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

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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 b

Department of Physiotherapy, School of Allied Health Sciences (SOAHS), Manipal University, Manipal, 576104, Karnataka, India Department of Medicine, Kasturba Hospital, Manipal University, Manipal, 576104, Karnataka, India

a r t i c l e

i n f o

Article history: Received 20 November 2013 Received in revised form 8 December 2013 Accepted 20 December 2013 Available online 27 December 2013 Keywords: Neuropathy Type 2 diabetes Exercise Aerobic adaptations Nerve functions

a b s t r a c t Objective: To evaluate the effect of moderate intensity aerobic exercise (40%–60% of Heart Rate Reserve (HRR)) on diabetic peripheral neuropathy. Methods: A parallel-group, randomized controlled trial was carried out in a tertiary health care setting, India. The study comprised of experimental (moderate intensity aerobic exercise and standard care) and control 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 control groups by computer generated random number tables. RANOVA was used for data analysis (p b 0.05 was significant). Results: A total of 87 patients with DPN were evaluated in the study. After randomization there were 47 patients in the control group and 40 patients in the experimental group. A comparison of two groups using 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 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: [email protected] (S. Dixit). 1056-8727/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jdiacomp.2013.12.006

Studies on lifestyle intervention programs have proven to be 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 complications 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

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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.

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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 2.1. Trial design It was a parallel group randomized controlled trial.

The study was conducted in the university tertiary hospital, from October 2009 to December 2012.

Fig. 1. Depicting enrollment and final outcome. †Relieved by food or sugar; ‡Episodes with impaired consciousness requiring consultation or hospitalization intake.

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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 management 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 correlation 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

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Statistical Package for the Social Sciences (SPSS) 15. Degrees of freedom, F and p values were reported in RANOVA statistics. 4. Results The flow of the participants is presented in Fig. 1. A total of 87 individuals with DPN were evaluated in the study. After randomization there were 47 participants in the control and 40 participants in the experimental group. In the control there were 31 males (64.6%) and 17 females (35.4%), whereas in the experimental group there were 22 males (56.4%) and 17 females (43.6%). In the control group there were 30 males (63.8 %) and 17 females (36.2%), whereas in the experimental group there were 23 males (57.5%) and 17 females (42.5 %). The control group had a mean age of 59.45 (1.16) years and experimental group had a mean age of 54.40 (1.24) years. By the end of the eighth week 37 individuals in the control group and 29 individuals in the experimental group completed the study program. There were 10 drop outs in the control and 11 drop outs in the experimental group. A possible reason for low participation and large drop outs in the study could be due to poor awareness levels among the Indian masses regarding the diabetic foot care (Dixit et al., 2011). Duration of diabetes, smoking and alcoholism, duration of insulin and medications in two groups are presented in Table 1. Independent t tests were used to measure the discrepancies in the baseline measures for duration of diabetes, smoking and alcohol and were found to be insignificant for both the groups with p b 0.05. In the control group the distribution of comorbidities among individuals was as follows: hypertensive, n = 20; ischemic heart disease, n = 2; and both hypertensive and ischemic heart disease, n = 1. In the experimental group individuals with hypertension alone were n = 17, those with ischemic heart disease were n = 1 and those with both hypertensive and ischemic heart disease were n = 2. The mean and standard deviation for Oral Hypoglycemic Agents (OHA) and insulin (long acting analogue) are presented in Table 2. Mean values for anthropometric measures of two groups are presented in Table 3. RANOVA statistic was used to analyze changes in the mean values of anthropometric measures of two groups which were insignificant 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 waist circumference Df = 1, 63, F = 3.02 and p = 0.09, for hip circumference Df = 1, 63, F = 0.06 and p = 0.81, and for Waist Hip Ratio (WHR) Df = 1, 63, F = 0.77 and p = 0.38. For the experimental group the mean and standard deviation for Post Prandial Sugar (PPBS) were 214.82 (73.73) and 149.22 (41.26) and Fasting Blood Sugar (FBS) was 145.42 (48.51) and 116.41 (23.71) at baseline and eight weeks respectively, whereas the control group had PPBS of 217.12 (92.58) and 202 (75.13) and FBS of 137.17 (41.14) and 141.58 (44.46) at baseline and eight weeks respectively. When two groups were compared using RANOVA there was no significant difference observed between PPBS and FBS of two groups (Df of 1, 48, F = 3.73 and p = 0.06, and Df of 1, 51, F = 3.44 and p value = 0.07 respectively).

