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Exercise training can modify the natural history of diabetic peripheral neuropathy
Journal of Diabetes and Its Complications 20 (2006) 216 – 223
Exercise training can modify the natural history of diabetic peripheral neuropathy Stefano Balduccia,b, Gianluca Iacobellisb,e,T, Leoluca Parisic, Nicolina Di Biasea,f, Eugenio Calandrielloa,c, Frida Leonettib, Francesco Falluccad a
Health Care Team, Metabolic Fitness Association, Monterotondo, Rome, Italy Department of Clinical Sciences, Endocrinology, University of Rome, La Sapienza, Rome, Italy c Department of Clinical Neurology, La Sapienza University, Rome, Italy d Department of Clinical Sciences, La Sapienza University II Faculty (St. Andrea Hospital), Rome, Italy e Center for Human Nutrition, The University of Texas Southwestern Medical Center at Dallas, TX 75390-9052, USA f St. Pietro Hospital, FBF, Rome, Italy b
Received 26 August 2004; received in revised form 25 February 2005; accepted 5 July 2005
Abstract Background: Diabetes is the most important cause of peripheral neuropathy (DPN). No definitive treatment for DPN has been established, and very few data on the role of exercise training on DPN have been reported. Aim of the study: We sought to examine the effects of long-term exercise training on the development of DPN in both Types 1 and 2 diabetic patients. Participants and methods: Seventy-eight diabetic patients without signs and symptoms of peripheral DPN were enrolled, randomized, and subdivided in two groups: 31 diabetic participants [15 f, 16 m; 49F15.5 years old; body mass index (BMI)=27.9F4.7], who performed a prescribed and supervised 4 h/ week brisk walking on a treadmill at 50% to 85% of the heart rate reserve (exercise group: EXE), and a control group of 47 diabetic participants (CON; 24 f, 23 m; 52.9F13.4 years old; BMI=30.9F8.4). Vibration perception threshold (VPT), nerve distal latency (DL), nerve conduction velocity (NCV), and nerve action potential amplitude (NAPA) in the lower limbs were measured. Results: We found significant differences on # (delta) in NCV for both peroneal and sural motor nerve between the EXE and CON groups during the study period ( Pb.001, for both). The percentage of diabetic patients that developed motor neuropathy and sensory neuropathy during the 4 years of the study was significantly higher in the CON than the EXE group (17% vs. 0.0%, Pb.05, and 29.8% vs. 6.45%, Pb.05, respectively). In addition, the percentage of diabetic patients who developed increased VPT (25 V) during the study was significantly higher in the CON than the EXE group (21.3% vs. 12.9%, Pb.05). Change on Hallux VPT from baseline to the end of the study was significantly different between the EXE and CON groups ( Pb.05); no significant change in Malleolus VPT between the two groups occurred. Conclusions: This study suggests, for the first time, that long-term aerobic exercise training can prevent the onset or modify the natural history of DPN. D 2006 Elsevier Inc. All rights reserved. Keywords: Diabetic peripheral neuropathy; Exercise training
1. Introduction Diabetic peripheral neuropathy (DPN) is a common complication and quality-of-life damaging factor in diabetic patients (Boulton, Malik, Arezzo, & Sosenko, 2004; T Corresponding author. Fax: +1 214 648 7150. E-mail address: [email protected] (G. Iacobellis). 1056-8727/06/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.jdiacomp.2005.07.005
Poncelet, 2003) and a leading cause of nontraumatic foot amputation (Boulton, 1998). Metabolic and vascular factors seem to be involved in the pathogenesis of DPN. Distal symmetric polyneuropathy is the most common form of DPN, involving usually both small and large nerve fibers (Boulton et al., 2004). Small nerve fiber neuropathies occur early in the course of diabetes and frequently develop with no objective signs or electrophysiologic evidence of nerve damage (Vinik, Erbas, Stansberry, & Pittenger, 2001).
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Although no definitive treatment for DPN has been established yet, several studies have shown that intensive therapy and optimal glycemic control can significantly reduce DPN (Azad et al., 1999; Dahl-Jorgensen et al., 1986; DCCT Research Group, 1995). Promising treatment for DPN include metabolic treatments, autoimmune therapies, and nerve growth factors (Vinik, 1999). Recent studies suggested that aerobic physical activity, alone or in combination with resistance exercise, may be an effective therapeutic modality for Type 2 diabetes (Castaneda et al., 2002; Dunston et al., 2002; Maiorana, O’Driscoll, Goodman, Taylor, & Green, 2002). The beneficial effects of a regular exercise on glycemic control, insulin sensitivity, lipid abnormalities, and hypertension in diabetic patients have been previously described (Balducci, Leonetti, Di Mario, & Fallucca, 2004; Goldhaber-Fiebert, Goldhaber-Fiebert, Tristan, & Nathan, 2003). Nevertheless, very few data on the effectiveness of exercise treatment on DPN have been reported (Richardson, Sandman, & Vela, 2001; Tesfaye, Harris, Wilson, & Ward, 1992). Prescribed and supervised long-term exercise programs may influence neuromuscular parameters in diabetic patients, thereby inducing adaptive changes in the neuromuscular system in response to exercise training. In this study, we sought to examine the effects of a longterm exercise training on the development of peripheral neuropathy in both Types 1 and 2 diabetic patients.
2. Study design This was a 4-year prospective randomized intervention study. Types 1 and 2 diabetic patients, from 500 consecutive diabetic patients admitted in our Department, without signs and symptoms of DPN and able to have a 1.6-km-distance walk were enrolled in this study. Patients who did not accept to perform the proposed exercise program were excluded from the study. The enrolled participants were subsequently randomized in two groups and followed up for each year of the study. All patients had their usual diet during the study period. The dietary regimen was based on the Mediterranean diet. In addition, no significant changes in pharmacological treatment for diabetes, lipid, and blood-pressure-lowering drugs during the study were applied. This study was conducted in accordance with the Declaration of Helsinki guidelines. Each participant gave an informed consent before the study began. 2.1. Inclusion criteria The following inclusion criteria were implemented: ! ! !
Type 2 and/or Type 1 diabetes No signs or symptoms of DPN Ability to walk a 1.6-km distance without assistance or with a device. The ability to complete this walk-distance
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was tested in the metabolic fitness center with heart rate monitoring. 2.2. Exclusion criteria Patients carrying at least one of the following conditions were excluded from the study: 1.
