German Sport University Cologne,
Institute of Physiology and Anatomy
Am Sportpark Müngersdorf 6
50933 Cologne
Germany
Phone: +49 221 4982 2911
Fax: +49 221 4982 6790
E-mail: j.koschate@dshs-koeln.de
1
For personal use only. This Just-IN manuscript is the accepted manuscript prior to copy editing and page composition. It may differ from the final official version of record. Page 2 of 37
Abstract
Purpose Cardiorespiratory kinetics were analyzed in type 2 diabetes patients before
and after a 12 week endurance exercise training intervention. It was hypothesized that
muscular oxygen uptake (V’O2musc) and heart rate (HR) kinetics would be faster after the
training intervention and that this would be identifiable using a standardized work rate (WR)
protocol with pseudo-random binary sequences.
Methods The cardiorespiratory kinetics of 13 male sedentary, aged, overweight type 2
diabetes patients (60±8 years, 33±4 kgm-2) were tested before and after the 12 week
exercise intervention. Subjects performed endurance training three times a week on non-
consecutive days. Pseudo-random binary sequences exercise protocols in combination with
time series analysis were used to estimate kinetics. Greater maxima in cross-correlation
functions (CCFmax) represent faster kinetics of the respective parameter.
Results CCFmax(V’O2musc) (pre: 0.31±0.03; post: 0.37±0.1, P=0.024) and CCFmax(HR)
(pre: 0.25±0.04; post: 0.29±0.06, P=0.007) as well as V’O2peak (pre: 24.4±4.7 mlkg-1min-1;
post: 29.3±6.5 mlkg-1min-1, P=0.004) increased significantly over the course of the exercise
intervention.
Conclusions Kinetic responses to changing work rates in the moderate intensity range are
similar to metabolic demands occurring in everyday habitual activities. Moderate endurance
training accelerated the kinetic responses of HR and V’O2musc. Furthermore, the
applicability of the utilized method to detect these accelerations was demonstrated.
Keywords
Type 2 diabetes, pseudo-random binary sequences, cardiorespiratory kinetics, endurance
exercise
2
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Abbreviations
ANOVA analysis of variance
ACF auto-correlation function

CCF cross-correlation function
CCFmax maximum of cross-correlation function
CCFlag lag between the maximum of the auto-correlation function and cross-
correlation function
ECG electrocardiogram
HR heart rate
HbA1c glycosylated hemoglobin
HRpeak peak heart rate
PRBS pseudo-random binary sequence
Q’ cardiac output
Q’rem perfusion of the passive part of the body
RBC red blood cell
SV stroke volume
T2D type 2 diabetes
V’O2 oxygen uptake
V’O2rem oxygen uptake of the passive part of the body
V’O2peak peak/maximum oxygen uptake
V’O2pulm pulmonary oxygen uptake

