Journal of Diabetes and Its Complications 28 (2014) 332–339

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Journal of Diabetes and Its Complications

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Effect of aerobic exercise on peripheral nerve functions of population with diabetic

peripheral neuropathy in type 2 diabetes: A single blind, parallel group randomized
controlled trial
Snehil Dixit a,⁎, Arun G. Maiya a, B.A. Shastry b
a
Department of Physiotherapy, School of Allied Health Sciences (SOAHS), Manipal University, Manipal, 576104, Karnataka, India
b
Department of Medicine, Kasturba Hospital, Manipal University, Manipal, 576104, Karnataka, India

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

Article history: Objective: To evaluate the effect of moderate intensity aerobic exercise (40%–60% of Heart Rate Reserve
Received 20 November 2013 (HRR)) on diabetic peripheral neuropathy.
Received in revised form 8 December 2013 Methods: A parallel-group, randomized controlled trial was carried out in a tertiary health care setting, India.
Accepted 20 December 2013 The study comprised of experimental (moderate intensity aerobic exercise and standard care) and control
Available online 27 December 2013
groups (standard care). Population with type 2 diabetes with clinical neuropathy, defined as a minimum score
of seven on the Michigan Diabetic Neuropathy Score (MDNS), was randomly assigned to experimental and
Keywords:
Neuropathy
control groups by computer generated random number tables. RANOVA was used for data analysis (p b 0.05
Type 2 diabetes was significant).
Exercise Results: A total of 87 patients with DPN were evaluated in the study. After randomization there were 47
Aerobic adaptations patients in the control group and 40 patients in the experimental group. A comparison of two groups using
Nerve functions RANOVA for anthropometric measures showed an insignificant change at eight weeks. For distal peroneal
nerve’s conduction velocity there was a significant difference in two groups at eight weeks (p b 0.05), Degrees
of freedom (Df) = 1, 62, F = 5.14, and p = 0.03. Sural sensory nerve at eight weeks showed a significant
difference in two groups for conduction velocity, Df =1, 60, F = 10.16, and p = 0.00. Significant differences in
mean scores of MDNS were also observed in the two groups at eight weeks (p value significant b 0.05).
Conclusion: Moderate intensity aerobic exercises can play a valuable role to disrupt the normal progression of
DPN in type 2 diabetes.
© 2014 Elsevier Inc. All rights reserved.

1. Introduction Studies on lifestyle intervention programs have proven to be

Currently, India is the second most populated country in the world,
and has the dubious fame of being the diabetic capital of the world
(Mohan et al., 2008). The highest regional prevalence is reported with
North America (10.2%) followed by South Asia (6.7%) (Shaw et al.,
2010). Estimates indicate that diabetes now affects almost 246 million
people worldwide and is expected to affect some 380 million by 2025,
representing as much as 7.1% of the global adult population
(International Diabetes Foundation, 2006).
Diabetic peripheral neuropathy (DPN) is the most common
complication of type 2 diabetes and the single most leading cause of
foot ulcers and amputations leading to a reduced quality of life (Ribu
et al., 2007).
Conflict of interest: None; financial support: none.
⁎ Corresponding author at: Manipal College of Allied Health Sciences (MCOAHS),
Department of Physiotherapy, 2nd Floor, Manipal University, Manipal 576104,
Karnataka, India. Tel.: +91 820 2922 069, +91 9986 375 051 (mobile).
E-mail address: snehildixit83@gmail.com (S. Dixit).
effective in glycemic control for type 2 diabetes patients (Balducci
et al., 2006; International Diabetes Foundation, 2006). There are
evidences that long-term supervised aerobic exercise training may
delay the onset of DPN. Even mild aerobic exercise training, could be
an effective treatment to prevent the onset the natural history of
DPN (Balducci et al., 2006; Lemaster et al., 2008). Moreover, an
experimental study also reported that people with DPN should limit
weight bearing activities as evidences from an experimental model
indicate that weight bearing activities in an insensate feet of rats on
repetitive mechanical stimulation lead to skin ulceration (Brand,
1975). Several studies have demonstrated an association between
high plantar foot pressures and increased diabetic foot ulcer risk
(Armstrong Dtî et al., 1998; Brand, 1975).
Though the risk of developing type 2 diabetes and its complica-
tions can be lowered through the glycemic control, still there
remains a need for a well-designed trial to establish that exercise
training can play a vital role in modulating physiological measures of
neuropathy. Heart Rate Reserve (HRR) which is defined as the
difference between an individual’s measured or predicted maximum