Table 1 Characteristics of two groups for duration of diabetes, smoking, alcoholism, OHA and insulin (Long acting analogue) usage at baseline. Group/Mean(SD)

Control (n = 47)

Experimental (n = 40)

Duration of diabetes (months) Duration of smoking (months) Duration of alcohol (months) Oral Hypoglycemic agents (OHA) duration (months) Insulin duration (months)

83.71 128.09 141.03 82.15

49.77 167.49 218.24 58.26

(3.21) (2.53) (3.14) (3.74)

20.70 (4.32)

(4.72) (2.26) (1.94) (3.54)

31.75 (2.84)

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In the experimental group at baseline there were 46.2% of patients 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 staging of neuropathy, whereas there were 35.9% of patients with no neuropathy. In the control group at baseline there were 37.5% of patients with mild staging of neuropathy and 62.5% with moderate staging of neuropathy. By the end of study duration, there were 22.9% of patients with mild staging and 50% of patients with moderate staging of neuropathy, only 2.1% patients had no neuropathy. The means and standard deviation [confidence interval] for scores of MDNS at baseline for control and experimental groups were 13.55 (1.75) [14.05–13.05] and 12.57 (1.74) [13.11–12.03]. Post eight weeks the means scores for the control and experimental group were 14.57 (1.5) [15–14.09] and 7.03 (1.86) [7.61–6.45] respectively. Total scores showed a significant difference for two groups with an F = 54.04 and p b 0.001. Each component had a Df of 1, 63. Mean scores for peroneal nerve variables are presented in Table 4. Two groups were compared using RANOVA statistics for the difference in latency, duration, and amplitude and conduction velocity. There was a significant difference in the two groups for conduction velocity of the distal segment of peroneal nerve with Df = 1, 62, F = 5.14, and p = 0.03 (p value less than 0.05 was considered significant), though no significant difference was observed in the two groups for latency (Df = 1, 63, F = 2.64 and p = 0.11), duration (Df = 1, 63, F =3.22, and p = 0.08) and amplitude (Df =1, 62 F value = 0.20, and p = 0.65) (p less than 0.05 was considered significant). The mean scores for sural nerve variables are provided in Table 4. Mean scores of sural nerve of the two groups were compared using RANOVA statistics for the difference in latency, duration, and amplitude and conduction velocity. Sural sensory nerve on comparison showed a significant difference for conduction velocity, Df = 1, 60, F = 10.16, and p b 0.001 (p value less than 0.05 was considered significant), though no significant difference was observed for latency (F = 0.96, Df =1, 60 and p = 0.33), duration (F = 1.25, Df = 1, 60 and p = 0.27) and amplitude in the two groups (F = 0.04, Df = 1, 60 and a p = 0.85) (p value less than 0.05 was considered significant). 5. Discussion Prevalence of DPN, is as high as 75% in the diabetic population (Bansal et al., 2006; Gimbel et al., 2003; Martyn & Hughes, 1997). DPN precipitates a complex mechanism due to poor glycemic control that leads to insensitive hands and feet (Bansal et al., 2006). Though many drug therapies are available for the management of DPN, still their role in the management is uncertain (Callaghan et al., 2012; Gimbel et al., 2003; Ismail-Beigi et al., 2010). On contrary moderate intensity (Heart rate intensity 40%–60% or rating of perceived exertion (RPE): somewhat hard) aerobic exercise of 30–45 min duration per session for eight weeks can play a vitally important role in controlling diabetic peripheral neuropathy (Fig. 2). A plausible mechanism of this could be modulation of sorbitol levels in the body as we know in DPN body initiates increased reliance on polyol–sorbitol pathway (anaerobic process) which has a deleterious effect on schwann cells due to increased intracellular sorbitol concentration, which may result in decreased endoneural blood flow causing chronic hypoxia of the nerves (Aminoff & Albers, 2005b; Kikkawa et al., 2005). Adaptations due to moderate intensity aerobic exercise may cause restoration of peripheral nerve functions by inhibition of aldose reductase (AR) leading to sparing of NADPH (Nicotinamide Adenine Dinucleotide Phosphate hydroxide) which may then participate in the synthesis of nitric oxide thereby relieving the nerves of their hypoxic state. Moreover hyperglycemia can also promote superoxide production as a consequence of glucose auto-oxidation, formation of advanced glycation end products, and activation of protein kinase C, which leads

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

Control Mean (SD), CI

Biguanides (mg) Secretegogues (mg) Alpha – glucosides Inh (mg) Insulin (Insulin units)

Experimental Mean (SD), CI

Control Mean (SD), CI

Experimental Mean (SD), CI

Baseline

Baseline

8th week

8th week

(n = 47)