3
VT
WR
Vvmusc
WRpeak
V’O2musc
work rate
peak work rate

ventilatory threshold
muscular oxygen uptake
muscular venous volume
4
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Introduction
Low cardiorespiratory capacities, determined by maximal exercise tests, have been reported
to be correlated with long-term mortality in type 2 diabetes (T2D) patients as well as healthy
subjects (Estacio et al. 1998; Kohl et al. 1992; Myers et al. 2002; Wei et al. 2000). Therefore,
improvements in physical capacities are important and cost-effective factors to treat T2D
patients. A meta analysis showed that maximal or peak oxygen uptake (V’O2peak), which is
considered the best measure of cardiorespiratory capacities (Fletcher et al. 2001), can be
increased in T2D patients by specific exercise interventions (Boulé et al. 2003).
An additional and potentially more differentiated measure of cardiorespiratory and vascular
functionality are cardiorespiratory kinetics. They offer insights into regulatory processes that
adjust the cardiorespiratory and vascular system to increased metabolic demands. The
adjustment of oxygen uptake (V’O2) to increased metabolic demands has a kinetic profile,
which reflects processes that regulate the speed of this adjustment. Faster V’O2 kinetics lead
to a lower oxygen deficit (Whipp 1971) which leads to less accumulation of metabolites and
lactate, which might increase exercise tolerance at higher work rates (Murgatroyd et al.
2011). Documentation of cardiorespiratory and vascular functionality without motivational
factors or high work rates (WRs) can be a valuable tool to show early improvements in
cardiorespiratory and vascular function in the initial phase of life style modification, including
physical activity. Slower V’O2 kinetics were observed in young and middle-aged T2D patients
compared with respective healthy control subjects (Mac Ananey et al. 2011; O’Connor et al.
2012; O’Connor et al. 2015; Regensteiner et al. 1998). This difference in V’O2 kinetics was
not observed in aged T2D patients (O’Connor et al. 2015; Wilkerson et al. 2011). In contrast,
HR kinetics were slower in aged T2D patients compared with healthy controls.
Since T2D patients are known to perceive higher efforts during exercise (Huebschmann et al.
2009), they might consequently lack motivation for regular exercise. Kinetics can be
measured with submaximal WRs, independent of motivational aspects, whereas motivation
is, in contrast, essential for determination of maximal capacities. Fast V’O2 kinetics lead to a
5
faster attainment of a steady-state after transitions from lower to higher energetic demands
as they regularly occur during every day habitual activities (Mezzani et al. 2013).
Fukuoka et al. (2002) found faster accelerations in V’O2 kinetics than increases in V’O2peak
during a three months training intervention in middle-aged and elderly healthy subjects.
Faster V’O2 kinetics as an indicator of cardiovascular and respiratory function were
recognized after only two weeks of training whereas increases in maximal capacities
occurred much later, after about 8 weeks (Fukuoka et al. 2002). Time courses of increases in
V’O2peak and accelerations of V’O2 kinetics seem to be dissociated (Fukuoka et al. 2002;
Grey et al. 2015; Murias et al. 2015). Accelerated V’O2 kinetics after exercise interventions
have been documented in several studies with different patient groups, e.g. in patients
suffering from chronic heart failure (Kemps et al. 2010; Roditis et al. 2007), in young and
elderly individuals (Murias et al. 2010) and in patients with renal disease (Reboredo et al.
2015). In young healthy subjects Murias et al. (2015) were able to show speeded V’O2
kinetics after a single training session, which was explained by improved matching of local O2
delivery to O2 utilization, caused by improved vascular regulation (see also Murias et al.
2014). Two articles analyzed the effects of endurance exercise training interventions on V’O2
kinetics in T2D patients. In both studies cardiorespiratory kinetics were tested in 3 different
intensity domains (50% ventilatory threshold [VT], 80% VT, and 50% ∆ between VT and
V’O2peak in Mac Ananey et al. [2012]; 20 W, 30 W and 80 W in Brandenburg et al. [1999])
before and after 12 weeks of endurance training. Both studies found significantly faster V’O2
kinetics, although at 80 W only an acceleration by trend was identified (Brandenburg et al.
1999). Mac Ananey et al. (2012) also reported speeded heart rate (HR) kinetics and a larger
increase of cardiac output (Q’) after the exercise training intervention.
In the presented literature square wave WRs were used to evaluate V’O2 kinetics. Subjects
performed two - three repetitions of each WR increase with appropriate recovery periods.
Since three repetitions are recommended, the measurements require at least 36 min
(Spencer et al. 2011), depending on the experimental protocol, either including or excluding
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resting recovery times between the repetitions. Muscular V’O2 (V’O2musc) kinetics were
calculated from pulmonary V’O2 (V’O2pulm) kinetics measured at the mouth by excluding the
cardiodynamic phase (phase 1) from data analysis. The time constant of phase 2 of the
V’O2pulm kinetics response was shown to represent V’O2musc kinetics (e.g. Grassi et al.
1996). Data are fitted with algorithms using certain assumptions (e.g. Barstow et al. 1990). In
the present study, pseudo-random binary sequences (PRBS) were used to evaluate
cardiorespiratory kinetics and a circulatory model combined with time series analysis was
applied to estimate V’O2musc from V’O2pulm and HR (Hoffmann et al. 2013). The method
considers distortions caused by O2 stores, varying Q’ and venous transport times from
muscle to mouth, using specific assumptions in a circulatory model. The PRBS WR protocol
requires one test and can be completed in about 20 min without the necessity of data fitting
to an explicit model. For practical reasons e.g. in clinical environments with T2D patients, the
PRBS-test might show good applicability. To the best of our knowledge, the method has only
been used for cross-sectional comparisons between different groups. So far, the method has
not been applied comparing T2D patients or other subjects before and after an endurance
exercise intervention.
This study aims to show the applicability of the PRBS WR protocol in T2D patients, to
evaluate whether it is sensitive enough to detect changes in HR and V’O2 kinetics after an
endurance exercise intervention in this group of subjects. It is hypothesized that V’O2musc as
well as HR kinetics measured using a PRBS WR protocol with a mean WR of 53.3 W will be
accelerated after a 12 weeks endurance training intervention in T2D patients.
Materials and methods
Overall, 21 male subjects participated in the study. All subjects were recruited through an
announcement in the local newspaper with the following inclusion criteria: older than 45
years of age, non-insulin-dependent, and overweight without secondary complications due to
diabetes or other chronic diseases. Eight subjects did not attend the post-tests and had to be
excluded from further analyses. Reasons for the drop out were either related to lack of time
7
during the training intervention (n = 6) or illness unrelated to the training intervention (n=2).
Data from 13 subjects (age: 60 ± 8 years) were included in statistical analyses. All subjects
were treated either with oral anti-diabetes drugs or with diet; none of the subjects were
insulin-dependent. Anthropometrics and key data for glycemic status are presented in Tab. 1.
The subjects confirmed by questionnaire that they had not participated in regular exercise
during the previous three years. No subject showed any contraindications for participation in
exercise testing. Ten of the subjects took cardiovascular medication (angiotensin converting
enzyme inhibitors [n = 4], ß blockers combined with other cardiovascular medication [n = 3],
calcium-channel-blockers [n = 2] and angiotensin II channel antagonists [n = 1]), two subjects
took statins. Unfortunately, the subgroups taking different medication were too small for
further differentiation.
<<< Table 1 about here >>>
For the pre- and post-tests subjects visited the laboratory several times: First, they had an
anamnestic interview with a physician. The second time, subjects arrived in the morning for
analysis of glycemic parameters in the fasting condition. During the third visit, anthropometric
measurements, a resting electrocardiogram (ECG), and a test for cardiorespiratory exercise
capacity (V’O2peak test) were performed. In case no contraindications in resting ECG or
V’O2peak test were identified, the subjects appeared at the laboratory a fourth time for a
cardiorespiratory kinetics test. After 12 weeks of endurance exercise, subjects were again
tested for glycemic parameters, V’O2peak and cardiorespiratory kinetics. A positive vote of
the ethical committee of the German Sport University Cologne, in accordance with the
Declaration of Helsinki (1964 including the amendments until 2013), was available before the
beginning of the tests. Written informed consent was obtained from all individual participants
included in the study.
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Test for cardiorespiratory exercise capacity
The subjects were tested in a seated position on a cycle ergometer (Ergoline, Bitz, Germany)
using the protocol recommended by the World Health Organization. WR was increased by 25
W every 2 min until subjective exhaustion or the occurrence of ST segment depression,

