Diabetes & Metabolic Syndrome: Clinical Research & Reviews 17 (2023) 102778

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Diabetes & Metabolic Syndrome: Clinical Research & Reviews

journal homepage: www.elsevier.com/locate/dsx

Progressive resistance training ameliorates deteriorating cardiac

autonomic dysfunction, subclinical inflammation and endothelial
dysfunction in type 2 diabetes mellitus: A randomized control trial
Pooja Bhati a, b, *, M. Ejaz Hussain a, b, K.K. Deepak c, Sarfaraz Masood d, Pooja Anand a
a
Shree Guru Gobind Singh Tricentenary University, Gurugram, Haryana, 122505, India
b
Diabetes Research Group, Centre for Physiotherapy and Rehabilitation Sciences, Jamia Millia Islamia (A Central University), New Delhi, 110025, India
c
Department of Physiology, All India Institute of Medical Sciences, New Delhi, 110029, India
d
Department of Computer Engineering, Faculty of Engineering, Jamia Millia Islamia (A Central University), New Delhi, 110025, India

a r t i c l e i n f o a b s t r a c t

Article history: Background and aims: To investigate the effect of resistance training (RT) on outcomes of cardiac auto-
Received 19 May 2022 nomic control, biomarkers of subclinical inflammation, endothelial dysfunction, and angiotensin II in
Received in revised form T2DM patients with CAN.
11 April 2023
Methods: Fifty six T2DM patients with CAN were recruited in the present study.After baseline assess-
Accepted 28 April 2023
ment of all outcome variables, patients were randomly allocated into two groups e RT (n ¼ 28) and
Control (n ¼ 28). The experimental group underwent 12 weeks of RT and the control group received
Keywords:
usual care. RT was performed at an intensity of 65%e75% of 1 RM, 3 times/week for 12 weeks. RT
Autonomic nervous system
Diabetes mellitus
program included 10 exercises of major muscle groups in the body. Cardiac autonomic control param-
Resistance training eters, subclinical inflammation and endothelial dysfunction biomarkers, and serum angiotensin II con-
Exercise centration were assessed at baseline and after 12 weeks.
Results: Parameters of cardiac autonomic control showed significant improvement after RT (p < 0.05).
Interleukin-6, interleukin-18 were significantly reduced while endothelial nitric oxide synthase was
significantly increased post-RT (p < 0.05).
Conclusions: Findings of the present study suggest that RT has the potential to enhance deteriorating
cardiac autonomic function in T2DM patients with CAN. RT also seems to have an anti-inflammatory role
and it may also play some role in vascular remodeling in these patients.
Trial registration: CTRI/2018/04/013321, Registered prospectively on 13th April 2018, Clinical Trial Reg-
istry, India.
© 2023 Research Trust of DiabetesIndia (DiabetesIndia) and National Diabetes Obesity and Cholesterol
Foundation (N-DOC). Published by Elsevier Ltd. All rights reserved.

1. Introduction increases up to three to five times in individuals with diabetes than

Diabetes mellitus (DM) has been recognized as a serious health
epidemic across the world with a global prevalence of 425 million
[1]. The Adult Treatment Panel III of the National Cholesterol Edu-
cation Program declared diabetes as an equivalent to coronary
heart disease (CHD) [2]. It is recognized that the risk of CHD
* Corresponding author. Faculty of Physiotherapy, Shree Guru Gobind Singh Tri-
centenary University, Gurugram, Haryana, 122505, India.
E-mail addresses: pooja.bhati092@gmail.com (P. Bhati), ejaz58jmi@gmail.com
(M.E. Hussain), kkdeepak@gmail.com (K.K. Deepak), smasood@jmi.ac.in
(S. Masood), pooja.physiotherapy@sgtuniversity.org (P. Anand).
non-diabetic individuals [3]. Despite the fact that it strongly and
independently predicts all-cause and cause-specific mortality,
cardiac autonomic neuropathy (CAN) is still considered to be one of
the most overlooked and under-diagnosed cardiovascular compli-
cation of type 2 diabetes mellitus (T2DM) [4,5].
Recent research has illustrated significant relationship between
biomarkers related to endothelial dysfunction and outcomes of
CAN [6] indicating some link between the two pathologies.
Angiotensin II is a systemic vasoconstrictor which adversely mod-
ulates cardiac autonomic function and it may be considered to be
involved in the pathogenesis of CAN [7].
Exercise intervention is an integral component in the lifestyle