1056-8727/$ – see front matter © 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.jdiacomp.2013.12.006
 S. Dixit et al. / Journal of Diabetes and Its Complications 28 (2014) 332–339
heart rate and resting heart rate is an effective way of prescribing
aerobic exercise in type 2 diabetic population (Marwick et al., 2009).
On the contrary, efficacy of moderate intensity (HRR of 40%–60%)
exercises as a therapy needs to be explored and established in DPN,
hence the objective of the present study was to evaluate the
therapeutic effect of aerobic exercise on nerve conduction velocity
of sural sensory and peroneal motor nerve in DPN.
2. Methods
Ethical clearance of the study was given by university ethical
committee (UEC/54/2009). Participants were recruited from the
hospital outpatient clinic; and the procedures of the study were
explained to them (Fig. 1). A written informed consent was obtained
from all the patients prior to their participation. The trial is
registered in clinical trial registry, India with the number CTRI/
2011/07/001884.
2.1. Trial design
It was a parallel group randomized controlled trial.
Fig. 1. Depicting enrollment and final outcome. †Relieved by food or sugar; ‡Episodes with impaired consciousness requiring consultation or hospitalization intake.
333
2.2. Study subjects
The patient population with type 2 diabetes has peripheral
neuropathy. The inclusion criteria for the study were if patients had
clinical neuropathy which was defined as a minimum score of seven
on the Michigan Diabetic Neuropathy Score (MDNS) (Feldman et al.,
1994). Patients were excluded if they were found to have vitamin B12
deficiency, postural hypotension, foot ulcers, walking with assistive
devices, part or complete foot amputation, peripheral arterial disease,
vision impairments, neurological or musculoskeletal impairments,
acute sciatica or vestibular dysfunction, cognitive impairments (n =
7), a score of 30 or greater on MDNS, known cardiac risks (coronary
heart disease with abnormal stress tests), recent history of active
retinal hemorrhage or there had been a recent laser therapy (less than
six months) for retinopathy, recent revascularization of coronary
artery bypass grafting (less than three months), already seeking other
therapies in DPN and age greater 70 years.
2.3. Study setting and duration
The study was conducted in the university tertiary hospital, from
October 2009 to December 2012.
334 S. Dixit et al. / Journal of Diabetes and Its Complications 28 (2014) 332–339
2.4. Protocols followed for two groups
2.4.1. Experimental group
Recommended guidelines for supervised physical activity put forth
by the American Heart Association (AHA) were followed (Marwick
et al., 2009). Education was, given via posters developed by the
medical hospital in accordance with the guidelines of the National
Institute for Clinical Excellence (NICE) for prevention and manage-
ment of foot problems in type 2 diabetes (Hutchinson et al., 2000).
Patients were given instructions for the diabetic diet by a dietitian and
were also reviewed for standard medical care by their physician.
Intensity of exercise was calculated using the Karvonen formula
for target heart rate (THR).
THR = [(Maximal Heart rate − the Resting Heart rate) × %
intensity] + Resting Heart rate. Exercise training was carried out in
the range of 40%–60% of heart rate reserve (HRR) as an adjunct to this
rating of perceived exertion (RPE) (scale ranging from 6 to 20) was
carried out before, during and post exercise. The RPE scale of
‘somewhat hard’ (scale ranging to 12–13) corresponds to an HRR of
40%–60% (Colberg et al., 2010; Marwick et al., 2009; Shigematsu et al.,
2004). The frequency of each exercise session was 3–6 days of the
week of moderate intensity treadmill exercises, accumulating a
minimum of 150 min/week to a maximum of 360 min/week of
work out.
Exercise training was completed on at least three days per week,
with a gap of no more than two consecutive days. RPE was used to
monitor exercise intensity in patients (Colberg et al., 2010; Marwick
et al., 2009; Shigematsu et al., 2004). At the initiation of the program,
patients were made to exercise with intensity of 40% of HRR and in
addition to that they were asked to rate RPE to the point they reach
‘somewhat hard’ (scale range 6–20). With subsequent weeks as the
patients became conditioned to exercise program, they were made to
exercise on higher intensity (60%) of HRR using RPE to the point they
reach ‘somewhat hard’ on the scale (scale range 6–20).
Special considerations during training regime were given to foot
care, and steps were taken to prevent any episodes of hypoglycemia
during and after exercise sessions (Colberg et al., 2010; Marwick et al.,
2009).
2.4.2. Control group