dizziness or similar events leading to early test termination and exclusion of the subject from
the study.
HR was measured continuously via 12-lead electrocardiography (GE Medical Systems,
Information Technologies, Munich, Germany). Pulmonary data were assessed using a gas
analyzer (ZAN Messgeräte GmbH, Oberthulba, Germany) into which the algorithms of
Beaver et al. (1981) are integrated. For V’O2peak the mean V’O2 during the last 30 s of the
highest achieved WR was set as the peak value. The criteria for true maximal V’O2 were set
as follows: either a plateau in V’O2 despite an increase in WR (as primary criterion) appeared
or the combination of a maximal HR higher than 200 min-1 minus individual age (Kindermann
1987) and a maximal respiratory exchange ratio higher than 1.06 (Aitken and Thompson
1988; Meyer 2003) appeared. Since not all subjects met these criteria, the data are reported
at V’O2peak.
Cardiorespiratory kinetics test
Subjects were tested on a semi-recumbent cycle ergometer (Cardiac Stress Table, Lode
B.V., Netherlands; backrest at 45°, legs at 42°, relative to ground level). PRBS were used as
WR protocol. The protocol consisted of 180 s of rest (-180 s – -1 s); 200 s constant phase at
30 W (Low: 0 s – 199 s); followed by two 300 s periods of PRBS (PRBS1 and PRBS2: 200 s
– 799 s), with changing WRs between 30 and 80 W; and ended with a 200 s constant phase
of 80 W (High: 800 s – 999 s) (Fig.1, left panel). HR was assessed beat to beat via
electrocardiography; stroke volume (SV) was measured beat to beat via impedance
cardiography (Task Force® Monitor, CNSystems Medizintechnik AG, Graz, Austria, see
Fortin et al. 2006). From SV and HR, Q’ was calculated. Pulmonary gas exchange data were
9
determined breath by breath (ZAN 680, ZAN Meßgeräte GmbH, Oberthulba, Germany),
incorporating the algorithms of Beaver et al. (1981). The instruments were calibrated before
each measurement, according to the manufacturer’s guidelines. Data were synchronized and
interpolated to 1 s - intervals to ensure homogeneous sampling (Lamarra et al. 1987). A low

pass filter (0.1 Hz) was applied for reduction of noise.
Cardiorespiratory kinetics were assessed by applying time series analysis and V’O2musc
was estimated using a circulatory model (Hoffmann et al. 2013). The model consists of two
compartments (working and remainder part). For estimation of V’O2musc assumptions on a
certain muscular venous blood volume (Vvmusc) (0.5 to 3.5 L) between muscle and mouth and
a V’O2 (V’O2rem) as well as perfusion (Q’rem) of the passive part of the body (ranging
between 1.5 and 6.0 Lmin-1) were considered. The V’O2 of the passive part of the body was
set to 82% (Barstow et al. 1990) of the V’O2 during the last 30 s of rest before the exercise
protocol. These variables were assumed to be constant for V’O2musc calculations. For
calculation of kinetics estimates time series analysis was used. For this purpose, correlation
functions of WR with itself (auto-correlation, ACF) and of WR with the respective
physiological parameter (cross-correlation, CCF) for time shifts over the two PRBS intervals
(lower panel of Fig. 1) were performed. These time shifts result in a virtual time scale and will
be called lag in the text. Lags from – 50 s to 250 s were analyzed (right panel, Fig. 1)
(Bendat and Piersol 2010).
>>> Fig. 1 <<<
For estimation of V’O2musc, Vvmusc and Q’rem were iteratively adjusted so that the CCF of
V’O2musc took on the characteristics, described by Hoffmann et al. (2013). Briefly, muscular
venous O2 content had to be always greater than zero, the increase of the CCF course of
V’O2musc should begin after the increase of the ACF (compare right panel, Fig. 1) and
should have a single peak, followed by a monotonous, smooth decrease. These analyses
were performed using a specific software. The results were interpreted as follows: The ACF
can be approximated as a WR impulse. The CCF is understood as the response of the