Physical and electrodiagnostic evidence of DPN, according to the reported criteria (Feldman et al., 1994). Exclusion criteria based on physical examination. The presence of DPN was evaluated with the Michigan Neuropathy Screening Instrument (MNSI). MNSI consisted of an inspection of the foot, examination of the Achilles reflexes, and evaluation of the vibratory threshold (VPT). Vibration perception was considered reduced when the patients said that they did not feel any vibration, while the operator perceives the vibrations at the index of their own hand for another 10 s. If the final score was of 2.5 or more (MNSI positivity), the patient was excluded from the study. Exclusion criteria based on electrodiagnostic examination: (a) Sural response: absent or decreased amplitude (b6 AV) with a normal or minimally prolonged distal latency (DL; b3 ms) stimulating 14 cm from the recording site posterior to the lateral Malleolus. If the sural response was absent bilaterally, the motor responses were not performed. (b) Peroneal responses: absent or decreased in amplitude (b 2 mV for peroneal), with a normal DL (b 6.2 ms stimulating 9 cm from recording sites over the extensor digitorum brevis). 2. A history or evidence on physical examination of significant central nervous system dysfunction (i.e., hemiparesis, myelopathy, and cerebellar ataxia). 3. Significant musculoskeletal deformity [i.e., amputation, scoliosis, abnormality of range of motion (ROM)] that would prevent participation (b908 of humeral abduction, inability to grip, b108 of combined ankle inversion/eversion). 4. Lower extremity arthritis or pain that limits exercise. 5. A history or clinical evidence of severe cardiovascular diseases that limit or contraindicate the exercise. 6. A history or evidence on physical examination of vestibular dysfunction. 7. A history of angina or angina-equivalent symptoms (i.e., nausea, diaphoresis, and shortness of breath with exercise). 8. Symptomatic postural hypotension defined as a fall in blood pressure (i.e., N20 mm Hg for systolic or N10 mm Hg for diastolic blood pressure) in response to postural change, from supine to standing (Position paper, 1996).
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Table 1 Patients’ clinical characteristics at baseline and at the end of the 4-years study CON n Sex (F/M) Type 1/Type 2 diabetes Age (years) Onset of diabetes (years) Mean duration (years) Height (m) Weight (kg) BMI (kg/m2) Waist circumference (cm) FM (%) FFM (kg) HbA1c (%) Fasting glucose (mg/dl) Total cholesterol (mg/dl) Tryglicerides (mg/dl) Creatinine (mg/dl) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Microalbuminuria (n) Smoking (n) Alcohol intake b250 ml/day (n) Alcohol intake N250 ml/day (n) HR at rest (beats min 1) VO2 max (ml kg 1 min 1)
–
EXE
Baseline
4 years
Baseline
4 years
47 24/23 14/33
47
31 15/16 7/24
31
14/33
52.9F13.4 43.6F16.3
49.0F15.5 40.8F15.9
9.1F6.6
8.4F5.7
7/24
1.64F0.1 1.65F0.1 73.4F11.3 73.2F12.2 77.2F13.7 75.6F13.1 27.2F3.6 27.3F4.5 27.9F4.7 27.5F4.4 87.4F13.2 91.2F10.5 98.0F11.8 92.3F13.1 30.9F8 51.2F7.7 7.95F1.6 164F68
30F9.4 49.6F11.5 8.09F1.4 158F83
29.5F9.8 29.5F10 54.5F12.2 54.7F14.4 8.26F 1.2 7.84F1.1 163F58 143F43
205F43
186F44
201F37
188F44
129F77 1.03F0.2 136F19
130F94 1.02F0.3 135F17
154F71 1.01F0.2 138F19
137F79 1.01F0.2 134F19
82F10
80F10
87F9
82F10
7 (15%) 12 (26%) 12 (26%)
7 (15%) 12 (26%) 12 (26%)
4 (13%) 10 (35%) 11 (36%)
4 (13%) 10 (35%) 11 (36%)
4 (9%)
4 (9%)
3 (10%)
3 (10%)
71.5F7.8
71.9F9.4
73.3F9.1
63.4F5.2
23.5F5.3
23.1F7.1
25.4F6.8
40.7F4.6
47 diabetic participants (24 f, 23 m; age =52.9F 13.4 years; BMI=30.9F8.4; 14 Type 1 diabetes and 33 Type 2 diabetes) with a sedentary lifestyle represented the control group (CON). The CON group did not perform supervised physical activity for the entire duration of the study.
2.4. Methods 2.4.1. Neurophysiological measurements Vibration perception threshold (VPT), nerve DL, nerve conduction velocity (NCV), and nerve action potential amplitude (NAPA) in the lower limbs were measured by experienced specialists in neurophysiology (L.P. and E.C.) using the same methods and instrumentation at baseline and for each year throughout the 4 years of the study. The measurements of mean peroneal motor nerve and sural sensory nerve were performed using a Medelec MS 928 Neurostar (Oxford Instruments Medical, Old Woking, U.K.). NCV and NAPA were analyzed for the sensory sural and motor peroneal nerves, and the reference values used were based on a large number of volunteers (Falck et al., 1991; Liveson & Ma, 1992). For NCV, the lowest reference value is 40 m/s ( 2 S.D.) for all nerves, and for NAPA, the lowest reference value ( 2 S.D.) is 5 AV for the sural nerve and 2 mV for the peroneal nerve. In our calculations, we used 15 m/s instead of 0 m/s for the patients with NCV registered as 0 m/s because, for this type of patient, the true value probably lies between the detection limit (approximately 30 m/s) and 0 m/s. If we had used 0 m/s in our calculations, the differences between the groups would have been greater; thus, the use of 15 m/s instead of 0 m/s reduces the possibility of overestimating the effect of exercise training (Larsen & Jorgensen, 2003).
Data are meanFS.D.
9.
A history or evidence on physical examination of plantar skin pressure ulcer.
2.3. Participants Seventy-eight diabetic patients (39 f, 39 m; age= 51.3F14.3 years, duration of diabetes =8.79F6.2 years) who met the inclusion criteria were enrolled and randomized in two treatment groups: –
31 diabetic participants [15 f, 16 m; age=49.0F 15.5 years; body mass index (BMI) =27.9F4.7; 7 Type 1 diabetes and 24 Type 2 diabetes] formed the exercise group (EXE). They performed a prescribed and supervised 4-h/week (four sessions per week) brisk walking on a treadmill (Technogym Gambettola, FC, Italy) at 50% to 85% of the heart rate reserve estimated every month.
Fig. 1. Change in NCV (DNCV) from baseline to the end of the study; **Pb.001.