At the beginning of the study standard medical care, education for
foot care and diet (same as the experimental group) were given. They
were then reminded telephonically every second week of the month
regarding foot care and dietary habits until their final evaluation.
Patients were also evaluated for medical care at the fourth and eight
weeks by their primary physician. After the completion of the study
period all the patients in the group were asked to undergo supervised
exercise sessions.
2.5. Outcome measure
2.5.1. Electrophysiological evaluation
Standard procedures were used for peroneal motor and sural
sensory nerve conduction studies as recommended by Misra and
Delisa (DeLisa, 1994; Misra & Kalita, 2006; Nasseri et al., 1998). Nerve
conduction velocity (NCV) was measured using the RMS Aleron 201
electromyogram/NCV machine (Chandigarh, India). For peroneal
motor nerve the pick-up point for active surface electrodes was
over the extensor digitorum brevis (EDB) muscle. Proximally, the
nerve was stimulated just below the head of fibula [100 milliamperes
(mA) intensity, 20 Hz to 3 kHz frequency, 5 milliseconds (ms)/
division (div) sweep speed, and gain of 5 millivolts (mV)], to obtain a
supramaximal stimulus. For sural nerve pick-up point for active
electrode was posterior and below the distal lateral malleolus of the
fibula. Stimulation (15–25 mA intensity, 20 Hz to 2 kHz frequency, 1
ms/division sweep speed, and gain of 20 kV/division) was applied
slightly lateral to the midline in the lower third of the posterior
aspects of the leg (10–14 cm). It was made sure that no variations
were produced due to temperature, hence skin temperature was
measured with a surface infrared device to ensure uniformity in lower
limbs measurements and an ambient room temperature of 26–32 °C
was maintained.
2.5.2. Scores
MDNS consists of a clinical neurological examination which was
developed by Feldman et al. and can be easily conducted in routine
clinical practice for staging of DPN. MDNS is a 46 point clinical score,
with score ranging from 0 to 3 (score of 0, normal; 1, mild to
moderate; 2, severe and score of 3, absent). In MDNS vibration, pain,
and light touch are assessed with a 128 Hz tuning fork, a pin, and a 10
g filament, respectively. Researchers have found a moderate correla-
tion of 0.59 (p b 0.05) of MDNS with nerve studies (Feldman et al.,
1994).
The outcome measures were performed by the investigator at
baseline and at the eighth week.
2.6. Sample size
The sample size was calculated based on the standard deviation of
the nerve conduction velocity of peroneal nerve (primary outcome
measure). The standard deviation between 2 mean observations of
samples of peroneal motor nerve was taken to be 3 from the previous
study (Partanen et al., 1995), and the estimated smallest difference of
2 was considered clinically significant for the study. Hence the sample
size with 80% power of study came to be n = 72, with 20% drop out
the estimated sample size was n = 86 or n = 43 in each group.
2.7. Randomization
Stratification was done (based on staging of DPN based on MDNS),
by forming risk groups (strata). The patients’ neuropathy risks scores
divided them into mild and moderate stratum. A separate block
randomization was conducted for each stratum. Each stratum had a
total number of 4 blocks with size of 20.Then the patients were
randomly assigned to experimental and control groups by the
computer generated random number tables. At the end, individual
stratum was summed into interventional and control groups
respectively, the result being a balance of overall groups. The flow
of the participants in the study is depicted in the flowchart (Fig. 1).
2.8. Blinding
Blinding was at a single level, the first evaluator determined the
eligibility criteria and evaluated the outcome measures at baseline
and then the second evaluator independently assessed the outcome
measures at the end of the study.
3. Data analysis
Log transformation was applied for skewed variables and
geometric mean and geometric standard deviation were reported as
a measure of central tendency and dispersion for all the continuous
variables (age, duration of diabetes, medications and insulin,
Anthropometric measures and primary outcome measures) and
categorical variables were expressed as frequency. The statistical
analysis was performed according to the number of participants
(denominator) included in each analysis and by the original assigned
groups. Repeated measures of Analysis of Variance (RANOVA) were
used to analyze the changes in outcome measures at multiple time
periods between the two groups. A p value of less than 0.05 was
considered statistically significant and the tests were carried out using
 S. Dixit et al. / Journal of Diabetes and Its Complications 28 (2014) 332–339 335