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respective parameter to this impulse. For detailed information on the kinetics responses, the
courses of the CCFs of the different parameters were analyzed at different lags (0 – 100 s,
compare x-axis of the right panel of Fig. 1). In a more comprehensive analysis, the kinetic
responses of the parameters were summarized by the maximum in CCF (CCFmax) (right
panel, Fig. 1) and the related lag, which is the time on the x-axis between the maximum of
the ACF and the CCFmax, which is called CCFlag. Greater CCFsmax indicate faster response
times of the particular parameter and therefore faster kinetics (shorter time constants).
Larger CCFslag can be explained by greater time delays. In the case of a first-order system,
time constants can be directly converted from CCFmax, which is sensitive to τ (Hoffmann et al.
2013). These were calculated for comparison with data from other studies and should only
be regarded as rough estimates.
Endurance training
All subjects participated in a 12-week (April – July) endurance exercise intervention on cycle
and elliptical ergometers as described by Brinkmann et al. (2015). Training was performed
three times per week on non-consecutive days and was supervised by professional trainers.
The training sessions were gradually increased; from 20 min in the first week to 50 min in
week seven (plus 5 min warm-up and 5 min cool-down), before this duration was held
constant up to the last training week.
The subjects exercised on cycle ergometers and elliptical cross-trainers (Technogym, Neu-
Isenburg, Germany), switching from one to the other halfway through each training session.
Their endurance intensity (heart rate measured via Sigma Sport RC 14.11, Sigma-Elektro
GmbH, Neustadt, Germany) was individually adapted and corresponded to ~70-80 % of their
respective peak heart rate (HRpeak) or their HR at ~75 % of their individual V’O2peak based
on the endurance test to assess V’O2peak conducted before the training period. Subjects
had to increase their WR on the ergometers to achieve the same HR over the exercise
training intervention.
11
Statistical analysis
Two-way analysis of variance (ANOVA) was applied to CCF for the factors ‘lag’ (0 – 100 s)
and ‘time’ (pre/post); to CCFmax and CCFlag for the factors ‘time’ and ‘parameter’ (V’O2musc,
HR); and to the means of HR, V’O2pulm, V’O2musc, SV, Q’ and mean blood pressure (mBP)
for the factors ‘time’ and ‘step’ (Low, PRBS1, PRBS2, High) of the PRBS protocol. In the
case of significant effects, the following post hoc comparisons were performed via LSD-test.
Depending on data distribution, t-tests or nonparametric Wilcoxon-tests were used to
compare CCFmax(V’O2pulm) and CCFlag(V’O2pulm) as well as V’O2peak and all blood
parameters between pre and post-intervention. The level of significance was set to P ≤ 0.05.
Graphics were created using Excel 2010 (Microsoft, Redmond, USA).
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Results
The subjects included in statistical analyses were supposed to achieve a HR of
109 ± 15 min-1 during warm-up and cool-down. They managed to achieve 106 ± 14 min-1
during warm-up and 111 ± 14 min-1 during cool-down. During the main training period they
attained 117 ± 16 min-1 of the 119 ± 15 min-1 target. The overall adherence to the 12 week
training period was 90 ± 19 % on average.
As presented in Tab. 1, body mass index (BMI), insulin concentrations and fasting blood
glucose did not change after 12 weeks of endurance exercise intervention. HbA1c tended to
be lower post-training (P = 0.083), whereas V’O2peak as well as peak WR (WRpeak)
increased significantly from pre- to post-intervention (Tab. 2).
Mean values for V’O2pulm, V’O2musc and HR as a response to the PRBS WR protocol for
pre- and post-intervention are shown in Fig. 2.
<<< Fig. 2 >>>
Further, means and standard deviations of relevant parameters of each WR step during the
PRBS protocol were analyzed for statistical differences (Tab. 3).
Data were examined for statistical differences from pre- to post-intervention at different lags
of the CCF course. For the CCF time courses of V’O2musc an effect on ‘lag’ (P < 0.001,
ŋ2 = 0.857) and the interaction ‘time x lag’ (P = 0.019, ŋ2 = 0.225), was found. CCFs of
V’O2musc were significantly different from pre- to post-intervention for lags of 10 s (P =
0.046), 20 s (P = 0.048) and 30 s (P = 0.013). For the CCFs of HR significant main effects on
‘time’ (P = 0.044, ŋ2 = 0.298), ‘lag’ (P < 0.001, ŋ2 = 0.656) and the interaction of ‘time x lag’
(P = 0.020, ŋ2 = 0.229) were detected. Post hoc, significant differences were found for lags of
10 s (P = 0.02), 20 s (P = 0.016), 80 s (P = 0.021) and 90 s (P = 0.043). Statistical analysis

13
for CCF courses of V’O2pulm revealed a significant effect on ‘time x lag’ (P = 0.041; ŋ2 =
0.189). Post hoc tests showed significant differences from pre- to post-intervention for lags of
20 s (P = 0.049) and 80 s (P = 0.017).
<<< Figure 3 about here >>>