S. Balducci et al. / Journal of Diabetes and Its Complications 20 (2006) 216 – 223
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Table 2 Neurological parameters at baseline and for each year of the study CON Baseline n Peroneal motor nerve DL (m/s) NAPA (mV) NCV (m/s) DNCV (m/s) Patients developed motor neuropathy Sural sensory nerve DL (m/s) NAPA (AV) NCV (m/s) DNCV (m/s) Patients developed sensory neuropathy VPT VPT Malleolus (mV) VPT Hallux (mV) Patients with VPT altered
EXE 4 years
Baseline
47
47
31
4.41F0.64 4.36F0.67 4.45F0.65 4.47F0.60 2.93F1.68 2.95F0.95 2.77F0.98 2.72F1.0 46.6F3.2 47.1F3.1 47.1F3.2 46.3F5.8
4.40F0.61 2.70F1.07 46F5.36 0.6F3.3 8 (17.0%)
4.38F0.83 4.15F0.57 4.23F0.52 4.3F0.5 4.34F0.49 3.19F1.99 3.07F0.7 2.9F1.0 2.9F0.9 2.81F0.98 47F3.27 48.1F3.52 48.3F2.48 48.9F1.9 48.8F2.24T +1.8F2.7TT 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) T
3.40F0.92 3.29F0.40 3.30F0.38 3.21F0.3 21.5F5.24 21.4F4.4 21.5F5.1 20.6F5.5 47.1F4.01 47.4F5.05 47.1F3.97 47.9F2.9 0 (0.0%)
17.9F6.20 18F6.6 14.1F4.00 14.1F5.1 0 (0.0%) 0 (0.0%)
0 (0.0%)
1 year
0 (0.0%)
2 years
2 (4.3%)
3 years
5 (10.6%)
3.43F0.54 3.30F0.46 3.32F0.39 3.33F0.50 20.3F5.02 20.8F4.05 19.9F3.9 19.7F3.9 47.0F3.5 46.5F5.9 45.8F7.0 45.1F6.7 0 (0.0%)
1 (2.1%)
4 (6.4%)
9 (19.1%)
3.27F0.52 19.4F4.66 44.3F7.84T 2.7F2.8 14 (29.8%)
18.6F8.5 14.2F6.7 0 (0%)
18.9F7.1 14.9F6.2 1 (2.1%)
19.6F7.2 16F7.4 2 (4.3%)
20.5F8.9 16.2F9.1 6 (12.8%)
21.4F9.60 16.7F9.23 10 (21.2%)
1 year
2 years
3 years
4 years 31
0 (0.0%)
0 (0.0%)
1 (3.2%)
3.25F0.50 21.7F5.44 47.5F3.18 + 0.4F3.3TT 2 (6.4%)T
18.4F6.21 18.0F7.1 17.9F6.90 14.0F4.6 13.6F4.3 13.6F7.00T 1 (3.2%) 3 (9.7%) 4 (12.9%)T
Data are meansFS.D. T Pb.05. TT Pb.001.
Large-fiber sensory nerve function was quantified by VPT at the Hallux and Malleolus by means of a Biothesiometer (Horwell, Nottingham, U.K.). We defined reduced vibration detection to be a VPT test score of 25 V (Abbott, Vileikyte, Williamson, Carrington, & Boulton, 1998; Young, Breddy, Veves, & Boulton, 1994). Participants were tested in a quiet environment in closed room with constant temperature. The Biothesiometer was applied to the skin surface but held lightly so that almost its full weight was on the foot to ensure that the pressure was always the same during testing. The vibration amplitude was increased until the participants could feel vibration at the site that was being tested. The patients were instructed not to respond to sensation perceived in other parts of the foot or leg. If vibration was perceived in the tested area, this was indicated by the patients by a verbal response. The values of VPT were determined as the mean of three measurements (Davis, Jones, Walsh, & Byrne, 1997). 2.4.2. Anthropometric measurements Weight (to the nearest 0.1 kg) and height (to the nearest 0.5 cm) were measured while the participants were fasting and wearing only their undergarments. BMI was calculated as body weight divided by height squared. Minimum waist circumference (W, in centimeters; minimum circumference between the lower rib margin and the iliac crest, midwaist) was measured while the participants were standing with their heels together.
2.4.3. Dual energy X-ray absorptiometry (DEXA) measurements Fat mass (FM, %) and free fat mass (FFM, kg) calculations were performed using a whole body densitometer (Hologic QDR 2000 plus, Hologic). 2.4.4. Exercise testing All participants were started on a walking program on a treadmill Technogym at baseline and for each year throughout the 4 years of the study after instruction by a qualified physical education instructor on suitable clothing, shoes, and other precautions. The patients were fitted with a heart rate feature strapped to the chest, for heart rate monitoring. Maximal aerobic capacity (VO2 max) was measured used a 1-mile track walk (Kline, Porcari, & Rippe, 1987). 2.4.5. Blood pressure measurements Blood pressure was measured using a standard manual mercury sphygmomanometer for at least three measurements in a seated position, after at least 15 min of rest, according to the NIH guidelines. 2.4.6. Lifestyle habits Information about smoking habits, use of medication, and alcohol was obtained through questionnaires. The Minnesota Leisure Time Physical Activity Questionnaire was used to obtain information on the average frequency
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measured using enzymatic kits (Ortho-Clinical Diagnostic, Milan, Italy). 2.5. Statistical analysis All the results are expressed as meansFS.D. We computed the changes over time in each group with paired t test with the calculation of 95% confidence interval (CI). Unpaired t test with the calculation of 95% CI was used to estimate the difference between the delta in NCV for both peroneal and sural motor nerves between the two treatment groups during the study period. We used this t test for deltas in NCV as equivalent to the test on the interaction term in the repeated measures analysis of variance. Fisher’s Exact Test was used to evaluate the percentage of number of patients developing PDN in both groups. Two-tailed Pb.05 indicated statistical significance. Statistical analysis was made by StatView, Version 4.5 (Abacus Concept, Berkeley, CA, USA).