Statistical Package for the Social Sciences (SPSS) 15. Degrees of In the experimental group at baseline there were 46.2% of patients
freedom, F and p values were reported in RANOVA statistics. with mild staging of neuropathy and 53.8% of patients with moderate
staging of neuropathy. Post therapy there were 25.6% patients with
mild staging of neuropathy and 12.8% of patients with moderate
4. Results
staging of neuropathy, whereas there were 35.9% of patients with no
neuropathy. In the control group at baseline there were 37.5% of
The flow of the participants is presented in Fig. 1. A total of 87
patients with mild staging of neuropathy and 62.5% with moderate
individuals with DPN were evaluated in the study. After randomiza-
staging of neuropathy. By the end of study duration, there were 22.9%
tion there were 47 participants in the control and 40 participants in
of patients with mild staging and 50% of patients with moderate
the experimental group. In the control there were 31 males (64.6%)
staging of neuropathy, only 2.1% patients had no neuropathy.
and 17 females (35.4%), whereas in the experimental group there
The means and standard deviation [confidence interval] for scores
were 22 males (56.4%) and 17 females (43.6%). In the control group
of MDNS at baseline for control and experimental groups were 13.55
there were 30 males (63.8 %) and 17 females (36.2%), whereas in the
(1.75) [14.05–13.05] and 12.57 (1.74) [13.11–12.03]. Post eight weeks
experimental group there were 23 males (57.5%) and 17 females (42.5 %).
the means scores for the control and experimental group were 14.57
The control group had a mean age of 59.45 (1.16) years and
(1.5) [15–14.09] and 7.03 (1.86) [7.61–6.45] respectively. Total scores
experimental group had a mean age of 54.40 (1.24) years. By the
showed a significant difference for two groups with an F = 54.04 and
end of the eighth week 37 individuals in the control group and 29
p b 0.001. Each component had a Df of 1, 63.
individuals in the experimental group completed the study program.
Mean scores for peroneal nerve variables are presented in Table 4.
There were 10 drop outs in the control and 11 drop outs in the
Two groups were compared using RANOVA statistics for the difference
experimental group. A possible reason for low participation and large
in latency, duration, and amplitude and conduction velocity. There
drop outs in the study could be due to poor awareness levels among
was a significant difference in the two groups for conduction velocity of
the Indian masses regarding the diabetic foot care (Dixit et al., 2011).
the distal segment of peroneal nerve with Df = 1, 62, F = 5.14, and
Duration of diabetes, smoking and alcoholism, duration of insulin
p = 0.03 (p value less than 0.05 was considered significant), though
and medications in two groups are presented in Table 1. Independent
no significant difference was observed in the two groups for latency
t tests were used to measure the discrepancies in the baseline
(Df = 1, 63, F = 2.64 and p = 0.11), duration (Df = 1, 63, F =3.22,
measures for duration of diabetes, smoking and alcohol and were
and p = 0.08) and amplitude (Df =1, 62 F value = 0.20, and p = 0.65)
found to be insignificant for both the groups with p b 0.05.
(p less than 0.05 was considered significant). The mean scores for sural
In the control group the distribution of comorbidities among
nerve variables are provided in Table 4.
individuals was as follows: hypertensive, n = 20; ischemic heart
Mean scores of sural nerve of the two groups were compared using
disease, n = 2; and both hypertensive and ischemic heart disease,
RANOVA statistics for the difference in latency, duration, and
n = 1. In the experimental group individuals with hypertension alone
amplitude and conduction velocity. Sural sensory nerve on compar-
were n = 17, those with ischemic heart disease were n = 1 and
ison showed a significant difference for conduction velocity, Df = 1,