With consideration given only to CCFmax and the respective CCFlag of HR, V’O2musc and
V’O2pulm, evaluated pre- and post-intervention, the following results were obtained (Fig. 4).
<<< Figure 4 about here >>>
For CCFmax of HR and V’O2musc significant main effects on the factors ‘time’ (P = 0.006; ŋ2 =
0.475) and ‘parameter’ (P = 0.002; ŋ2 = 0.563) were identified. Post hoc tests revealed
significant differences between pre- and post-test for CCFmax(V’O2musc) (P = 0.024) as well
as CCFmax(HR) (P = 0.007). Additionally, CCFmax(HR) was significantly lower than
CCFmax(V’O2musc) before and after the training intervention (pre: P < 0.001; post: P = 0.015).
CCFmax values were converted into time constants τ, for better comparability with data from
other studies (Tab. 4). It should be mentioned, that these time constants are only rough
estimates.
Investigating the model parameters, used for calculation of V’O2musc, significant changes
were observed in V’O2rem (pre: 0.30 ± 0.05 Lmin-1 vs. post: 0.34 ± 0.06 Lmin-1; P = 0.023).
Vvmusc (pre: 2450 ± 1147 ml vs. post: 2042 ± 756 ml) and Q’rem (pre: 2757 ± 1134 ml vs. post:
2602 ± 874 ml) did not change significantly.
Discussion
The present study showed a significant acceleration of HR and V’O2musc kinetics after 12
weeks of endurance training, conducted at an intensity of 70-80 % of individuals’ peak HR in
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male T2D patients. Therefore, the applied PRBS WR protocol in combination with time series
analysis and a circulatory model is sensitive enough to detect these changes.
The comparison of the CCF course (Fig. 3) before and after the endurance training
intervention revealed significant differences at several lags of the CCF courses of HR,
V’O2musc and V’O2pulm. Hoffmann et al. (2013) described certain characteristics of a CCF
course (right panel, Fig. 1). The occurrence of only a single peak, followed by monotonic
decrease without negative curvature and superimposed oscillations was expected.
Comparing the pre- and post-intervention data, one finds that the post-intervention CCF
courses seem to comply better with these criteria (Fig. 3). The CCF course represents on-
(increasing part before the CCFmax) and off-kinetics (decreasing part after the CCFmax). The
peak of the CCF is higher in HR and V’O2musc responses and therefore the kinetics faster
(time constants would be shorter). Additionally, the decreasing parts of the CCF courses of
the parameters show faster returns to the initial levels. For a first order system the parameter
should increase immediately, without delay and can be fitted with a certain time constant. For
V’O2musc and HR kinetics the CCF course is consistent with a first order response (compare
Fig. 3). The CCF course of V’O2pulm indicates contradictions to a first-order response.
Therefore it is not useful to fit a first-order model through CCFmax and the increasing and
decreasing parts of the CCF course of the V’O2pulm response (third panel in Fig. 3). This is
in line with the non-steady-state (transition-) phase preceded by a cardio dynamic phase as
shown by Whipp et al. (1982).
Considering the comprehensive description of kinetics values by the maxima of the CCFs,
HR and V’O2musc kinetics but not V’O2pulm kinetics were significantly faster after the
training intervention (Fig. 4). Transient metabolic demands, as applied during the
assessment of cardiorespiratory kinetics are very similar to everyday metabolic demands e.g.
climbing a flight of stairs; the clinical relevance of fast kinetics is therefore significant.
Furthermore, HR kinetics were found to be significantly slower than V’O2musc kinetics in the
pre and post measurements. HR and V’O2musc kinetics seem to be speeded to a similar
15
extent following the exercise intervention. This is interesting, since Hoffmann et al. (2013)
and Drescher et al. (2015) observed V’O2musc kinetics which were slower than HR kinetics
in young healthy subjects. This might be an effect of age, status of health and/or training,
since V’O2peak was higher in the younger subjects.

The reasons for the faster cardiorespiratory kinetics after the exercise intervention need to be
elucidated. Possible limiting factors for V’O2 kinetics in aging or disease can be summarized
by the following: delivery of oxygen to the muscle, mismatch between O2 delivery and O2
consumption, the flux of oxygen into the muscle, diffusion of oxygen into the mitochondria or
malfunctions in the mitochondrial electron-transport chain. Each factor alone or in
combination can be limiting and can be caused by various mechanisms (e.g. Heinonen et al.
2015; Koga et al. 2014; Murias and Paterson 2015; Poole et al. 2008; Roditis et al. 2007).
Brandenburg et al. (1999) did not present explanations for the faster V’O2 kinetics after the
exercise intervention in their subjects and focused on the more beneficial effect of the
exercise intervention for T2D patients compared with the controls. Mac Ananey et al. (2012)
associated accelerated V’O2 kinetics with faster dynamic responses of HR and SV after
exercise training. In this study HR responses were faster as well, but Q’ and SV did not show
a larger increase. In contrast, absolute values of Q’ and SV were similar pre- and post-
intervention, whereas absolute values of V’O2pulm but not V’O2musc increased. This can be
explained either by improved redistribution of blood flow or by the limitations of the method
(impedance cardiography), used in this study in assessing Q’. The reduced mBP after the
endurance training intervention, shown in Table 3, possibly caused by vascular dilatation
might indicate an improved redistribution of blood flow.
In diabetes a reduced oxygen supply in skeletal muscle can also occur due to a decreased
capillary RBC flux in a substantial proportion of muscle capillaries (Padilla et al. 2006; Poole
et al. 2013). Additionally, a reduction in microvascular O2 delivery by ~70 % was reported
(Padilla et al. 2006). Hyperglycemia has been demonstrated to negatively affect endothelial
surface layer (Zuurbier et al. 2005) thereby reducing RBC flux. It can thus be speculated that
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physical training can increase RBC flux in muscle capillaries and improve oxygen supply by
reducing hyperglycemia-induced modifications to patients` endothelium. Brinkmann et al.
(2015) recognized an improved turnover of RBCs and an increased proportion of young,
more deformable RBCs in T2D patients participating in the same training intervention.
Simchon et al. (1987) showed that reduced deformability of RBCs impedes blood flow
through selected regions of the microcirculation.
Other studies investigating the adaptations of T2D patients to exercise interventions, but not
their cardiorespiratory kinetics, have observed improvements of large artery compliance
accompanied by increased cardiorespiratory exercise capacity (McGavock et al. 2004).
Further, improved vascular responsiveness was observed after exercise training in diabetic
humans and rats (Haram et al. 2006; Murias et al. 2013; Okada et al. 2010; Schreuder et al.
2015). Faster vascular responsiveness after short and long-term interventions such as
training was assumed to be beneficial for speeded V’O2 kinetics (Murias et al. 2014). Aspects
of microcirculation were not measured in this investigation; the influence on V’O2musc
kinetics remains therefore speculative in this data set.
Explanatory approaches for accelerated V’O2 kinetics after exercise interventions in patients
with other diseases and in healthy test subjects include improved matching of local O2
delivery to muscle V’O2 in old and young subjects (Murias et al. 2010), increased peak
peripheral oxygen extraction and an increased number of endothelial progenitor cells leading
to reduced perturbation of metabolic homeostasis after WR increases (Mezzani et al. 2013).
Further, increased parallel activation of oxidative phosphorylation (Zoladz et al. 2013) has
been found. Tomczak et al. (2013) assumed that accelerated V’O2 kinetics after 12 weeks of
aerobic and strength training in heart transplant patients can be explained by favorable
adaptations in skeletal muscle oxidative function.
No significant differences were observed for the CCFmax of VO2pulm. This might be caused
by the fact, that pulmonary measured V’O2 is a mixture of circulatory and skeletal muscle
dynamic responses. The accelerations in V’O2musc kinetics might have been confounded by
17
other factors between the exercising muscle and the mouth as the site of measurement when
applying PRBSs as the WR protocol (Benson et al. 2013; Hoffmann et al. 2013).
The decrease of 18 % of the estimated time constants of VO2musc kinetics were a little lower
than the results of other studies analyzing T2D patients. In those studies the patients were
able to achieve accelerations of 22-45 % (Brandenburg et al. 1999; Mac Ananey et al. 2011).
For patients with congestive heart failure differences of 23 % (Roditis et al. 2007), 37 %
(Tomczak et al. 2013) and 15 % (Kemps et al. 2010) have been reported, while 18 % faster
V’O2 kinetics have been identified for patients suffering from renal disease (Reboredo et al.
2015). Murias et al. (2010) observed 45 % faster V’O2 kinetics in young and 26 % in elderly
subjects. Mac Ananey et al. (2011) observed a speeding in HR kinetics of about 35% in
different intensity domains. In the present study the estimated time constants of HR were
21% and therefore slightly less accelerated than in other investigations.
The mean absolute values of HR of each WR step were significantly decreased after the
training intervention, which reflects the effectiveness of the training on the cardiovascular
system.
V’O2peak and WRpeak increased over the training intervention as well. The subjects in the
study of Mac Ananey et al. (2012) showed increases of V’O2peak by 18 %. Brandenburg et
al. (1999) documented an increase of 28 %. A meta-analysis including studies applying
exercise intensities between 30 % and 75 % of V’O2peak in the training intervention revealed
an increase of 11.8 % in V’O2peak (Boulé et al. 2003). In the present study V’O2peak was
17 % higher after the exercise intervention and was therefore within the range of expected
increases.
Methodological Considerations
In order to analyze the time course of the changes in V’O2musc, V’O2pulm and HR kinetics in
more detail, the measurements of these parameters should have been performed more
frequently. Murias et al. (2015) documented first effects on V’O2 kinetics in young healthy
18
Page 19 of 37
subjects after only one week of training, similar to Fukuoka et al. (2002) and Murias et al.
(2010), who observed effects after 2 and 3 weeks of training in middle-aged and aged
subjects, respectively. The obtained data in this study are limited to evaluate the overall
training effect on the cardiorespiratory kinetics.