3. Results We obtained an excellent compliance, and all patients completed the study and attended N90% of the prescribed program sessions. No adverse effects throughout the entire study were observed. 3.1. Clinical parameters
Fig. 2. Percentage of patients developing (A) motor neuropathy, (B) sensory neuropathy, and (C) VPT z25 V during 4 years of follow-up in the (– –) control and (—) exercise group.
and duration of participation for a specific list of physical activities. Sedentary lifestyle was defined as performing no vigorous activity and performing no light to moderate activity during the past 1 week, 1 month, 3 months, and 1 year preceding the survey. 2.4.7. Analytic procedures Glycosylated hemoglobin (HbA1c) and microalbuminuria were measured using monoclonal antibody method (DCA 2000+Analyzer, Milan, Italy). Overnight urine collections for microalbuminuria detection were performed. Microalbuminuria was defined as urinary albumin excretion between 20 and 200 Ag/min in two consecutive samples. Plasma glucose was determined by the glucose oxidase method [Autoanalyzer, Beckman Coulter, Fullerton, CA; coefficient of variation (CV), 1.9F0.2%]. Plasma total cholesterol (CV, 3.4F0.2%), triglycerides (CV, 3.1F 0.5%), and creatinine (CV, 1F0.4%) concentrations were
The participants’ characteristics for both groups at baseline and for each year of the study are summarized in Table 1. No significant difference on baseline clinical parameters between the EXE and CON groups were found (Table 1). 3.2. Neurophysiological parameters from baseline to the end of the 4-year study 3.2.1. NCV parameters We found significant differences on D (delta) in NCV for both peroneal and sural motor nerve between the EXE and CON groups during the study period ( Pb.001, 95% CI= 0.53 to 2.26; Pb.001, 95% CI= 4.48 to 1.71, respectively; Fig. 1). Peroneal motor NCV significantly increased in the EXE group ( Pb.05, 95% CI= 0.37 to 3.22) and insignificantly decreased in the CON group. For sural sensory NCV, there was no significant increase in the EXE group (95% CI=1.53 to 5.11), while a significant decrease in the CON group ( Pb.05, 95% CI=1.21 to 4.26) was found. No significant difference in both peroneal and sural DL and NAPA between the two groups was observed (Table 2). 3.2.2. PDN development during the 4-year study The percentage of diabetic patients who developed motor neuropathy during the 4 years of the study was
S. Balducci et al. / Journal of Diabetes and Its Complications 20 (2006) 216 – 223
Fig. 3. Malleulus and Hallux VPT at baseline and after 4 years on the control and exercise groups; *Pb.05.
significantly higher in the CON than the EXE group (17.0% vs. 0.0%, Pb.05, OR= 0.07; 95% CI=0.003– 0.77). Similarly, the percentage of diabetic patients that developed sensory neuropathy during the 4 years of the study was significantly higher in the CON than the EXE group (29.8% vs. 6.5%, Pb.05, OR= 0.16; 95% CI=0.004 –1.3). In addition, the percentage of diabetic patients who developed increased VPT (25 V) during the study was statistically significantly higher in the CON than the EXE group (21.3% vs. 12.9%, Pb.05, OR=0.554; 95% CI= 0.04– 0.97; Fig. 2). 3.2.3. VPT parameters Change on Hallux VPT from baseline to the end of the study was significantly different between the EXE and CON groups ( Pb.05); no significant change in Malleolus VPT between the two groups occurred (Fig. 3). No significant differences on NCV and VPT parameters between Types 1 and 2 diabetic patients during the study were observed.
4. Discussion Our study shows, for the first time, that long-term aerobic exercise training can modify the natural history of peripheral diabetic neuropathy or even prevent its onset. In fact, we found that a prescribed aerobic exercise regimen, although of mild intensity, can positively influence and modify both motor and sensory neuromuscular parameters in diabetic patients. The treatment of DPN has traditionally focused on the control of hyperglycemia. The impact of an intensive glycemic control on DPN has been widely evaluated (Azad et al., 1999; Balducci et al., 2004; Castaneda et al., 2002; Dahl-Jorgensen et al., 1986; DCCT Research Group, 1995; Dunston et al., 2002; Goldhaber-Fiebert et al., 2003; Maiorana et al., 2002; Vinik, 1999), but with controversial results. In fact, some studies showed substantial improve-
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ments on peroneal NCV in Type 1 diabetic patients (Muller-Felber et al., 1993; Muller-Felber et al., 1991; Navarro, Sutherland, & Kennedy, 1997), whereas others failed to demonstrate significant changes in the progression of somatic or autonomic neuropathy (Azad et al., 1999; Ruiz, 2004). Our study can provide original information of potential interest. First, this is the first long-term follow up study on the effect of aerobic exercise training on the development of DPN, because only short-term studies were previously performed (Richardson et al., 2001). We evaluated the progression of neurophysiological parameters for each year of the 4-year study period. Second, we studied diabetic patients without baseline signs or symptoms of DPN. This study design allowed us to evaluate the DPN development in two groups of diabetic patients with the same baseline neurological condition. Third, we prescribed mild submaximal aerobic exercise training, as well as brisk walking, to evaluate physical exercise easily reproducible and reliable within the lifestyle of diabetic patients. Our data seem to indicate the effectiveness of a submaximal and reliable exercise on DPN. Fourth, no difference at baseline on age, duration of diabetes, BMI, waist circumference, glycemic control, smoking, alcohol intake, blood pressure, and nephropathy between the study and control groups occurred. We believe that this latter point could allow us to evaluate the effect of exercise on DPN without the confounding role of the most important risk factors. In fact, it is well known that DPN is associated with poor glycemic control, obesity, dyslipidemia, retinopathy, microalbuminuria, and smoking (Boulton et al., 2004). The absence of statistically significant changes on BMI, waist circumference, and metabolic profile could suggest a possible direct and local effect of exercise on peripheral nerves in our diabetic patients. This partially unexpected finding could be due to the mild intensity of the training and to the fact that no modifications on participants’ dietary habitus have been applied in this study. However, these data should be interpreted with caution. Finally, this study included the expertise of a highly specialized metabolic fitness assistant who supervised on the technical aspects of the proposed exercise and took good care of the patients. The presence of this professional figure could explain the good compliance of the patients. Several exercise-induced vascular and metabolic changes could be invoked to explain the effects of training on DPN development. Human and experimental studies suggest that short-term exercise stimulates endotheliumdependent vasodilatation. Higher vascular endothelial growth factor (VEGF) expression during short-term exercise has been proposed to play a role in endoneurial blood flow increase (Gustafsson, Puntschart, Kaijser, Jansson, & Sundberg, 1999). Exercise may also improve abnormal perfusion and plasma viscosity facilitating oxygen delivery (Terjung, Mathien, Erney, & Ogilvie, 1988; FuchsjagerMayrl et al., 2002). It is known that exercise training
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exposes the vessels to repeated episodes of hyperemia. The elevated shear stress from the increased blood flow of aerobic exercise augments vasodilatation over the long term by increasing the vascular expression of nitric oxide synthase and by enhancing the release of nitric oxide (NO; Fukai et al., 2000; Maiorana, O’Driscoll, Taylor, & Green, 2003; McAllister, Hirai, & Musch, 1995; Niebauer & Cooke, 1996). The increase of NO synthesis or bioavailability may be useful in preventing diabetes-induced changes in the polyol pathway (Ramana, Chandra, Srivastava, Bhatnagar, & Srivastava, 2003). Exercise-induced nerve function changes could be also related to an improvement of Na/K ATPase activity. In fact, training has been reported to increase the concentration of Na/K ATPase in rat muscle cells (Kjeldsen, Richter, Galbo, Lortie, & Clausen, 1986). In addition, K (ATP) channel openers have been shown to provide marked beneficial effects on nerve perfusion and function in experimental diabetic neuropathy (Hohman, Cotter, & Cameron, 2000). In conclusion, this study suggests, for the first time, that long-term prescribed and supervised aerobic exercise training may modify the natural history of DPN or even delay its onset. Mild aerobic exercise training, like brisk walking, could be an effective and reasonable treatment tool to prevent the onset or modify the natural history of DPN.