https://doi.org/10.1016/j.dsx.2023.102778
1871-4021/© 2023 Research Trust of DiabetesIndia (DiabetesIndia) and National Diabetes Obesity and Cholesterol Foundation (N-DOC). Published by Elsevier Ltd. All rights
reserved.
P. Bhati, M.E. Hussain, K.K. Deepak et al.
management of T2DM [8]. A recent systematic review [9] indicated
that exercise training has positive impact on cardiac autonomic
control of T2DM patients. However, majority of the trials in this
review had adopted either aerobic training (AT) or combined
training protocols [9]. Considering various weight-bearing limita-
tions in T2DM patients due to the existence of complications and
coexisting conditions (obesity, degenerative arthritis etc.), partici-
pation of these patients is largely precluded in aerobic activities
which involve prolonged weight bearing [10]. In such situations,
resistance training (RT) may be considered as an effective alterna-
tive in which body weight is supported. Findings of a meta-analysis
[11] suggest that RT may modulate cardiac autonomic control in
diseased population and recommended more research in this area
specifically in populations wherein cardiac autonomic dysfunction
is prevalent such as DM. Moreover, since subclinical inflammation,
endothelial dysfunction and angiotensin II play an integral role in
the pathophysiology of CAN [6,12], it would be equally relevant to
investigate the biomarkers associated with these systems in order
to elucidate or comment on the physiological pathways involved in
RT-induced autonomic adaptations. It is to be noticed that assess-
ment of these biomarkers along with autonomic function has not
been done yet with respect to RT despite the physiological impor-
tance of these biomarkers in pathophysiology of CAN. This study is
a pioneering study in the area of T2DM induced CAN. The objective
of the present study was to investigate the effect of progressive RT
on outcomes of cardiac autonomic control, biomarkers of subclin-
ical inflammation, endothelial dysfunction, and angiotensin II in
T2DM patients with CAN. We hypothesized that progressive RT will
lead to a significant improvement in above mentioned outcomes
variables in T2DM patients with CAN.
2. Subjects
Sample size was calculated using Software G. Power 3.1.9. 2
(Franz F, Universitat Kiel, Kiel, Germany) using the data of changes
in HbA1c from a previous study [14]. A sample size of 48 T2DM
patients (24 per group) was deemed to be necessary with an effect
size of 0.69 and power of 0.95 at 0.05 a level to test the study hy-
pothesis. Considering 12% drop-outs, we targeted to recruit 54
T2DM patients with CAN for the present study. Diagnosed T2DM
cases [American Diabetes Association (ADA) criteria: HbA1c > 6.5%)
[15] which were found to be positive for CAN (early and definite
stage) as per Ewing's criteria [16] with a duration of T2DM  1 year
were recruited into the study. Patients with any severe cardiovas-
cular disease [17] morbid obesity (>40 kg/m2) or those who suf-
fered from uncontrolled hypertension i.e. systolic blood pressure/
diastolic blood pressure (SBP/DBP) > 165/95 mmHg, or any clinical
orthopedic problem that could limit his/her ability to participate in
exercise training without inducing pain and those involved in any
structured exercise training from last 6 months were excluded.
3. Materials and methods
The present study is reported in accordance with CONSORT
statement (checklist of information to include when reporting
randomized trial) (Supplementary File 1) [13].
3.1. Study design and settings
The present trial constituted a parallel arm single blinded
(blinding of the outcome assessor) randomized control trial design
registered prospectively under Clinical Trial Registry, India (regis-
tration number: CTRI/2018/04/013321). The study was conducted
conjointly at medical centre, Jamia Millia Islamia (JMI) and centre
for physiotherapy and rehabilitation sciences, JMI between April
2
Diabetes & Metabolic Syndrome: Clinical Research & Reviews 17 (2023) 102778
2018 and May 2019. Patients were recruited from university's
medical centre and initial assessment to screen eligible participants
was carried out there itself by the medical professionals. Later part
of the study (assessment of outcome variables and treatment) was
conducted at Human Performance Laboratory, centre for physio-
therapy and rehabilitation sciences. Blood samples for biochemical
analysis of biomarkers were collected at medical center by
competent professionals.
3.2. Study protocol
The present investigation was carried out after taking approval
from the Institutional Ethics Committee, JMI. The research pro-
cedures were carried out in accordance with the Declaration of
Helsinki, 1964.After explaining the study procedures to the par-
ticipants, a written informed consent was obtained for their
participation into the study. Initial screening identified a total of
105 T2DM patients which were further evaluated by cardiovascular
autonomic reflex tests (CARTs) for CAN. 64 came out to be positive
for CAN which were randomly allocated to either resistance
training (RT) (n ¼ 28) or control group (n ¼ 28) after baseline
assessment of outcome variables. RT group received whole body
resistance exercises for a period of 12 weeks and the control group
received usual care. All outcome variables were again assessed after
a period of 12 weeks. Assessment of outcome variables was per-
formed over a period of 2 days in a pre-defined order. On day 1,
blood samples were collected for the assessment of glycaemic
control and biomarkers. On day 2, autonomic function assessment
was performed in a set order i.e. resting heart rate variability (HRV),
cardiovascular autonomic reflex tests (CARTs) and post-exercise
HRV. Baroreflex sensitivity (BRS) data was derived from resting
HRV data.
3.3. Outcome measures
3.3.1. Cardiac autonomic control
3.3.1.1. Cardiovascular autonomic reflex testing. Prior to autonomic
testing, participant preparation was performed as per the standard
guidelines [18].The CARTs battery proposed by Ewing et al. [16]
comprises of three heart rate (HR) tests [deep breathing test (DBT),
Valsalva maneuver (VM) and head-up tilt (HUT) test] and two BP
tests [(HUT and hand-grip test (HGT)]. CARTs were performed as
per the standard procedures proposed by Ewing et al. (1985). Based
on the findings of CARTs, patients were classified as no-CAN (all
tests normal or 1 test borderline) or with CAN using the Ewing's
criteria [16] which stages CAN into early (1 HR test abnormal or 2
borderline), definite (two HR test abnormal) and severe (2 HR test
abnormal þ 1 or both BP tests abnormal) category.
3.3.1.2. HRV assessment and analysis. HRV recordings were per-
formed between 9 a.m. and 12 p.m. for all the participants to pre-
vent any diurnal variations. ANS modifying drugs were prohibited
24 h prior to the assessment. Participants were provided a rest
period of 15 min in supine position prior to testing. Standard lead II
electrocardiogram (ECG) configuration was utilized for this study
and ECG was recorded for 10 min in supine position. Analysis was
performed by detecting R waves during the last 5 min of the entire
record.
Post-exercise HRV was recorded after an acute sub-maximal
resistance exercise bout [19].The acute resistance exercise bout
(at sub-maximal intensity: 10 RM leg press) consisted of 5 sets of 10
repetitions each on a leg press machine (8 station multi-gym,
Fitness World, India). Two minutes of rest period was provided
between each set. Immediately after completion of the exercise
bout, participants were asked to lie down in supine position on the
P. Bhati, M.E. Hussain, K.K. Deepak et al.
bed adjacent to the leg press machine. ECG was recorded for the
next 10 min which included a 3-min transitional phase. Analysis
was performed on the R-R intervals between 3 and 8 minutes of the
ECG recorded post-exercise [20].
HRV data acquisition and analysis was performed in accordance
with the procedures published previously [18] and standard time
domain variables such as average of NeN intervals (Mean NN),
standard deviation of NeN intervals (SDNN), root mean square of
successive differences between adjacent R-R intervals (RMSSD),
standard deviation of successive differences (SDSD), percentage of
NeN intervals that vary by more than 50 ms (pNN50) and fre-
quency domain variables such as total power (TP), low frequency
(LF) power (0.04e0.15 Hz) and high frequency (HF) (0.15e0.4 Hz)
power were calculated at rest and after exercise along with the ratio
of LF and HF power i.e. LF/HF ratio. Non-linear variables such as
SD1and SD2 were obtained [21]. HRV data was recorded by lab
chart software version 7.3.7. (Power Lab 8 SP, AD Instruments, New
Zealand).
3.3.1.3. Heart rate recovery. HRR can be defined as the rate of
decline in HR during the first few minutes after exercise and it is
considered to be a valid measure of cardiac autonomic recovery
[22]. HR was derived from a continuous ECG record post-resistance
exercise bout described under “3.3.1.2. HRV assessment and analysis”