Identification of V’O2max was performed using secondary criteria which might lead to over- or
underestimation of V’O2max (Barker et al. 2011; Day et al. 2003; Poole et al. 2008).
Therefore, the term V’O2peak was introduced to describe peak exercise tolerance (Midgley et
al. 2007). It is suggested to perform supramaximal tests to ensure the attainment of V’O2max
from incremental protocols (e.g. Barker et al. 2011; Day et al. 2003; Poole et al. 2008). It is
assumed that, since HRpeak was similar before and after the exercise intervention, V’O2peak
and therefore exercise capacity increased following the exercise intervention in the present
investigation.
Further, the anthropometric data of our subjects should be considered when discussing the
results. The subjects were not only T2D patients, but also overweight and predominantly
aged individuals. Comparing aged T2D subjects with controls in the same age range did not
reveal differences in V’O2 kinetics (O’Connor et al. 2015; Wilkerson et al. 2011), although HR
kinetics were slower in T2D patients (O’Connor et al. 2015). It was also shown that V’O2
kinetics in aged individuals can be accelerated up to values observed in young subjects
(Fukuoka et al. 2002). Overweight was not identified as an influencing factor on V’O2 or HR
kinetics (Mac Ananey et al. 2011; Regensteiner et al. 1998). Therefore, only age might have
had an influence on the results of HR kinetics.
Regarding the risk of overestimation of absolute Q’-values as a limitation of the impedance
method (Fortin et al. 2006), which was used for estimation of Q‘, it should be mentioned that
SV remained similar over the WR protocol (Table 3). Therefore, the changes in Q’ are mainly
influenced by variations in HR.
19
Conclusions
The exercise intervention led to faster V’O2musc and HR kinetics as well as increased
V’O2peak in the T2D patients. The accelerations in kinetics responses were not only seen in
the maxima of CCF but also in a broad range of lags of the CCF courses, which reflects the
sufficient sensitivity of the applied method. The speeded V’O2musc kinetics might be
explained by several factors as an increased redistribution of blood flow as indicated by the
reduced mBP, the elevated portion of young RBCs and their increased flexibility as obtained
in the same subjects by Brinkmann et al. (2015), improved vascular responsiveness (Haram
et al. 2006; Murias et al. 2013; Murias et al. 2014; Okada et al. 2010; Schreuder et al. 2015)
and improved microvascular O2 delivery (Padilla et al. 2006; Zuurbier et al. 2005).
The results of this study also show the possibilities of the evaluation and comparison of
cardiorespiratory kinetics before and after exercise interventions. The applied test does not
require high levels of physical effort or motivation and can be performed in a short time
period.
Acknowledgements
The study was supported by the DLR (Deutsches Zentrum für Luft- und Raumfahrt),
Germany (FKZ 50WB1426). We thank Sigma-Elektro GmbH, Neustadt, Germany, for the
provision of Sigma Sport RC 14.11 watches.
Conflict of interest
The authors declare that there is no conflict of interest.
20
Page 21 of 37
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Page 29 of 37
Tables
Table 1 Characteristics of the subjects before and after the training intervention
N = 13 pre post Sig.
Body mass mean 102.2 102.6

n.s.
[kg] SD 15.6 16.7
BMI mean 33.2 33.0

-2 n.s.
[kgm ] SD 4.2 4.4
Fasting blood
mean 193 178
glucose n.s.
[mgdl-1] SD 103 54
HbA1c mean 7.8 7.3