those with both hypertensive and ischemic heart disease were n = 2.
60, F = 10.16, and p b 0.001 (p value less than 0.05 was considered
The mean and standard deviation for Oral Hypoglycemic Agents
significant), though no significant difference was observed for latency
(OHA) and insulin (long acting analogue) are presented in Table 2.
(F = 0.96, Df =1, 60 and p = 0.33), duration (F = 1.25, Df = 1, 60
Mean values for anthropometric measures of two groups are
and p = 0.27) and amplitude in the two groups (F = 0.04, Df = 1, 60
presented in Table 3.
and a p = 0.85) (p value less than 0.05 was considered significant).
RANOVA statistic was used to analyze changes in the mean values
of anthropometric measures of two groups which were insignificant
5. Discussion
at eight weeks. The results were as follows for Body Mass Index (BMI)
degrees of freedom were (Df) =1, 61, F = 0. 94 and p = 0.34, for
Prevalence of DPN, is as high as 75% in the diabetic population
waist circumference Df = 1, 63, F = 3.02 and p = 0.09, for hip
(Bansal et al., 2006; Gimbel et al., 2003; Martyn & Hughes, 1997). DPN
circumference Df = 1, 63, F = 0.06 and p = 0.81, and for Waist Hip
precipitates a complex mechanism due to poor glycemic control that
Ratio (WHR) Df = 1, 63, F = 0.77 and p = 0.38.
leads to insensitive hands and feet (Bansal et al., 2006). Though many
For the experimental group the mean and standard deviation for
drug therapies are available for the management of DPN, still their
Post Prandial Sugar (PPBS) were 214.82 (73.73) and 149.22 (41.26)
role in the management is uncertain (Callaghan et al., 2012; Gimbel
and Fasting Blood Sugar (FBS) was 145.42 (48.51) and 116.41 (23.71)
et al., 2003; Ismail-Beigi et al., 2010).
at baseline and eight weeks respectively, whereas the control group
On contrary moderate intensity (Heart rate intensity 40%–60% or
had PPBS of 217.12 (92.58) and 202 (75.13) and FBS of 137.17 (41.14)
rating of perceived exertion (RPE): somewhat hard) aerobic exercise
and 141.58 (44.46) at baseline and eight weeks respectively. When
of 30–45 min duration per session for eight weeks can play a vitally
two groups were compared using RANOVA there was no significant
important role in controlling diabetic peripheral neuropathy (Fig. 2).
difference observed between PPBS and FBS of two groups (Df of 1, 48,
A plausible mechanism of this could be modulation of sorbitol levels
F = 3.73 and p = 0.06, and Df of 1, 51, F = 3.44 and p value = 0.07
in the body as we know in DPN body initiates increased reliance on
respectively).
polyol–sorbitol pathway (anaerobic process) which has a deleterious
effect on schwann cells due to increased intracellular sorbitol
Table 1
concentration, which may result in decreased endoneural blood
Characteristics of two groups for duration of diabetes, smoking, alcoholism, OHA and flow causing chronic hypoxia of the nerves (Aminoff & Albers, 2005b;
insulin (Long acting analogue) usage at baseline. Kikkawa et al., 2005). Adaptations due to moderate intensity aerobic
exercise may cause restoration of peripheral nerve functions by
Group/Mean(SD) Control Experimental
(n = 47) (n = 40) inhibition of aldose reductase (AR) leading to sparing of NADPH
(Nicotinamide Adenine Dinucleotide Phosphate hydroxide) which
Duration of diabetes (months) 83.71 (3.21) 49.77 (4.72)
Duration of smoking (months) 128.09 (2.53) 167.49 (2.26) may then participate in the synthesis of nitric oxide thereby relieving
Duration of alcohol (months) 141.03 (3.14) 218.24 (1.94) the nerves of their hypoxic state.
Oral Hypoglycemic agents (OHA) 82.15 (3.74) 58.26 (3.54) Moreover hyperglycemia can also promote superoxide production
duration (months) as a consequence of glucose auto-oxidation, formation of advanced
Insulin duration (months) 20.70 (4.32) 31.75 (2.84)
glycation end products, and activation of protein kinase C, which leads
336 S. Dixit et al. / Journal of Diabetes and Its Complications 28 (2014) 332–339