HRR was calculated as the absolute difference between HR at peak
exercise and heart rate recorded at 30 s-(HRR30s), 1- (HRR1min), 2-
min (HRR2min) and 3-min (HRR3min) after exercise.
3.3.1.4. Spontaneous baroreflex sensitivity. Spontaneous BRS is
determined by measuring “spontaneous change in R-R intervals in
response to changes in blood pressure (BP)” [23]. Last 5 min of the
continuous ECG record obtained for HRV analysis was utilized for
BRS assessment. Pulse wave was recorded by a piezoelectric pulse
transducer which was attached and firmly secured to the finger of
the participant. Changes in HR were assessed through changes in R-
R intervals and beat to beat fluctuations in blood pressure were
estimated through pulse transit time (PTT) due to unavailability of
continuous beat-to-beat blood pressure monitor. PTT was defined
as “the time taken by the pulse pressure waveform to propagate
through a length of the arterial tree” and is calculated as the time
interval between each R wave peak (which represents left ven-
tricular contraction) and the slope (defined as the point at which
signal voltage is 50% above the preceding baseline value and rep-
resents the time point when the circulating blood reaches pe-
riphery) of the corresponding pulse waveform [24]. There exists an
inverse relationship between PTT and BP [25]and literature has
shown that BP can be reliably estimated from PTT data [26,27]. In
the present study, beat to beat mean BP was estimated from the
corresponding PTT values using the following equation [28,29]:
2 least one session of training were included in the statistical anal-
Mean blood pressure ¼ Pb   DPTT
gPTTb
Where Pb is the first blood pressure during recording (base blood
pressure), PTTb is the value of the PTT corresponding to the pressure
Pb, while DPTT is the change in subsequent PTTs with respect to the
first PTT. g is a coefficient ranging from 0.016 to 0.018 (mmHg1). g
value of 0.017 (average of the range) was used for the present
analysis.
Calculation of PTT for the entire 5 min record and estimation of
BP using the above-mentioned equation was performed on MAT-
LAB software (The MathWorks, Inc, Natick, MA). Further, beat-to-
beat blood pressure values, along with R-R intervals obtained
from the ECG segment were processed on MATLAB software for
spectral analysis in order to estimate spectral measures of BRS
3
Diabetes & Metabolic Syndrome: Clinical Research & Reviews 17 (2023) 102778
using the code proposed by Akimoto et al. [30] Parameters such as
a-LF and a-HF were obtained which represents sympathetic and
parasympathetic contributions to change in BRS respectively [23].
3.3.2. Biochemical analysis for biomarkers
Venous blood samples were collected for all participants after
overnight fasting of around 8e12 h. Serum concentrations of
endothelial function biomarkers [nitric oxide (NO), endothelial
nitric oxide synthase (eNOS), endothelin-1 (ET-1)], inflammatory
biomarkers [interleukin-6 (IL-6), interleukin-18 (IL-18)] and
angiotensin II were examined using the ELISA method and pro-
cedures were executed as per the manufacturer's instructions
(Bioassay Technology Laboratory, China). Levels of High sensitivity
C-reactive protein (hs CRP) (an inflammatory biomarker) were
evaluated using a highly sensitive ELISA kit (Elabscience, USA).
3.4. Progressive resistance training
Intervention utilized in the present study i.e. RT is reported in
accordance with the TIDieR (Template for Intervention Description
and Replication) checklist (Supplementary File 2) [31]. Moderate
intensity [65e75% of 1 repetition maximum (RM)] progressive RT
was performed 3 times/week for 12 weeks. All the sessions were
conducted in laboratory and supervised by a trained physiothera-
pist. Two to three sets of 8e12 repetitions (with 2e3 min of rest
between the sets) were performed for each exercise in each session
in a set order: leg press, abdominal curl, lateral pull-down, seated
row, bicep curl, butterfly, bench press, knee extension, overhead
triceps extension, standing leg curls. Each exercise session lasted
for around 60 min. Exercise intensity was progressed gradually
from 65% of 1 RM to 75% of 1 RM over a period of 12 weeks. For the
initial four weeks, intensity was kept at 65% of 1 RM. It was pro-
gressed to 70% of mid-study 1RM at the end of 4th week and then to
75% of 1RM calculated at 8th week. Warm up and cool down con-
sisted of 10 min of cycling on self-selected pace and low load
prolonged stretches (2e3 repetitions) of the exercising muscles [8].
Whole-body resistance exercises were executed with the help of
weight machines and free weights in a set order.
3.5. Statistical analysis
Statistical analysis was performed on SPSS Inc. version 21.0,
Chicago, IL, USA. Normality of the continuous outcome variables
was examined by Kolmogorov-Smirnov test and non-normal vari-
ables were log transformed prior to further analysis. A p-value
<0.05 was considered significant for the analysis. Data is presented
as mean ± standard deviation, median (interquartile range) and as
frequencies/percentages wherever required. The Intention-To-Treat
(ITT) principle was employed in the present analysis in which all
participants who were randomized to the study and received at
ysis. Demographic, clinical characteristics and outcome variables
were compared between the RT and control group using inde-
pendent t-test. Chi-square test was used to compare the fre-
quencies (sex, DM complications and medications) between
groups. A 2  2 repeated measures analysis of variance (ANOVA)
was employed to examine the effects of RT on outcome variables
and main effects of group (RT versus control), time (baseline and
12th week), and group  time interaction were calculated.
4. Results
A total of 105 T2DM patients were screened for CAN in the
present study, of which 64 were found to be positively diagnosed
for CAN. Fifty-six of the positive CAN cases were recruited into the
P. Bhati, M.E. Hussain, K.K. Deepak et al.
present study which were randomized into RT (n ¼ 28) and control
group (n ¼ 28). A total of 8 patients, 4 in each RT [disinterest (n ¼ 2),
other illness (n ¼ 2)], and 4 in control group [disinterest (n ¼ 3),
other illness (n ¼ 1)] dropped out of the study (Fig. 1). No adverse
events were reported in the present study in response to RT.
However, the data of all 58 patients was analyzed using ITT prin-
ciple. Demographic and outcome variables were found to be com-
parable between the groups at baseline (Tables 1 and 2).
Among CARTs, variables of parasympathetic cardiac control
such as E:I ratio, DHR, VR, and 30:15 ratio showed significant im-
provements after RT (Table 3). Among time domain HRV variables
at rest, all variables showed either a significant group effect or
group  time effect or both (p < 0.05) (Table 3). All frequency
domain variables of HRV showed significant group  time inter-
action demonstrating significant effect of RT on resting HRV
(Table 3). Among non-linear HRV measures, SD1 showed a signifi-
cant time (p ¼ 0.03), and group  time interaction effect (p < 0.001)
showing a significant increase after RT (Table 3).
All post-exercise time domain HRV parameters showed signifi-
cant improvements after RT (Table 4). Except for post-exercise LF/
HF ratio, all other frequency domain variables demonstrated either
significant main effect of group or group  time interaction
(Table 4). Post-exercise SD1 showed significant time (p ¼ 0.003)
and group  time interaction effect (p < 0.001). HRR30s and HRR1min
Fig. 1. Participant flow through the study.
4
Diabetes & Metabolic Syndrome: Clinical Research & Reviews 17 (2023) 102778
showed significant group [HRR30s, p < 0.001; HRR1min, p ¼ 0.01],
time [HRR30s, p < 0.001; HRR1min, p ¼ 0.02] and interaction effect
[HRR30s, p < 0.001; HRR1min, p ¼ 0.001] (Table 4). Both a-LF and a-
HF demonstrated significant interaction effects post-RT [a-LF,
p ¼ 0.003; a-HF, p ¼ 0.002] showing a significant effect of RT on BRS
gain (Table 4).
Among biomarkers of subclinical inflammation, serum IL-6 and
IL-18 showed a significant reduction by 12.6% and 12% respectively
after RT while serum hsCRP was found to be reduced in both the
groups (RT: 12.5%, Control: 8.6%).Among endothelial function bio-
markers, only serum eNOS showed a significant increase (32.6%)
after RT while other biomarkers did not show a significant change
(Table 5).
5. Discussion
Main findings of the present study suggested that moderate
intensity progressive RT (1) leads to a significant improvement in
outcomes of CAN, (2) down-regulates serum levels of IL-6 and IL-
18, (3) up-regulates serum levels of eNOS, and (4) significantly
improves glycaemic control in T2DM patients with CAN.
Findings of the present study revealed significant improvements
in parameters of cardiac autonomic control in T2DM patients with
CAN after 12 weeks of moderate intensity progressive RT. In the
P. Bhati, M.E. Hussain, K.K. Deepak et al. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 17 (2023) 102778