5. Study limitations Our data are promising, but further studies on a larger population are necessary to confirm these findings. No conclusions on the possible exercise-related mechanisms inducing a delayed development of DPN can be drawn from this study.
Acknowledgments The authors thank Gianluca Balducci, Lorella Senigagliesi, and the participants, for their contribution to these studies. We also express our gratitude to Philippa Mungra in the preparation of the manuscript.
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S. Balducci et al. / Journal of Diabetes and Its Complications 20 (2006) 216 – 223 Liveson, J. A., & Ma, D. M. (Eds.). (1992). Laboratory reference for clinical neurophysiology (pp. 278 – 317). Philadelphia7 FA Davis. Maiorana, A., O’Driscoll, G., Goodman, C., Taylor, R., & Green, D. (2002). Combined aerobic and resistance exercise improves glycemic control and fitness in type 2 diabetes. Diabetes Research and Clinical Practice, 56, 115 – 123. Maiorana, A., O’Driscoll, G., Taylor, R., & Green, D. (2003). Exercise and the nitric oxide vasodilator system. Sports Medicine, 33, 1013 – 1035. McAllister, R. M., Hirai, T., & Musch, T. I. (1995). Contribution of endothelium-derived nitric oxide (EDNO) to the skeletal muscle blood flow response to exercise. Medicine and Science in Sports and Exercise, 27, 1145 – 1151. Muller-Felber, W., Landgraf, R., Scheuer, R., Wagner, S., Reimers, C. D., Nusser, J., Abendroth, D., Illner, W. D., & Land, W. (1993, Oct.). Diabetic neuropathy 3 years after successful pancreas and kidney transplantation. Diabetes, 42 (10), 1482 – 1486. Muller-Felber, W., Landgraf, R., Wagner, S., Mair, N., Nusser, J., Landgraf-Leurs, M. M., Abendroth, A., Illner, W. D., & Land, W. (1991). Follow-up study of sensory-motor polyneuropathy in type 1 (insulin-dependent) diabetic subjects after graft rejection. Diabetologia, (Suppl. 1), S113 – S117. Navarro, X., Sutherland, D. E., & Kennedy, W. R. (1997). Long-term effects of pancreatic transplantation on diabetic neuropathy. Annals of Neurology, 42, 727 – 736. Niebauer, J., & Cooke, J. P. (1996). Cardiovascular effects of exercise: Role of endothelial shear stress. Journal of the American College of Cardiology, 28, 1652 – 1660. Poncelet, A. N. (2003). Diabetic polyneuropathy. Risk factors, patterns of presentation, diagnosis, and treatment. Geriatrics, 58, 16 – 18.
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Position paper. (1996). The Consensus Committee of the American Autonomic Society and the American Academy of Neurology: The definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. Journal of Autonomic Nervous System, 58, 123 – 124. Ramana, K. V., Chandra, D., Srivastava, S., Bhatnagar, A., & Srivastava, S. K. (2003). Nitric oxide regulates the polyol pathway of glucose metabolism in vascular smooth muscle cells. Federation of American Societies for Experimental Biology, 17, 417 – 425. Richardson, J. K., Sandman, D., & Vela, S. (2001). A focused exercise regimen improves clinical measures of balance in patients with peripheral neuropathy. Archives of Physical Medicine and Rehabilitation, 82, 205 – 209. Ruiz, J. (2004). Intensive care of type 2 diabetes: What does the STENO 2 study teach us? Revue Medicale De La Suisse Romande, 124, 125 – 127. Terjung, R. L., Mathien, G. M., Erney, T. P., & Ogilvie, R. W. (1988). Peripheral adaptations to low blood flow in muscle during exercise. The American Journal of Cardiology, 62, 15E – 19E. Tesfaye, S., Harris, N. D., Wilson, R. M., & Ward, J. D. (1992). Exerciseinduced conduction velocity increment: A marker of impaired peripheral nerve blood flow in diabetic neuropathy. Diabetologia, 35, 155 – 159. Vinik, A. I. (1999). Diabetic neuropathy: Pathogenesis and therapy. The American Journal of Medicine, 107 (2B), 17S – 26S. Vinik, A. I., Erbas, T., Stansberry, K. B., & Pittenger, G. L. (2001). Small fiber neuropathy and neurovascular disturbances in diabetes mellitus. Experimental and Clinical Endocrinology and Diabetes, 109 (Suppl. 2), S451 – S473. Young, M. J., Breddy, J. L., Veves, A., & Boulton, A. J. M. (1994). The prediction of diabetic foot ulceration using vibration perception thresholds: A prospective study. Diabetes Care, 17, 557 – 560.