Table 2
A comparison of mean dosage of insulin and Oral Hypoglycemic agents (OHA) at baseline and 8th week.

Drug Control Experimental Control Experimental

Mean (SD), CI Mean (SD), CI Mean (SD), CI Mean (SD), CI

Baseline Baseline 8th week 8th week

(n = 47) (n = 40) (n = 37) (n = 29)

Biguanides (mg) 569.81 (1.95) 787.77 (1.79) 590.05 (2.35) 769.7 (1.81)
(570.47–569.16) (788.42–787.12) (590.94–589.16) (770.43–768.98)
Secretegogues (mg) 9.7(5.80) 5 (4.61) 10.83 (5.71) 4.92 (5.66)
(11.60–7.80) (6.74–3.26) (12.91–8.75) (7.18–2.65)
Alpha – glucosides Inh (mg) 18.56 (1.97) 10.71 (4.13) 28.02 (3.75) 10.25 (4.11)
(19.27–17.84) (12.27–9.15) (29.41–26.63) (11.89–8.61)
Insulin (Insulin units) 34.06 (1.77) 35.8 (1.61) 34.06 (1.77) 35.8 (1.61)
(35.22–32.90) (37.38–34.22) (35.22–32.90) (37.38–34.22)

Inh: inhibitors, CI: confidence of interval at 95% confidence level, SD: Standard Deviation.
Commercially available long acting insulin were used with concentrations of 40 units/ml (Designated U-40, 1 unit equals ∼ 36 μg of insulin).

to inactivation of Nitric Oxide (NO) production which is an important
mechanism of endothelial dysfunction in DPN (Fuchsjager-Mayrl
et al., 2002; Sheetz & King, 2002). There are evidences that aerobic
exercise training has effects on endothelial dysfunction and vascular
distensibility in type 2 diabetes (Hutchinson et al., 2000). Hence it
may be hypothesized from the previous evidences that an improve-
ment in endothelial derived NO may also cause restoration of nerve
functions in DPN population. The aerobic adaptation due to aerobic
exercise may cause inhibition of excessive production of protein
kinase C and activation of endothelial derived NO.
Nerve conduction studies (NCS) or NCV is considered the
pragmatic standards in the study of nerves and still remains the
most accurate, sensitive and reliable measure for the study of
peripheral nerve functions (Nasseri et al., 1998). Early work of
Buchthal and Rosenfalck revealed that conduction velocity is a more
reproducible measure than amplitude (Aminoff & Albers, 2005b).
Studies have revealed that peroneal motor nerve conduction
velocities can predict foot problems and is a reliable measure to
predict new ulcerations and deaths in type 2 diabetes (Carrington et
al., 2002; Charles et al., 2010). In the present study we found that
moderate intensity aerobic exercises can lead to modulation of nerve
functions (Table 4, 5) which was significantly different for both
groups (p b 0.05). However the sustainability of such gains in nerve
functions in long term still remains to be answered.
A study measuring the effect of 10 weeks supervised exercise
program on neuropathic symptoms, nerve function, and cutaneous
innervation found that supervised aerobic exercise causes im-
provement in outcomes related to neuropathic symptoms and
cutaneous nerve fiber branching (Kluding et al., 2012). Another
study reported that an eight-week supervised aerobic exercise
program may be adequate to cause improvement in nerve functions
(Fisher et al., 2007).
A study comparing two treatment regime comprised of conven-
tional insulin therapy (one or two injections of insulin/day) and
intensive insulin therapy (comprising of multiple insulin injections/
day) reported a small, but a significant mean annual change in
peroneal motor nerve conduction velocity of the intensive insulin
group as compared to the conventional insulin group, whereas the
authors reported an annual decline in mean velocity of peroneal
motor nerve in the conventional group (Callaghan et al., 2012).
The study by Kikkawa et al. which investigated acute changes in
nerve conduction due to glycemic control with oral agents and insulin
therapy found that glycemic control attained by drug therapy can
slow down the progression of DPN in early type 1 diabetics (Kikkawa
et al., 2005). In the present study, we found that in the control group
there was a decline in the mean velocity of distal peroneal nerve by −
0.192 m/s whereas in the experimental group there was an increase in
the mean velocity by 3.08 m/s, which was significant (p b 0.05) at
eight weeks.
The present study demonstrates that exercise combined with drug
therapy yields greater benefit than drug therapy alone. Further the
researchers reported that weight gain and number of deaths were
reportedly higher in the intensive therapy group. Weight gain and
number of deaths were also reportedly higher in the intensive therapy
group (Callaghan et al., 2012; Ismail-Beigi et al., 2010). The authors in
the present study feel that moderate intensity aerobic exercise
should be the cornerstone in the management of type 2 diabetes
complications as aerobic adaptations due to exercise have the
potential to halt the progression of neuropathy and achieve enhanced
glycemic control when used in combination with Oral Hypoglycemic
Agents (OHA) as compared to adverse consequences as commonly
seen with intensive therapy.
The sural sensory nerve is sensitive to changes induced by
hyperglycemia and is affected early in diabetes (Shigematsu et al.,
2004). Sensory nerve conduction studies not only add to the clinical
picture of neuropathy, but also suggests a decrease in the number of
large myelinated peripheral axons (Aminoff & Albers, 2005). In our
study we observed a gain of 7.729 m/s (mean difference) in the