Table 1 and LF/HF ratio post 4 months of RT. Findings of Bellavere et al. [35]
Comparison of demographic and clinical characteristics between the groups at suggested that RT enhances sympatho-vagal balance and causes
baseline.
vagal modulation in T2DM patients without CAN and the present
Variables RT (n ¼ 28) Control (n ¼ 28) p-value study confirms the same on T2DM patients with CAN. Improve-
Mean ± SD Mean ± SD ments seen in post-exercise HRV parameters in the present study
Demographics are in accordance with the findings of Caruso et al. [36] in which a
Age (years) 52.8 ± 6.82 54.0 ± 8.18 0.56 significant increase in parameters of cardiac vagal control [RMSSD,
Sex (M/F) 15/13 17/11 0.58
SD1, SDNN (assessed during exercise)] was observed after 8 weeks
DM duration (years) 9.5 ± 7.70 7.7 ± 5.09 0.61
Height (m) 1.61 ± 0.09 1.61 ± 0.08 0.91 of low intensity (30% of 1RM) RT.
Weight (kg) 74.0 ± 8.36 73.3 ± 9.81 0.78 RT-mediated adaptations in resting cardiac autonomic activity
BMI (kg/m2) 28.4 ± 3.35 28.0 ± 3.82 0.67 could be attributed to baroreflex-NO axis since significant im-
Physical activity (MET-min/week) 572.8 ± 271.30 580.3 ± 303.38 0.78
provements in BRS and eNOS function were also observed in the
Comorbidities, n (n%)
Hypertension 12 (42.8) 13 (46.4) 0.78
present study. Baroreflex-NO axis primarily works on enhancing
Dyslipidemia 21 (75) 17 (60.7) 0.25 vagal modulation and decreasing cardiac and vascular sympathetic
Thyroid dysfunction 4 (14.2) 9 (32.1) 0.75 modulation [37]. An enhanced vascular endothelial function
Musculoskeletal issues 3 (10.7) 4 (14.2) 0.68 observed in the present study might have caused cardiac auto-
DM complications, n (n%)
nomic modulation in the present sample since it is directly linked
Peripheral neuropathy 4 (14.2) 7 (25) 0.31
Retinopathy 1 (3.5) 2 (7.1) 0.08 to autonomic nerve fibers. Reductions in pro-inflammatory cyto-
Nephropathy 2 (7.1) 0 (0) 0.15 kines were also observed in the present investigation which may
Drugs, n (n%) explain modulation in cardiac autonomic tone in the present study
Metformin 13 (46.4) 15 (53.5) 0.59 as they are related via the “cholinergic anti-inflammatory
Sulfonylureas 6 (21.4) 5 (17.8) 0.73
ACE inhibitors 4 (14.2) 1 (3.5) 0.16
pathway”. Interestingly, improvement in cardiac autonomic re-
Statins 6 (21.4) 5 (17.8) 0.73 covery in response to RT in the present investigation could be
Ca channel blockers 1 (3.5) 0 (0) 0.31 explained by the complex model of autonomic recovery which says
DPP4 inhibitors 2 (7.1) 1 (3.5) 0.55 that after completion of exercise, there is an abrupt removal of
Thiazolidnedione 1 (3.5) 1 (3.5) 1.00
“central command” along with reduced feedback from the mech-
Dapagliflozin 0 (0) 1 (3.5) 0.31
a-glucosidase inhibitor 3 (10.7) 2 (7.1) 0.63 anoreceptors in the muscles after cessation from exercise which
Insulin 4 (14.2) 2 (7.1) 0.38 altogether re-sets the baroreflex to a lower operating point in order
b-blocker 2 (7.1) 1 (3.5) 0.55 to decrease HR [38]. [39].
T2DM: type 2 diabetes mellitus; RT: resistance training; m: meters; kg: kilogram; The present experiment found a significant decrease in a-LF and
SD: standard deviation; M: males; F: females; BMI: body mass index; ACE: angio- a significant increase in a-HF baroreflex gain which indicates
tensin converting enzyme; Ca: calcium; DPP4:dipeptidyl peptidase 4; DM: diabetes improvement in both sympathetic and parasympathetic baroreflex
mellitus; m: meters; kg: kilogram; min: minute; mmHg: millimeters of mercury;
control post-RT. Cooke and Carter [40] conducted a study on 22
mg: milligram; dl: decileters; mm: millimeters; MET: metabolic equivalent; p-
value: probability value; Data are presented as mean ± standard deviation. healthy young men and investigated the effects of 8 weeks of RT on
BRS parameters. Findings of their study [40] revealed no change in
BRS after RT whereas in contrary to the findings of Cooke and Carter
present study, CARTs that denote parasympathetic reactivity such [40] and in accordance with our findings, Jakovljevic et al. [41]
as E:I ratio, DHR, 30:15 ratio and VR demonstrated a significant found significant increase in BRS post-RT of 8 weeks in non-
increase post-RT. However, measures of cardiac sympathetic reac- alcoholic fatty liver disease. Enhanced BRS in the present study
tivity (DSBP, DDBP) did not demonstrate any group differences could be explained by baroreflex-NO axis (since improvement in
post-RT which indicates that 12 weeks of RT does not positively endothelial function was also seen in the present study) [37].
influence sympathetic cardiac control whereas it causes some vagal The present study demonstrated significant reductions in IL-6
modulation. We could not find any study where effect of RT was (12.6%) and IL-18 (12%) post-RT of 12 weeks whereas hsCRP
examined on CARTs in T2DM but a study [32] on the effect of showed a significant reduction in both the groups (RT as well as
combined aerobic and RT was unable to change CARTs significantly control). In accordance with our findings, RT has shown significant
in T2DM patients. However, in the study of Sacre et al. [32] CAN was reductions in the serum concentration of inflammatory biomarkers
not evaluated at baseline in contrary to the present study where such as CRP, TNF-a and IL-6 in animal models of diabetes [42].
T2DM patients with CAN were recruited. Though non-significant, Though we could not find any study on the effects of RT on IL-18 in
an increase was observed in E:I ratio in the exercise group as T2DM patients, a study investigating the effects of combined AT and
compared to control (Exercise: 0.18 to 0.21, Control: 0.24 to 0.24) in RT was found in which statistically significant reduction in the
the study of Sacre et al. [32] which indicates some sort of modu- serum concentrations of IL-18 was observed in T2DM patients
lation in autonomic reflexes by exercise training. Hence, there ex- suggesting positive influence of exercise on pro-inflammatory
ists very scarce literature on RT and CARTs to compare the present mediators [43]. In the present experiment, significant improve-
findings, but some existing evidence [33] suggests that trained ments were also observed in parameters of cardiac vagal control
subjects possess better cardiovascular reflex control than untrained and thus, it may be speculated that enhanced vagal function might
and speculated that modulation of cardiovascular responses after have modulated inflammatory responses through “cholinergic
training involves alteration of descending cortical drive [34]. anti-inflammatory pathway” [44].
Significant improvements in most of the HRV parameters (both In the present investigation, we did not find any significant
at rest and post-exercise) were seen post-RT in the present study. improvement in either serum levels of NO or ET-1.However, a sig-
Our findings are in conformity with a recent rigorous meta-analysis nificant increase was observed in serum eNOS concentration after
[11] which showed that RT leads to significant improvements in RT. These findings compel us to speculate that RT probably
RMSSD, LF/HF ratio and some non-linear measures of HRV in increased the endothelial NO which might not be reflected in the
diseased individuals. Though there exists no study on T2DM pa- total serum concentration of NO that comprises of the total NO
tients with CAN, a pilot investigation [35] on T2DM patients secreted by other NO isoforms too apart from eNOS. It may be
without CAN demonstrated significant increase in HF power of HRV speculated that, in the present study, we might have obtained
5
P. Bhati, M.E. Hussain, K.K. Deepak et al. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 17 (2023) 102778