Exercise training can modify the natural history of diabetic peripheral neuropathy Stefano Balduccia,b, Gianluca Iacobellisb,e,T, Leoluca Parisic, Nicolina Di Biasea,f, Eugenio Calandrielloa,c, Frida Leonettib, Francesco Falluccad a
Health Care Team, Metabolic Fitness Association, Monterotondo, Rome, Italy Department of Clinical Sciences, Endocrinology, University of Rome, La Sapienza, Rome, Italy c Department of Clinical Neurology, La Sapienza University, Rome, Italy d Department of Clinical Sciences, La Sapienza University II Faculty (St. Andrea Hospital), Rome, Italy e Center for Human Nutrition, The University of Texas Southwestern Medical Center at Dallas, TX 75390-9052, USA f St. Pietro Hospital, FBF, Rome, Italy b
Received 26 August 2004; received in revised form 25 February 2005; accepted 5 July 2005
Abstract Background: Diabetes is the most important cause of peripheral neuropathy (DPN). No definitive treatment for DPN has been established, and very few data on the role of exercise training on DPN have been reported. Aim of the study: We sought to examine the effects of long-term exercise training on the development of DPN in both Types 1 and 2 diabetic patients. Participants and methods: Seventy-eight diabetic patients without signs and symptoms of peripheral DPN were enrolled, randomized, and subdivided in two groups: 31 diabetic participants [15 f, 16 m; 49F15.5 years old; body mass index (BMI)=27.9F4.7], who performed a prescribed and supervised 4 h/ week brisk walking on a treadmill at 50% to 85% of the heart rate reserve (exercise group: EXE), and a control group of 47 diabetic participants (CON; 24 f, 23 m; 52.9F13.4 years old; BMI=30.9F8.4). Vibration perception threshold (VPT), nerve distal latency (DL), nerve conduction velocity (NCV), and nerve action potential amplitude (NAPA) in the lower limbs were measured. Results: We found significant differences on # (delta) in NCV for both peroneal and sural motor nerve between the EXE and CON groups during the study period ( Pb.001, for both). The percentage of diabetic patients that developed motor neuropathy and sensory neuropathy during the 4 years of the study was significantly higher in the CON than the EXE group (17% vs. 0.0%, Pb.05, and 29.8% vs. 6.45%, Pb.05, respectively). In addition, the percentage of diabetic patients who developed increased VPT (25 V) during the study was significantly higher in the CON than the EXE group (21.3% vs. 12.9%, Pb.05). Change on Hallux VPT from baseline to the end of the study was significantly different between the EXE and CON groups ( Pb.05); no significant change in Malleolus VPT between the two groups occurred. Conclusions: This study suggests, for the first time, that long-term aerobic exercise training can prevent the onset or modify the natural history of DPN. D 2006 Elsevier Inc. All rights reserved. Keywords: Diabetic peripheral neuropathy; Exercise training
1. Introduction Diabetic peripheral neuropathy (DPN) is a common complication and quality-of-life damaging factor in diabetic patients (Boulton, Malik, Arezzo, & Sosenko, 2004; T Corresponding author. Fax: +1 214 648 7150. E-mail address: [email protected] (G. Iacobellis). 1056-8727/06/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.jdiacomp.2005.07.005
Poncelet, 2003) and a leading cause of nontraumatic foot amputation (Boulton, 1998). Metabolic and vascular factors seem to be involved in the pathogenesis of DPN. Distal symmetric polyneuropathy is the most common form of DPN, involving usually both small and large nerve fibers (Boulton et al., 2004). Small nerve fiber neuropathies occur early in the course of diabetes and frequently develop with no objective signs or electrophysiologic evidence of nerve damage (Vinik, Erbas, Stansberry, & Pittenger, 2001).
S. Balducci et al. / Journal of Diabetes and Its Complications 20 (2006) 216 – 223
Although no definitive treatment for DPN has been established yet, several studies have shown that intensive therapy and optimal glycemic control can significantly reduce DPN (Azad et al., 1999; Dahl-Jorgensen et al., 1986; DCCT Research Group, 1995). Promising treatment for DPN include metabolic treatments, autoimmune therapies, and nerve growth factors (Vinik, 1999). Recent studies suggested that aerobic physical activity, alone or in combination with resistance exercise, may be an effective therapeutic modality for Type 2 diabetes (Castaneda et al., 2002; Dunston et al., 2002; Maiorana, O’Driscoll, Goodman, Taylor, & Green, 2002). The beneficial effects of a regular exercise on glycemic control, insulin sensitivity, lipid abnormalities, and hypertension in diabetic patients have been previously described (Balducci, Leonetti, Di Mario, & Fallucca, 2004; Goldhaber-Fiebert, Goldhaber-Fiebert, Tristan, & Nathan, 2003). Nevertheless, very few data on the effectiveness of exercise treatment on DPN have been reported (Richardson, Sandman, & Vela, 2001; Tesfaye, Harris, Wilson, & Ward, 1992). Prescribed and supervised long-term exercise programs may influence neuromuscular parameters in diabetic patients, thereby inducing adaptive changes in the neuromuscular system in response to exercise training. In this study, we sought to examine the effects of a longterm exercise training on the development of peripheral neuropathy in both Types 1 and 2 diabetic patients.
2. Study design This was a 4-year prospective randomized intervention study. Types 1 and 2 diabetic patients, from 500 consecutive diabetic patients admitted in our Department, without signs and symptoms of DPN and able to have a 1.6-km-distance walk were enrolled in this study. Patients who did not accept to perform the proposed exercise program were excluded from the study. The enrolled participants were subsequently randomized in two groups and followed up for each year of the study. All patients had their usual diet during the study period. The dietary regimen was based on the Mediterranean diet. In addition, no significant changes in pharmacological treatment for diabetes, lipid, and blood-pressure-lowering drugs during the study were applied. This study was conducted in accordance with the Declaration of Helsinki guidelines. Each participant gave an informed consent before the study began. 2.1. Inclusion criteria The following inclusion criteria were implemented: ! ! !
Type 2 and/or Type 1 diabetes No signs or symptoms of DPN Ability to walk a 1.6-km distance without assistance or with a device. The ability to complete this walk-distance
217
was tested in the metabolic fitness center with heart rate monitoring. 2.2. Exclusion criteria Patients carrying at least one of the following conditions were excluded from the study: 1.
Physical and electrodiagnostic evidence of DPN, according to the reported criteria (Feldman et al., 1994). Exclusion criteria based on physical examination. The presence of DPN was evaluated with the Michigan Neuropathy Screening Instrument (MNSI). MNSI consisted of an inspection of the foot, examination of the Achilles reflexes, and evaluation of the vibratory threshold (VPT). Vibration perception was considered reduced when the patients said that they did not feel any vibration, while the operator perceives the vibrations at the index of their own hand for another 10 s. If the final score was of 2.5 or more (MNSI positivity), the patient was excluded from the study. Exclusion criteria based on electrodiagnostic examination: (a) Sural response: absent or decreased amplitude (b6 AV) with a normal or minimally prolonged distal latency (DL; b3 ms) stimulating 14 cm from the recording site posterior to the lateral Malleolus. If the sural response was absent bilaterally, the motor responses were not performed. (b) Peroneal responses: absent or decreased in amplitude (b 2 mV for peroneal), with a normal DL (b 6.2 ms stimulating 9 cm from recording sites over the extensor digitorum brevis). 2. A history or evidence on physical examination of significant central nervous system dysfunction (i.e., hemiparesis, myelopathy, and cerebellar ataxia). 3. Significant musculoskeletal deformity [i.e., amputation, scoliosis, abnormality of range of motion (ROM)] that would prevent participation (b908 of humeral abduction, inability to grip, b108 of combined ankle inversion/eversion). 4. Lower extremity arthritis or pain that limits exercise. 5. A history or clinical evidence of severe cardiovascular diseases that limit or contraindicate the exercise. 6. A history or evidence on physical examination of vestibular dysfunction. 7. A history of angina or angina-equivalent symptoms (i.e., nausea, diaphoresis, and shortness of breath with exercise). 8. Symptomatic postural hypotension defined as a fall in blood pressure (i.e., N20 mm Hg for systolic or N10 mm Hg for diastolic blood pressure) in response to postural change, from supine to standing (Position paper, 1996).