(n = 40)

(n = 37)

(n = 29)

569.81 (1.95) (570.47–569.16) 9.7(5.80) (11.60–7.80) 18.56 (1.97) (19.27–17.84) 34.06 (1.77) (35.22–32.90)

787.77 (1.79) (788.42–787.12) 5 (4.61) (6.74–3.26) 10.71 (4.13) (12.27–9.15) 35.8 (1.61) (37.38–34.22)

590.05 (2.35) (590.94–589.16) 10.83 (5.71) (12.91–8.75) 28.02 (3.75) (29.41–26.63) 34.06 (1.77) (35.22–32.90)

769.7 (1.81) (770.43–768.98) 4.92 (5.66) (7.18–2.65) 10.25 (4.11) (11.89–8.61) 35.8 (1.61) (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 improvement 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 improvement 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 conventional 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

BMI Waist circumference Hip circumference WHR

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

25.95 (5.68) (27.57–24.35) 93.42 (10.17) (96.33–90.51) 95.75 (8.46) (98.17–93.33) 0.98 (0.08) (1.14–0.82)

26.38 (3.77) (27.6–25.16) 95.83 (9.69) (98.95–92.71) 95.44 (9.81) (98.60–92.28) 1.0 (0.10) (1.03–0.97)

25.81 (6.16) (27.88–23.74) 93.54 (9.96) (96.71–90.37) 95.75 (8.46) (98.51–92.99) 0.97 (0.07) (1.10–0.83)

26.35 (4.16) (27.86–24.84) 94.61 (10.76) (98.53–90.69) 95.77 (10.76) (99.69–91.85) 0.99 (0.11) (1.03–0.95)

BMI: Body Mass Index, WHR: Waist to Hip Ratio, CI: Confidence Interval at 95% confidence level, SD: Standard Deviation.

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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.

Baseline

8th week

Latency Duration Amplitude Conduction velocity Latency Duration Amplitude Conduction velocity

Control

Experimental

Peroneal nerve

Peroneal nerve

p Value

n

Mean (SD), CI

n

Mean (SD), CI

47

3.33 (1.78) 10.69 (1.27) 4.55 (2.28) 38.40 (1.36) 3.16 (1.83) 10.89 (1.23) 4.75 (2.13) 38.21 (1.31)

40

4.04 9.99 6.81 42.48 4.34 10.76 6.31 45.56

37

(3.86–2.80) (11.07–10.31) (5.23–3.88) (38.80–38) (3.77–2.57) (11.30–10.49) (5.45–4.05) (38.64–37.78)

29

(1.57) (4.53–3.55) (1.27) (10.05–9.93) (2.07) (7.46–6.16) (1.25) (42.87–42.09) (1.25) (4.80–3.89) (1.23) (11.21–10.31) (2) (7.02–5.59) (1.24) (46.01–45.11)

0.11 0.08 0.65 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 (FuchsjagerMayrl 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.

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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.

Baseline

Latency

Control

Experimental

Sensory sural

Sensory sural

n

Mean(SD), CI

n

Mean (SD), CI

47

3.39 (1.35) (3.80–2.99) 1.49 (1.50) (1.94–1.04) 3.23 (2.19) (3.89–2.57) 28.23 (1.49) (28.68–27.78) 3.39 (1.45) (3.87–2.90) 1.46 (1.90) (2.10–0.82) 3.94 (2.23) (4.69–3.19) 28.53 (1.49) (29.02–28.04)

40

3.51 (1.50) (3.98–3.04) 1.45 (1.89) (2.04–0.86) 2.48 (2.55) (3.28–1.68) 23.67 (1.81) (24.24–23.10) 3.45 (1.38) (3.95–2.95) 1.86 (1.75) (2.5–1.22) 2.14 (2.38) (3.01–1.27) 31.39 (1.58) (31.97–30.81)

Duration Amplitude Conduction velocity 8th week

Latency

p value

37

Duration Amplitude Conduction velocity

29

0.33 0.27 0.85 b 0.001

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 modulate neuropathy i.e. large fiber dysfunction. - Aerobic exercises when combined with standard medical care can yield greater benefits in the treatment 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. References American Diabetes Association. (2007). Standards of medical care in diabetes—2007. Diabetes Care, 30, S4–S41. Aminoff, M. J., & Albers, J. W. (2005). Electrophysiological techniques in the evaluation of patients with suspected neurotoxic disorder. In M. J. Aminoff (Ed.), Electrodiagnosis in clinical neurology (pp. 782) (5th ed.). Philadelphia: Churchill Livingstone.

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