Table 2
Comparison of outcome variables between the groups at baseline.

Variables RT (n ¼ 28) Control (n ¼ 28) p-value

Mean ± SD Mean ± SD
Glycaemic parameters
FBG (mg/dl) 163.4 ± 50.98 166.5 ± 67.15 0.91
PPBG (mg/dl) 242.1 ± 78.97 231.0 ± 91.68 0.91
HbA1c (%) 8.4 ± 1.52 8.2 ± 1.73 0.57
CARTs
Diagnosis, n (n%)
Early 18 (64.2) 21 (75.0) 0.38
Definite 10 (35.7) 7 (25.0) 0.38
Severe e e e
E:I ratio 1.12 ± 0.11 1.16 ± 0.10 0.15
DHR 11.0 ± 4.59 10.3 ± 5.30 0.44
VR 1.21 ± 0.32 1.01 ± 0.66 0.23
DDBP (mmHg) 17.7 ± 5.10 17.7 ± 4.06 0.79
30:15 ratio 1.15 ± 0.15 1.11 ± 0.21 0.20
DSBP (mmHg) 2.0 (18, 20) 3.5 (18, 14) 0.61
Resting HRV parameters
Mean NN (ms) 753.3 ± 110.46 748.6 ± 109.44 0.87
SDNN (ms) 30.6 ± 18.84 28.4 ± 10.36 0.58
RMSSD (ms) 26.4 ± 14.60 27.6 ± 8.21 0.70
pNN50 (%) 1.73 ± 1.35 1.63 ± 1.26 0.87
SDSD (ms) 23.0 ± 15.85 18.9 ± 14.65 0.06
TP (ms2) 618.0 ± 223.49 767.6 ± 361.69 0.25
LFpower(ms2) 218.8 ± 108.02 275.5 ± 215.22 0.21
LFnu power 45.5 ± 14.45 54.0 ± 46.39 0.36
HF power (ms2) 258.2 ± 129.89 302.0 ± 166.27 0.27
HFnu power 53.6 ± 13.99 44.7 ± 19.10 0.053
LF/HF ratio 0.99 ± 0.58 1.55 ± 1.92 0.16
SD1 (ms) 22.5 ± 10.32 23.5 ± 9.00 0.66
SD2 (ms) 33.6 ± 15.18 31.9 ± 15.25 0.55
Post-exercise HRV parameters
Mean NN (ms) 673.6 ± 80.84 683.9 ± 91.80 0.68
SDNN (ms) 26.9 ± 13.15 23.5 ± 4.86 0.51
RMSSD (ms) 15.5 ± 3.88 15.3 ± 5.94 0.48
pNN50 (%) 1.21 ± 1.06 1.14 ± 1.02 0.54
SDSD (ms) 17.6 ± 6.71 21.0 ± 9.70 0.13
TP (ms2) 560.7 ± 134.24 501.2 ± 88.51 0.06
LF power (ms2) 209.3 ± 89.56 202.5 ± 54.85 0.95
LFnu power 53.1 ± 9.58 56.4 ± 10.76 0.20
HF power (ms2) 176.3 ± 48.05 158.9 ± 38.36 0.15
HFnu power 46.8 ± 9.58 48.32 ± 6.84 0.053
LF/HF ratio 1.23 ± 0.54 1.20 ± 0.33 0.85
SD1 (ms) 22.5 ± 10.32 24.9 ± 8.27 0.22
SD2 (ms) 35.0 ± 12.74 30.5 ± 13.49 0.15
Heart rate recovery
Peak HR (beats/min) 155.7 ± 11.82 152.3 ± 9.90 0.24
HRR30s (beats/min) 3.0 ± 12.00 2.40 ± 2.20 0.27
HRR1 (beats/min) 21.1 ± 8.41 17.1 ± 13.6 0.19
HRR2 (beats/min) 32.1 ± 10.17 27.2 ± 11.6 0.09
HRR3 (beats/min) 63.3 ± 14.45 59.4 ± 15.0 0.33
Baroreflex sensitivity
a -LF (ms/mmHg) 18.9 ± 8.75 15.1 ± 5.85 0.16
a eHF (ms/mmHg) 16.7 ± 7.55 13.2 ± 8.67 0.34
Biomarkers
IL-6 (ng/L) 21.4 ± 9.64 19.6 ± 13.49 0.17
IL-18 (ng/L) 182.9 ± 93.77 175.5 ± 105.45 0.65
hs CRP (mg/L) 2.40 ± 1.64 2.37 ± 1.27 0.59
NO (mmol/L) 80.5 ± 37.03 80.3 ± 42.61 0.81
eNOS (U/mL) 82.3 ± 46.44 95.4 ± 43.40 0.41
ET-1 (ng/L) 134.0 ± 56.97 117.7 ± 44.47 0.25
Angiotensin II (ng/L) 74.8 ± 36.61 62.7 ± 23.10 0.19