Table 3
Mean and standard deviation of anthropometrics measures at baseline and 8th week in the two groups.

Variables Control Mean (SD), CI n = 47 Experimental Mean (SD),CI n = 40 Control Mean (SD),CI n = 37 Experimental Mean (SD),CI n = 29

Baseline Baseline 8th week 8th week

BMI 25.95 (5.68) 26.38 (3.77) 25.81 (6.16) 26.35 (4.16)

(27.57–24.35) (27.6–25.16) (27.88–23.74) (27.86–24.84)
Waist circumference 93.42 (10.17) 95.83 (9.69) 93.54 (9.96) 94.61 (10.76)
(96.33–90.51) (98.95–92.71) (96.71–90.37) (98.53–90.69)
Hip circumference 95.75 (8.46) 95.44 (9.81) 95.75 (8.46) 95.77 (10.76)
(98.17–93.33) (98.60–92.28) (98.51–92.99) (99.69–91.85)
WHR 0.98 (0.08) 1.0 (0.10) 0.97 (0.07) 0.99 (0.11)
(1.14–0.82) (1.03–0.97) (1.10–0.83) (1.03–0.95)

BMI: Body Mass Index, WHR: Waist to Hip Ratio, CI: Confidence Interval at 95% confidence level, SD: Standard Deviation.
 S. Dixit et al. / Journal of Diabetes and Its Complications 28 (2014) 332–339 337

Table 4
Depicting the change in mean and standard deviation for parameters of nerve conduction for peroneal and sural nerve at baseline and 8th week in two groups respectively.

Control Experimental p Value

Peroneal nerve Peroneal nerve

n Mean (SD), CI n Mean (SD), CI

Baseline Latency 47 3.33 (1.78) (3.86–2.80) 40 4.04 (1.57) (4.53–3.55)

Duration 10.69 (1.27) (11.07–10.31) 9.99 (1.27) (10.05–9.93)
Amplitude 4.55 (2.28) (5.23–3.88) 6.81 (2.07) (7.46–6.16)
Conduction velocity 38.40 (1.36) (38.80–38) 42.48 (1.25) (42.87–42.09)
8th week Latency 37 3.16 (1.83) (3.77–2.57) 29 4.34 (1.25) (4.80–3.89) 0.11
Duration 10.89 (1.23) (11.30–10.49) 10.76 (1.23) (11.21–10.31) 0.08
Amplitude 4.75 (2.13) (5.45–4.05) 6.31 (2) (7.02–5.59) 0.65
Conduction velocity 38.21 (1.31) (38.64–37.78) 45.56 (1.24) (46.01–45.11) 0.03

CI: Confidence Interval at 95% confidence level, SD: Standard Deviation.