P = 0.083
[%] SD 1.8 1.3
Insulin median 20.1 22.5

n.s.
[µIU/ml] 25. / 75. quartile 13.6 / 25.2 12.7 / 27
Duration since
diagnosis of mean 4
T2D
[years]
SD 5
BMI: body mass index; HbA1c: glycosylated hemoglobin; n.s.: not

significant; Sig.: significance; T2D: type 2 diabetes; SD: standard
deviation. Due to an outlier in the insulin values the median and the 25.
and 75. quartiles are presented.
29
Table 2 Means and standard deviations of peak cardiorespiratory capacities
before and after 12 weeks of endurance exercise
N=13 pre post Sig.

V’O2peak mean 24.4 29.3

[mlkg-1min-1] P = 0.004
SD 4.7 6.5
mean 146 144

HRpeak
-1 n.s.
[min ]
SD 21 23
mean 150 185

WRpeak
P = 0.006
[W] SD 21 30
V’O2peak: peak oxygen uptake; HRpeak: peak heart rate; WRpeak: peak work
rate; Sig.: Significance; SD: standard deviation.
30
Page 31 of 37
Table 3 Means and standard deviations of each work rate step during the PRBS
protocol
pre post main effect

N = 13
mean SD mean SD 'time'
Low 0.71 0.10 0.69 0.07
V’O2musc PRBS 1 0.92 0.11 0.97 0.09

n.s.
[Lmin-1] PRBS 2 0.93 0.12 0.96 0.09
High 1.14 0.17 1.19 0.20
Low 0.97 0.15 1.04 0.12
V’O2pulm PRBS 1 1.21 0.14 1.31 * 0.12 P = 0.016
-1 2
[Lmin ] PRBS 2 1.22 0.15 1.30 * 0.13 ŋ = 0.396
High 1.47 0.16 1.57 * 0.12
Low 97 13 90 * 13
HR PRBS 1 103 13 97 * 14 P = 0.016
-1 2
[min ] PRBS 2 105 14 98 * 14 ŋ = 0.394
High 115 15 107 * 15
Low 84 19 84 13
SV PRBS 1 86 15 84 17
n.s.
[mL] PRBS 2 85 16 84 14
High 84 20 86 15
Low 8.0 1.3 7.5 1.2
Q’ PRBS 1 8.5 1.4 8.2 1.3

-1 n.s.
[Lmin ] PRBS 2 8.7 1.4 8.3 1.3
High 9.5 1.4 9.0 1.2
Low 114 10 107 * 10
mBP PRBS 1 114 10 109 * 10 P = 0.05
2
[mmHg] PRBS 2 112 11 110 8 ŋ = 0.284
High 117 15 112 11
V’O2musc: muscular oxygen uptake; V’O2pulm: pulmonary oxygen uptake;
HR: heart rate; SV: stroke volume; Q’: cardiac output; mBP: mean blood
pressure; PRBS: pseudo-random binary sequences; SD: standard deviation.
*: significantly different from pre (p < 0.05)
31
Table 4 Means and standard deviations for time constants of V’O2musc, V’O2pulm and
HR
N = 13 pre post
τ(V’O2musc) mean 47.04 38.42

[s] SD 7.98 13.37
τ(V’O2pulm) mean 47.73 48.62

[s] SD 11.21 13.04
τ(HR) mean 67.17 52.99
[s] SD 18.04 14.46
τ: time constant; V’O2musc: muscular oxygen uptake;
V’O2pulm: pulmonary oxygen uptake; HR: heart rate.
32
Page 33 of 37
Figure Captions
Fig. 1 Description of the method utilized to estimate cardiorespiratory kinetics.
ACF: auto-correlation function, CCF: cross-correlation function, HR: heart rate,
V’O2pulm: pulmonary oxygen uptake, V’O2musc: muscular oxygen uptake.