RT: resistance training; SD: standard deviation; HRV: heart rate variability; FBG: fasting blood glucose; PPBG: post-prandial blood glucose; HbA1c: glycosylated hemoglobin;
CARTs: cardiovascular autonomic reflex tests; E:I ratio: ratio of the average of longest R-R interval during expiration and the shortest R-R interval during inspiration of the deep
breathing test; DHR: change in R-R intervals during six consecutive cycles of deep inspiration and expiration; 30:15 ratio: ratio of the longest R-R interval during 30s and the
shortest R-R interval during 15th s of the head-up tilt test; VR: valsalva ratio; DSBP: change in systolic blood pressure during head-up tilt test; DDBP: change in diastolic blood
pressure during hand grip test; Mean NN: average of NeN intervals; SDNN: standard deviation of NeN intervals; RMSSD: root mean square of successive differences between
adjacent NeN intervals; pNN50: Proportion of differences in consecutive NeN intervals that are longer than 50 ms; SDSD: standard deviation of successive differences; TP:
total power; LF: low frequency; HF: high frequency; LF/HF ratio: ratio of low and high frequency power; SD1: standard deviation of instantaneous beat-to-beat NeN vari-
ability; SD2: standard deviation of continuous beat-to-beat interval variability; HR: heart rate; HRR: heart rate recovery; aeLF: sympathetic nervous system-mediated
baroreflex sensitivity; a-HF: parasympathetic nervous system-mediated baroreflex sensitivity; IL-interleukin; NO: nitric oxide; eNOS: endothelial nitric oxide synthase;
ET-1: endothelin-1; hs CRP: high sensitivity C reactive protein ms: milliseconds; %: percent; mmHg: millimeters of mercury; ng: nanogram; mL: milliliters; L: liters; mg;
milligram; mmol: micro-mole; dl: deciliter; p-value: probability values. Data are presented as mean ± standard deviation except for DSBP which is presented as median
(interquartile range).

6
P. Bhati, M.E. Hussain, K.K. Deepak et al. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 17 (2023) 102778

Table 3
Comparison of glycaemic control parameters, CARTs and resting heart rate variability parameters between the groups before and after 12 weeks study period.

Variables RT (n ¼ 28) Control (n ¼ 28) p-values

Baseline 12th week Baseline 12th week Mean difference between groups (CI) Group Time Group  Time
Mean ± SD Mean ± SD Mean ± SD Mean ± SD
FBG (mg/dl) 163.4 ± 50.98 141.0 ± 33.87 166.5 ± 67.15 166.6 ± 64.11 25.50 (52.36, 1.36) 0.32 0.001* 0.001*
PPBG(mg/dl) 242.1 ± 78.97 200.7 ± 70.40 231.0 ± 91.68 227.8 ± 85.53 27.10 (68.13, 13.93) 0.71 <0.001* <0.001*
HbA1c (%) 8.4 ± 1.52 7.6 ± 1.34 8.2 ± 1.73 8.2 ± 1.79 0.60 (1.43, 0.23) 0.52 <0.001* <0.001*
E:I ratio 1.12 ± 0.11 1.16 ± 0.08 1.16 ± 0.10 1.16 ± 0.07 0.00 (5.59, 5.59) 0.44 0.01* 0.03*
DHR (beats/min) 11.0 ± 4.59 13.9 ± 5.09 10.3 ± 5.30 10.5 ± 5.37 3.40 (1.51, 5.29) 0.81 0.11 0.001*
VR 1.21 ± 0.32 1.33 ± 0.35 1.01 ± 0.66 0.97 ± 0.62 0.36 (0.10, 0.62) 0.47 0.15 0.005*
30:15 ratio 1.15 ± 0.15 1.29 ± 0.28 1.11 ± 0.21 1.05 ± 0.06 0.24 (0.01, 0.49) <0.001* 0.18 0.002*
D DBP (mmHg) 17.75 ± 5.10 18.0 ± 5.47 17.4 ± 4.06 17.78 ± 4.19 0.22 (3.40, 3.84) 0.77 0.53 0.96
D SBP (mmHg) 2 (18, 20) 5 (16, 16) 3.5 (18, 14) 6 (18, 14) e 0.71ǂ
Mean NN (ms) 753.3 ± 110.46 769.7 ± 119.32 748.6 ± 109.44 754.2 ± 119.76 15.50 (47.12, 78.12) 0.73 0.02* 0.54
SDNN (ms) 30.6 ± 18.84 34.5 ± 17.88 28.4 ± 10.36 26.3 ± 9.82 8.20 (0.64, 15.76) 0.17 0.41 0.01*
RMSSD (ms) 26.4 ± 14.60 35.7 ± 13.85 27.6 ± 8.21 26.4 ± 8.08 9.30 (3.36, 15.24) 0.17 <0.001* <0.001*
pNN50 (%) 1.73 ± 1.35 2.91 ± 2.03 1.63 ± 1.26 2.04 ± 1.80 0.87 (108.09, 109.83) 0.004* 0.001* 0.12
SDSD (ms) 23.0 ± 15.85 31.5 ± 17.08 18.9 ± 14.65 18.5 ± 12.93 12.60 (4.27, 20.93) 0.004* 0.01* 0.02*
TP (ms2) 618.0 ± 223.49 790.0 ± 368.78 767.6 ± 361.69 680.6 ± 294.16 109.40 (39.72, 258.52) 0.79 0.21 <0.001*
LF power (ms2) 218.8 ± 108.02 200.8 ± 100.67 275.5 ± 215.22 285.4 ± 148.1 84.60 (122.26, 46.94) 0.18 0.39 0.01*
LFnu power 45.5 ± 14.45 34.5 ± 13.76 54.0 ± 46.39 58.7 ± 14.31 24.20 (31.55, 16.85) 0.006* 0.72 <0.001*
HF power (ms2) 258.2 ± 129.89 410.4 ± 226.59 302.0 ± 166.27 198.8 ± 146.94 211.6 (111.57, 311.63) 0.01* 0.06 <0.001*
HFnu power 53.6 ± 13.99 65.4 ± 13.6 44.7 ± 19.10 39.3 ± 16.29 26.10 (28.56, 80.76) <0.001* 0.08 <0.001*
LF/HF ratio 0.99 ± 0.58 0.61 ± 0.43 1.55 ± 1.92 1.86 ± 1.06 1.25 (7.29, 4.79) <0.001* 0.30 <0.001*
SD1 (ms) 22.5 ± 10.32 30.6 ± 11.63 23.5 ± 9.00 23.2 ± 9.55 7.40 (1.83, 12.97) 0.26 0.02* 0.01*
SD2 (ms) 33.6 ± 15.18 31.4 ± 13.01 31.9 ± 15.25 33.7 ± 20.30 2.30 (9.56, 4.96) 0.76 0.95 0.38