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S. Balducci et al. / Journal of Diabetes and Its Complications 20 (2006) 216 – 223
Table 1 Patients’ clinical characteristics at baseline and at the end of the 4-years study CON n Sex (F/M) Type 1/Type 2 diabetes Age (years) Onset of diabetes (years) Mean duration (years) Height (m) Weight (kg) BMI (kg/m2) Waist circumference (cm) FM (%) FFM (kg) HbA1c (%) Fasting glucose (mg/dl) Total cholesterol (mg/dl) Tryglicerides (mg/dl) Creatinine (mg/dl) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Microalbuminuria (n) Smoking (n) Alcohol intake b250 ml/day (n) Alcohol intake N250 ml/day (n) HR at rest (beats min 1) VO2 max (ml kg 1 min 1)
–
EXE
Baseline
4 years
Baseline
4 years
47 24/23 14/33
47
31 15/16 7/24
31
14/33
52.9F13.4 43.6F16.3
49.0F15.5 40.8F15.9
9.1F6.6
8.4F5.7
7/24
1.64F0.1 1.65F0.1 73.4F11.3 73.2F12.2 77.2F13.7 75.6F13.1 27.2F3.6 27.3F4.5 27.9F4.7 27.5F4.4 87.4F13.2 91.2F10.5 98.0F11.8 92.3F13.1 30.9F8 51.2F7.7 7.95F1.6 164F68
30F9.4 49.6F11.5 8.09F1.4 158F83
29.5F9.8 29.5F10 54.5F12.2 54.7F14.4 8.26F 1.2 7.84F1.1 163F58 143F43
205F43
186F44
201F37
188F44
129F77 1.03F0.2 136F19
130F94 1.02F0.3 135F17
154F71 1.01F0.2 138F19
137F79 1.01F0.2 134F19
82F10
80F10
87F9
82F10
7 (15%) 12 (26%) 12 (26%)
7 (15%) 12 (26%) 12 (26%)
4 (13%) 10 (35%) 11 (36%)
4 (13%) 10 (35%) 11 (36%)
4 (9%)
4 (9%)
3 (10%)
3 (10%)
71.5F7.8
71.9F9.4
73.3F9.1
63.4F5.2
23.5F5.3
23.1F7.1
25.4F6.8
40.7F4.6
47 diabetic participants (24 f, 23 m; age =52.9F 13.4 years; BMI=30.9F8.4; 14 Type 1 diabetes and 33 Type 2 diabetes) with a sedentary lifestyle represented the control group (CON). The CON group did not perform supervised physical activity for the entire duration of the study.
2.4. Methods 2.4.1. Neurophysiological measurements Vibration perception threshold (VPT), nerve DL, nerve conduction velocity (NCV), and nerve action potential amplitude (NAPA) in the lower limbs were measured by experienced specialists in neurophysiology (L.P. and E.C.) using the same methods and instrumentation at baseline and for each year throughout the 4 years of the study. The measurements of mean peroneal motor nerve and sural sensory nerve were performed using a Medelec MS 928 Neurostar (Oxford Instruments Medical, Old Woking, U.K.). NCV and NAPA were analyzed for the sensory sural and motor peroneal nerves, and the reference values used were based on a large number of volunteers (Falck et al., 1991; Liveson & Ma, 1992). For NCV, the lowest reference value is 40 m/s ( 2 S.D.) for all nerves, and for NAPA, the lowest reference value ( 2 S.D.) is 5 AV for the sural nerve and 2 mV for the peroneal nerve. In our calculations, we used 15 m/s instead of 0 m/s for the patients with NCV registered as 0 m/s because, for this type of patient, the true value probably lies between the detection limit (approximately 30 m/s) and 0 m/s. If we had used 0 m/s in our calculations, the differences between the groups would have been greater; thus, the use of 15 m/s instead of 0 m/s reduces the possibility of overestimating the effect of exercise training (Larsen & Jorgensen, 2003).
Data are meanFS.D.
9.
A history or evidence on physical examination of plantar skin pressure ulcer.
2.3. Participants Seventy-eight diabetic patients (39 f, 39 m; age= 51.3F14.3 years, duration of diabetes =8.79F6.2 years) who met the inclusion criteria were enrolled and randomized in two treatment groups: –
31 diabetic participants [15 f, 16 m; age=49.0F 15.5 years; body mass index (BMI) =27.9F4.7; 7 Type 1 diabetes and 24 Type 2 diabetes] formed the exercise group (EXE). They performed a prescribed and supervised 4-h/week (four sessions per week) brisk walking on a treadmill (Technogym Gambettola, FC, Italy) at 50% to 85% of the heart rate reserve estimated every month.
Fig. 1. Change in NCV (DNCV) from baseline to the end of the study; **Pb.001.