CCFmax: maximum of cross-correlation function.
Fig. 2 Means and standard errors for pre- and post-test responses of HR, V’O2pulm and
V’O2musc to the PRBS WR protocol.
HR: heart rate, V’O2pulm: pulmonary oxygen uptake, V’O2musc: muscular
oxygen uptake, PRBS: pseudo-random binary sequences; WR: work rate.
Fig. 3 Means and standard errors for CCF for the lags 0 s to 100 s for HR, and
V’O2musc for pre- and post-test (N = 13)
*: P < 0.05, significant difference between pre- and post-test.
CCF: cross-correlation function; HR: heart rate; V’O2musc: muscular oxygen
uptake; V’O2pulm: pulmonary oxygen uptake; a.u.: arbitrary units.
Fig. 4 Means and standard errors for CCFmax and CCFlag for HR, V’O2musc and
V’O2pulm for pre- and post-test (N = 13)
*: P < 0.05
**: P < 0.01
***: P < 0.001
CCFmax: maximum in cross-correlation function; CCFlag: lag between maximum of
auto-correlation function and cross-correlation function; HR: heart rate;
V’O2musc: muscular oxygen uptake; V’O2pulm: pulmonary oxygen uptake; a.u.:
arbitrary units.
33
Description of the method utilized to estimate cardiorespiratory kinetics. ACF: auto-correlation function,
CCF: cross-correlation function, HR: heart rate, V’O2pulm: pulmonary oxygen uptake, V’O2musc: muscular
oxygen uptake. CCFmax: maximum of cross-correlation function.
Fig. 1
125x86mm (300 x 300 DPI)
Page 35 of 37
Means and standard errors for pre- and post-test responses of HR, V’O2pulm and V’O2musc to the PRBS WR
protocol. HR: heart rate, V’O2pulm: pulmonary oxygen uptake, V’O2musc: muscular oxygen uptake, PRBS:
pseudo-random binary sequences; WR: work rate.
Fig. 2
185x69mm (300 x 300 DPI)
Means and standard errors for CCF for the lags 0 s to 100 s for HR, and V’O2musc for pre- and post-test (N
= 13) *: P < 0.05, significant difference between pre- and post-test. CCF: cross-correlation function; HR:
heart rate; V’O2musc: muscular oxygen uptake; V’O2pulm: pulmonary oxygen uptake; a.u.: arbitrary units.
Fig. 3
86x167mm (300 x 300 DPI)
Page 37 of 37
Means and standard errors for CCFmax and CCFlag for HR, V’O2musc and V’O2pulm for pre- and post-test (N =
13) *: P < 0.05 **: P < 0.01 ***: P < 0.001 CCFmax: maximum in cross-correlation function; CCFlag: lag
between maximum of auto-correlation function and cross-correlation function; HR: heart rate; V’O2musc:
muscular oxygen uptake; V’O2pulm: pulmonary oxygen uptake; a.u.: arbitrary units.
Fig. 4
129x83mm (300 x 300 DPI)

Faster Heart Rate and Muscular Oxygen Uptake Kinetics in Type 2 Diabetes Patients Followin

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Page 1 of 37

Patients following Endurance Training

Joachim Latsch4, Klara Brixius2, Uwe Hoffmann1

and Cellular Sport Medicine, German Sport University Cologne, Germany

Sport University Cologne, Germany

and Rehabilitative Sport Medicine, German Sport University Cologne, Germany

Purpose Cardiorespiratory kinetics were analyzed in type 2 diabetes patients before

protocol with pseudo-random binary sequences.

Methods The cardiorespiratory kinetics of 13 male sedentary, aged, overweight type 2

consecutive days. Pseudo-random binary sequences exercise protocols in combination with

functions (CCFmax) represent faster kinetics of the respective parameter.

Results CCFmax(V’O2musc) (pre: 0.31±0.03; post: 0.37±0.1, P=0.024) and CCFmax(HR)

similar to metabolic demands occurring in everyday habitual activities. Moderate endurance

training accelerated the kinetic responses of HR and V’O2musc. Furthermore, the

applicability of the utilized method to detect these accelerations was demonstrated.

Type 2 diabetes, pseudo-random binary sequences, cardiorespiratory kinetics, endurance

ANOVA analysis of variance

ACF auto-correlation function

CCF cross-correlation function

CCFmax maximum of cross-correlation function

HbA1c glycosylated hemoglobin

HRpeak peak heart rate

PRBS pseudo-random binary sequence

Q’rem perfusion of the passive part of the body

RBC red blood cell

T2D type 2 diabetes

V’O2 oxygen uptake

V’O2rem oxygen uptake of the passive part of the body

V’O2peak peak/maximum oxygen uptake

V’O2pulm pulmonary oxygen uptake

peak work rate

muscular venous volume

increased in T2D patients by specific exercise interventions (Boulé et al. 2003).

An additional and potentially more differentiated measure of cardiorespiratory and vascular

2011). Documentation of cardiorespiratory and vascular functionality without motivational

measured with submaximal WRs, independent of motivational aspects, whereas motivation

Faster V’O2 kinetics as an indicator of cardiovascular and respiratory function were

V’O2peak in Mac Ananey et al. [2012]; 20 W, 30 W and 80 W in Brandenburg et al. [1999])

kinetics, although at 80 W only an acceleration by trend was identified (Brandenburg et al.

increase of cardiac output (Q’) after the exercise training intervention.

endurance exercise intervention in this group of subjects. It is hypothesized that V’O2musc as

accelerated after a 12 weeks endurance training intervention in T2D patients.

Materials and methods

years of age, non-insulin-dependent, and overweight without secondary complications due to

calcium-channel-blockers [n = 2] and angiotensin II channel antagonists [n = 1]), two subjects

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measurements, a resting electrocardiogram (ECG), and a test for cardiorespiratory exercise

capacity (V’O2peak test) were performed. In case no contraindications in resting ECG or

included in the study.

Test for cardiorespiratory exercise capacity

W every 2 min until subjective exhaustion or the occurrence of ST segment depression,

HR was measured continuously via 12-lead electrocardiography (GE Medical Systems,

Cardiorespiratory kinetics test

interpolated to 1 s - intervals to ensure homogeneous sampling (Lamarra et al. 1987). A low

pass filter (0.1 Hz) was applied for reduction of noise.

compartments (working and remainder part). For estimation of V’O2musc assumptions on a

functions of WR with itself (auto-correlation, ACF) and of WR with the respective