RT: resistance training; CI: confidence intervals; SD: standard deviation; FBG: fasting blood glucose; PPBG: post-prandial blood glucose; HbA1c: glycosylated hemoglobin;
CARTs: cardiovascular autonomic reflex tests; E:I ratio: Ratio of the average of longest R-R interval during expiration and the shortest R-R interval during inspiration of the
deep breathing test; DHR: change in heart during deep breathing test; VR: valsalva ratio; D DBP: change in diastolic blood pressure during hand grip test; 30:15 ratio: ratio of
R-R intervals at 30th and 15th s of head-up tilt test; DSBP: change in systolic blood pressure during head-up tilt test; MeanNN: average of NeN intervals; SDNN: standard
deviation of NeN intervals; RMSSD: root mean square of successive differences between adjacent R-R intervals; pNN50:Proportion of differences in consecutive NeN intervals
that are longer than 50 ms; SDSD: standard deviation of successive differences; TP: total power; LF: low frequency; HF: high frequency; nu: normalized units; LF/HF ratio: ratio
of low and high frequency power; SD1: standard deviation of instantaneous beat-to-beat NeN variability; SD2: standard deviation of continuous beat-to-beat interval; ms:
millisecond; p-values: probability values; ǂnon-parametric test applied; *significant difference.

significant rise in endothelial NO levels, however, we could not observed in the present study. Importantly, eNOS is primarily
measure it directly (serum NO does not reflect endothelial NO). responsible for the production of majority of the endothelial NO
Nevertheless, despite no significant change in serum NO concen- since it oxidizes L-arginine to L-citrulline to produce NO. Thus,
tration, a significant increase in the serum eNOS concentration was endothelial dysfunction could occur due to reduced eNOS

Table 4
Comparison of post-exercise HRV, HRR and baroreflex sensitivity between the groups before and after 12 weeks study period.

Variables RT (n ¼ 28) Control (n ¼ 28) p-values

Baseline 12th week Baseline 12th week Between group difference (CI) Group Time Group  Time
Mean ± SD Mean ± SD
Mean NN (ms) 673.6 ± 80.84 703.3 ± 79.13 683.9 ± 91.80 736.9 ± 126.76 33.60 (88.95, 21.75) 0.43 <0.001* 0.40
SDNN (ms) 26.9 ± 13.15 30.5 ± 13.10 23.5 ± 4.86 21.7 ± 5.79 8.80 (3.62,13.98) 0.04* 0.43 <0.001*
RMSSD (ms) 15.5 ± 3.88 22.4 ± 8.10 15.3 ± 5.94 17.2 ± 5.48 5.20 (1.58, 8.82) 0.051 <0.001* 0.01*
pNN50 (%) 1.21 ± 1.06 1.67 ± 1.38 1.14 ± 1.1.02 0.80 ± 0.67 0.87 (14.91, 16.65) 0.02* 0.40 0.003*
SDSD (ms) 17.6 ± 6.71 20.1 ± 9.87 21.0 ± 9.70 23.4 ± 14.81 3.30 (9.89, 3.29) 0.02* 0.25 <0.001*
TP (ms2) 560.7 ± 134.24 620.0 ± 215.22 501.2 ± 88.51 477.9 ± 99.42 142.10 (54.29, 229.91) 0.004* 0.90 0.17
LF power (ms2) 209.3 ± 89.56 202.7 ± 62.83 202.5 ± 54.85 215.4 ± 68.46 12.7 (47.12, 21.72) 0.62 0.66 0.56
LFnu power 53.1 ± 9.58 50.9 ± 9.78 56.4 ± 10.76 59.1 ± 11.24 8.20 (13.72, 2.68) 0.01* 0.96 0.15
HF power (ms2) 176.3 ± 48.05 196.4 ± 78.68 158.9 ± 38.36 146.7 ± 41.18 49.7 (16.81, 82.59) 0.005* 0.95 0.03*
HFnu power 46.8 ± 9.58 49.0 ± 9.78 48.3 ± 6.84 41.4 ± 11.52 7.60 (2.08, 13.12) <0.001* 0.08 <0.001*
LF/HF ratio 1.23 ± 0.54 1.15 ± 0.41 1.20 ± 0.33 1.25 ± 0.33 0.10 (0.39, 0.19) 0.46 0.96 0.15
SD1 (ms) 22.5 ± 10.32 32.5 ± 11.32 24.97 ± 8.27 22.1 ± 8.11 10.40 (5.24, 15.56) 0.17 0.003* <0.001*
SD2 (ms) 35.0 ± 12.74 35.0 ± 13.46 30.5 ± 13.49 31.9 ± 15.58 3.10 (4.53, 10.73) 0.16 0.80 0.16
HRpeak (beats/min) 155.7 ± 11.82 151.7 ± 12.45 152.3 ± 9.90 149.7 ± 11.87 2.00 (4.37, 8.37) 0.34 0.01* 0.56
HRR30s (beats/min) 3.0 ± 2.00 11.7 ± 8.02 2.4 ± 2.2 3.0 ± 2.88 8.66 (3.35, 13.97) <0.001* <0.001* <0.001*
HRR1min beats/min) 21.1 ± 8.41 28.5 ± 14.71 17.1 ± 13.6 15.9 ± 12.9 12.60 (7.05, 18.15) 0.01* 0.02* 0.001*
HRR2min (beats/min) 32.1 ± 10.17 33.0 ± 14.18 27.2 ± 11.6 26.3 ± 15.40 6.70 (0.20, 13.60) 0.07 0.99 0.53
HRR3min (beats/min) 63.3 ± 14.45 64.6 ± 14.41 59.4 ± 15.0 57.2 ± 15.10 7.40 (0.33, 15.13) 0.13 0.76 0.23
a-LF (ms/mmHg) 18.9 ± 8.75 14.1 ± 7.01 15.1 ± 5.85 16.8 ± 8.28 2.70 (6.72, 1.32) 0.97 0.06 0.003*
a-HF (ms/mmHg) 16.7 ± 7.55 20.4 ± 7.52 13.2 ± 8.67 15.1 ± 10.24 5.30 (0.59, 10.01) 0.02* 0.02* 0.002*

RT: resistance training; CI: confidence intervals; SD: standard deviation; HRV: heart rate variability; HR: heart rate; HRR: heart rate recovery; BRS: baroreflex sensitivity; Mean
NN: mean of NeN intervals; SDNN: standard deviation of NeN intervals; RMSSD: root mean square of successive differences between adjacent R-R intervals; pNN50: Pro-
portion of differences in consecutive NeN intervals that are longer than 50 ms; SDSD: standard deviation of successive differences; TP: total power; LF: low frequency; HF:
high frequency; LF/HF ratio: ratio of low and high frequency power; SD1: standard deviation of instantaneous beat-to-beat NeN variability; SD2: standard deviation of
continuous beat-to-beat interval variability; aeLF: sympathetic nervous system-mediated baroreflex sensitivity; a-HF: parasympathetic nervous system-mediated baroreflex
sensitivity; ms: milliseconds; mmHg: millimeters of mercury; min: minute; p-values: probability values; *significant difference.