experimental group which was significant at eight weeks (p b 0.05),
though we also observed a small increment in sural nerve velocity of the
control group that could possibly have been due to the effect of insulin
dosage which also increased simultaneously at the end of the study in
the control group (mean increase of 3.242 insulin-units), whereas, there
was a decrease (mean decrease 1.644 insulin-units) in the dosage of
insulin with exercise in the experimental group (Table 2).
Despite the short duration of the study (8 weeks) we found
ameliorating effects of exercise on the dosage of OHA and insulin
(Table 2). Aerobic exercises should be considered in the management
of diabetic neuropathy before starting insulin therapy or should be
considered in combination with OHA and insulin therapy to prevent,
halt or slow down the progression of neuropathy.
Long term usage of insulin and OHA is questionable as a study with
five years of follow-up determining the efficacy of metformin,
sulfonylureas and insulin found that there was an increase in
mortality related outcome in sulfonylurea and insulin group as
compared to metformin group (Bowker et al., 2006; Gu et al., 2013).
Antagonistically exercise has an evanescent effect on peripheral
nerve functions. A plausible reason for the reversibility of clinical
neuropathy in the study could be due to the reversal of impaired
oxygenation of the peripheral nerves. Moreover aerobic exercises
leads to metabolic adaptations in the body and initiates activation of
NO production that averts deactivation of free radicals, thereby
preventing both macro and micro vascular complications (Fuchsjager-
Mayrl et al., 2002).

Fig. 2. Postulated therapeutic effect of aerobic exercise on pathogenesis of diabetic peripheral neuropathy. Footnote: ¥ Exercise with the inhibitory effects on AR is marked in red and
facilitative effects in blue. AGE: advanced glycation end products. GF: growth factor. DAG: diacylglycerol. AR: aldose reductase. PKC: protein kinase C. PG: prostaglandin. NO: nitric
oxide. ET: endothelin. Modified and adapted from (Boucek, 2006) with permission from the publisher.
338 S. Dixit et al. / Journal of Diabetes and Its Complications 28 (2014) 332–339

Table 5
Depicting the change in mean and standard deviation for parameters of nerve conduction for peroneal and sural nerve at baseline and 8th week in two groups respectively.

Control Experimental p value

Sensory sural Sensory sural

n Mean(SD), CI n Mean (SD), CI

Baseline Latency 47 3.39 (1.35) 40 3.51 (1.50)

(3.80–2.99) (3.98–3.04)
Duration 1.49 (1.50) 1.45 (1.89)
(1.94–1.04) (2.04–0.86)
Amplitude 3.23 (2.19) 2.48 (2.55)
(3.89–2.57) (3.28–1.68)
Conduction velocity 28.23 (1.49) 23.67 (1.81)
(28.68–27.78) (24.24–23.10)
8th week Latency 37 3.39 (1.45) 29 3.45 (1.38) 0.33
(3.87–2.90) (3.95–2.95)
Duration 1.46 (1.90) 1.86 (1.75) 0.27
(2.10–0.82) (2.5–1.22)
Amplitude 3.94 (2.23) 2.14 (2.38) 0.85
(4.69–3.19) (3.01–1.27)
Conduction velocity 28.53 (1.49) 31.39 (1.58) b 0.001
(29.02–28.04) (31.97–30.81)

CI: Confidence Interval at 95% confidence level, SD: Standard Deviation.

6. Conclusion
We observed novel benefits associated with moderate intensity
exercise in the study, hence aerobic exercise appears to be the most
prudent way to halt or disrupt the progression of DPN without any
major adverse events in patients suffering from diabetic peripheral
neuropathy (American Diabetes Association, 2007; Colberg et al.,
2003; Eaton et al., 2003.
SD is the guarantor of this work and has full access to all the data in
the study and takes responsibility for the integrity of the data and the
accuracy of the data analysis. SD researched data.SD and AM wrote the
manuscript. BA Reviewed/edited the manuscript.
Strengths and limitations of this study:
- Effect of aerobic exercises to halt or disrupt the natural
process of DPN has never been studied. Study outlines
how moderate intensity aerobic exercises can modu-
late neuropathy i.e. large fiber dysfunction.
- Aerobic exercises when combined with standard
medical care can yield greater benefits in the treat-
ment of neuropathy. In addition to that moderate
intensity aerobic exercise may have an ameliorative
effect on oral drug dosage.
- The study had a large number of drop outs by the end
of the trial for each group.
Acknowledgment
Authors are grateful to Dr Shashikiran Umakanth, Professor and
Head, Department of Medicine, TMA Pai hospital, Mr. Vasudev
Guddattu, Senior Grade Lecturer, Department of Statistics.
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