7
P. Bhati, M.E. Hussain, K.K. Deepak et al. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 17 (2023) 102778

Table 5
Comparison of biomarkers between the groups before and after 12 weeks study period.

Variables RT (n ¼ 28) Control (n ¼ 28) Mean difference between groups (CI) p-values

Baseline 12th week Baseline 12th week Group Time Group  Time
Mean ± SD Mean ± SD Mean ± SD Mean ± SD
IL-6 (ng/L) 21.4 ± 9.64 18.7 ± 9.76 19.6 ± 13.49 20.6 ± 14.11 1.90 (8.25, 4.45) 0.61 0.42 0.03*
IL-18 (ng/L) 182.9 ± 93.77 160.8 ± 104.76 175.5 ± 105.45 179.0 ± 103.69 18.20 (72.80, 36.40) 0.65 0.02* 0.004*
hsCRP (mg/L) 2.4 ± 1.64 2.1 ± 1.42 2.3 ± 1.27 2.1 ± 1.08 0.00 (0.82, 0.26) 0.41 0.02* 0.16
NO (mmol/L) 80.5 ± 37.03 83.3 ± 56.6 80.3 ± 42.6 79.8 ± 38.6 3.50 (17.47, 24.47) 0.92 0.71 0.74
eNOS (U/mL) 82.3 ± 46.44 109.2 ± 54.05 95.4 ± 43.40 92.6 ± 39.37 16.60 (8.17, 41.37) 0.94 0.01* 0.03*
ET-1 (ng/L) 134.0 ± 56.97 125.5 ± 48.22 117.7 ± 44.4 114.8 ± 33.2 10.70 (12.36, 33.76) 0.16 0.55 0.77
Angiotensin II (ng/L) 74.8 ± 36.61 75.5 ± 34.61 62.7 ± 23.10 60.7 ± 24.16 14.80 (0.83, 30.43) 0.09 0.70 0.16

RT: resistance training; SD: standard deviation; CI: confidence intervals; SD: standard deviation; IL-6: interleukin-6; hsCRP: high sensitivity C-reactive protein; NO: nitric
oxide; eNOS: endothelial nitric oxide synthase; ET-1: endothelin-1; ng: nanongram; L: litre; mg: milligram; mmol: micro-mole; mmol: milli-mole; U: standard units; p-values:
probability values; *significant difference.

expression, the main precursor of endothelial NO which is involved 6. Conclusion

in vascular remodeling [45]. In accordance with the findings of
present investigation, a previous study [46] also found significant
increase in the eNOS messenger ribonucleic acid after 10 weeks of
RT. Moreover, it is also believed that RT-induced increase in blood
flow in the vessels or the shear stress applied by muscle contrac-
tions enhances endothelial function by increasing NO production
since shear stress and stretch has a role in vascular mechanobiology
[47]. In the present study, we could not find any changes in serum
levels of angiotensin II after RT though positive changes in car-
diovagal control and baroreflex control were observed which sug-
gests that RT-mediated vascular and autonomic adaptations are
independent of the action of angiotensin II and RAAS. Moreover, RT
is known to improve muscle strength and function, largely due to
induction of muscle hypertrophy and neuromuscular remodeling
[48] through phosphatidylinositol 3 kinase (P13k)-Akt-mammalian
target of rapamycin (mTOR) pathway [49]. Moreover, RT also in-
duces morphological (increased skeletal muscle cross-sectional
area, volume) and functional neuromuscular adaptations
(increased number and size of motor units, enhanced recruitment
and synchronized firing of motor units) [49]. Existing literature
suggests an intricate link between muscle function and sympatho-
vagal balance [50] and therefore, it could be speculated that RT-
induced neuromuscular adaptations might have contributed to an
extent in autonomic function re-modelling in T2DM patients with
CAN.
To the best of our knowledge, present study is the first which
holistically and rigorously evaluates the effect of progressive RT on
outcomes of cardiac autonomic control in T2DM patients with CAN.
Moreover, novelty and strength of this study lies in the fact that it
comments on the mechanisms related to RT-induced autonomic
adaptations in T2DM patients based on true experiments. The
present study has added significant knowledge in the area of T2DM
patients with CAN which will help the scientific fraternity in a great
way. There were some limitations to this study though. T2DM pa-
tients in the present study were on drugs that may modulate car-
diac autonomic function which might have confounded cardiac
autonomic function data. However, to address the same, con-
sumption of ANS-modifying drugs was prohibited 24 h prior to
assessment. The fact to be noted is that T2DM patients in the pre-
sent study were affected by comorbidities such as hypertension and
dyslipidemia which have effects on cardiac autonomic function.
Most importantly, due to unavailability of the equipment, we did
not obtain direct beat-to-beat blood pressure measurements for
BRS assessment; rather it was estimated from pulse transit time.
Although all enrolled subjects were provided dietary counselling,
confounding effects of their caloric intake were not taken into
account.
8
The present study provides preliminary evidence regarding the
beneficial effects of RT on cardiac autonomic control in T2DM pa-
tients and concludes that it has the potential to enhance deterio-
rating cardiac autonomic function in T2DM patients with CAN. RT
down-regulates serum concentration of inflammatory biomarkers
(IL-6 and IL-18) which suggests its role as an anti-inflammatory
agent for T2DM patients and up-regulates serum eNOS concen-
tration which indicates that it may play some role in vascular
remodeling in T2DM patients.
7. Clinical relevance
Findings of the present study are clinically relevant and add
significant new knowledge in the existing literature and reinforces
the existing literature regarding the beneficial effects of RT and
recommends its utilization as an adjunct exercise form in South
Asian T2DM patients suffering from CAN. These findings are worthy
for both clinicians and researchers working with T2DM patients.
Funding
The present study was not funded by any external funding
organization.
Ethics approval and consent to participate
The present trial was ethically approved by the Institutional
Ethics Committee, Jamia Millia Islamia. A written informed consent
was obtained from each participant for their participation in the
study.
Consent for publication
Not applicable.
Authors’ contributions
PB and MEH designed and conceptualized the study. PB
collected and analyzed the data and wrote the manuscript. MEH
and PA critically revised the manuscript. KKD and SM helped in
data analysis and proof reading. The final version of the manuscript
was approved by all authors.
Declaration of competing interest
All authors declare that they have no competing interests.
P. Bhati, M.E. Hussain, K.K. Deepak et al.
Acknowledgments
A sincere thanks to Jamia Millia Islamia for providing financial
and logistic help during the course of this study. Thanks to M.A.
Ansari Medical Centre, Jamia Millia Islamia for helping in the data
collection process. We would also like to extend our gratitude to the
University Grants Commission, India for providing fellowship to the
author PB during this study.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.dsx.2023.102778.
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