S. Balducci et al. / Journal of Diabetes and Its Complications 20 (2006) 216 – 223
219
Table 2 Neurological parameters at baseline and for each year of the study CON Baseline n Peroneal motor nerve DL (m/s) NAPA (mV) NCV (m/s) DNCV (m/s) Patients developed motor neuropathy Sural sensory nerve DL (m/s) NAPA (AV) NCV (m/s) DNCV (m/s) Patients developed sensory neuropathy VPT VPT Malleolus (mV) VPT Hallux (mV) Patients with VPT altered
EXE 4 years
Baseline
47
47
31
4.41F0.64 4.36F0.67 4.45F0.65 4.47F0.60 2.93F1.68 2.95F0.95 2.77F0.98 2.72F1.0 46.6F3.2 47.1F3.1 47.1F3.2 46.3F5.8
4.40F0.61 2.70F1.07 46F5.36 0.6F3.3 8 (17.0%)
4.38F0.83 4.15F0.57 4.23F0.52 4.3F0.5 4.34F0.49 3.19F1.99 3.07F0.7 2.9F1.0 2.9F0.9 2.81F0.98 47F3.27 48.1F3.52 48.3F2.48 48.9F1.9 48.8F2.24T +1.8F2.7TT 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) T
3.40F0.92 3.29F0.40 3.30F0.38 3.21F0.3 21.5F5.24 21.4F4.4 21.5F5.1 20.6F5.5 47.1F4.01 47.4F5.05 47.1F3.97 47.9F2.9 0 (0.0%)
17.9F6.20 18F6.6 14.1F4.00 14.1F5.1 0 (0.0%) 0 (0.0%)
0 (0.0%)
1 year
0 (0.0%)
2 years
2 (4.3%)
3 years
5 (10.6%)
3.43F0.54 3.30F0.46 3.32F0.39 3.33F0.50 20.3F5.02 20.8F4.05 19.9F3.9 19.7F3.9 47.0F3.5 46.5F5.9 45.8F7.0 45.1F6.7 0 (0.0%)
1 (2.1%)
4 (6.4%)
9 (19.1%)
3.27F0.52 19.4F4.66 44.3F7.84T 2.7F2.8 14 (29.8%)
18.6F8.5 14.2F6.7 0 (0%)
18.9F7.1 14.9F6.2 1 (2.1%)
19.6F7.2 16F7.4 2 (4.3%)
20.5F8.9 16.2F9.1 6 (12.8%)
21.4F9.60 16.7F9.23 10 (21.2%)
1 year
2 years
3 years
4 years 31
0 (0.0%)
0 (0.0%)
1 (3.2%)
3.25F0.50 21.7F5.44 47.5F3.18 + 0.4F3.3TT 2 (6.4%)T
18.4F6.21 18.0F7.1 17.9F6.90 14.0F4.6 13.6F4.3 13.6F7.00T 1 (3.2%) 3 (9.7%) 4 (12.9%)T
Data are meansFS.D. T Pb.05. TT Pb.001.
Large-fiber sensory nerve function was quantified by VPT at the Hallux and Malleolus by means of a Biothesiometer (Horwell, Nottingham, U.K.). We defined reduced vibration detection to be a VPT test score of 25 V (Abbott, Vileikyte, Williamson, Carrington, & Boulton, 1998; Young, Breddy, Veves, & Boulton, 1994). Participants were tested in a quiet environment in closed room with constant temperature. The Biothesiometer was applied to the skin surface but held lightly so that almost its full weight was on the foot to ensure that the pressure was always the same during testing. The vibration amplitude was increased until the participants could feel vibration at the site that was being tested. The patients were instructed not to respond to sensation perceived in other parts of the foot or leg. If vibration was perceived in the tested area, this was indicated by the patients by a verbal response. The values of VPT were determined as the mean of three measurements (Davis, Jones, Walsh, & Byrne, 1997). 2.4.2. Anthropometric measurements Weight (to the nearest 0.1 kg) and height (to the nearest 0.5 cm) were measured while the participants were fasting and wearing only their undergarments. BMI was calculated as body weight divided by height squared. Minimum waist circumference (W, in centimeters; minimum circumference between the lower rib margin and the iliac crest, midwaist) was measured while the participants were standing with their heels together.
2.4.3. Dual energy X-ray absorptiometry (DEXA) measurements Fat mass (FM, %) and free fat mass (FFM, kg) calculations were performed using a whole body densitometer (Hologic QDR 2000 plus, Hologic). 2.4.4. Exercise testing All participants were started on a walking program on a treadmill Technogym at baseline and for each year throughout the 4 years of the study after instruction by a qualified physical education instructor on suitable clothing, shoes, and other precautions. The patients were fitted with a heart rate feature strapped to the chest, for heart rate monitoring. Maximal aerobic capacity (VO2 max) was measured used a 1-mile track walk (Kline, Porcari, & Rippe, 1987). 2.4.5. Blood pressure measurements Blood pressure was measured using a standard manual mercury sphygmomanometer for at least three measurements in a seated position, after at least 15 min of rest, according to the NIH guidelines. 2.4.6. Lifestyle habits Information about smoking habits, use of medication, and alcohol was obtained through questionnaires. The Minnesota Leisure Time Physical Activity Questionnaire was used to obtain information on the average frequency
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measured using enzymatic kits (Ortho-Clinical Diagnostic, Milan, Italy). 2.5. Statistical analysis All the results are expressed as meansFS.D. We computed the changes over time in each group with paired t test with the calculation of 95% confidence interval (CI). Unpaired t test with the calculation of 95% CI was used to estimate the difference between the delta in NCV for both peroneal and sural motor nerves between the two treatment groups during the study period. We used this t test for deltas in NCV as equivalent to the test on the interaction term in the repeated measures analysis of variance. Fisher’s Exact Test was used to evaluate the percentage of number of patients developing PDN in both groups. Two-tailed Pb.05 indicated statistical significance. Statistical analysis was made by StatView, Version 4.5 (Abacus Concept, Berkeley, CA, USA).
3. Results We obtained an excellent compliance, and all patients completed the study and attended N90% of the prescribed program sessions. No adverse effects throughout the entire study were observed. 3.1. Clinical parameters
Fig. 2. Percentage of patients developing (A) motor neuropathy, (B) sensory neuropathy, and (C) VPT z25 V during 4 years of follow-up in the (– –) control and (—) exercise group.
and duration of participation for a specific list of physical activities. Sedentary lifestyle was defined as performing no vigorous activity and performing no light to moderate activity during the past 1 week, 1 month, 3 months, and 1 year preceding the survey. 2.4.7. Analytic procedures Glycosylated hemoglobin (HbA1c) and microalbuminuria were measured using monoclonal antibody method (DCA 2000+Analyzer, Milan, Italy). Overnight urine collections for microalbuminuria detection were performed. Microalbuminuria was defined as urinary albumin excretion between 20 and 200 Ag/min in two consecutive samples. Plasma glucose was determined by the glucose oxidase method [Autoanalyzer, Beckman Coulter, Fullerton, CA; coefficient of variation (CV), 1.9F0.2%]. Plasma total cholesterol (CV, 3.4F0.2%), triglycerides (CV, 3.1F 0.5%), and creatinine (CV, 1F0.4%) concentrations were
The participants’ characteristics for both groups at baseline and for each year of the study are summarized in Table 1. No significant difference on baseline clinical parameters between the EXE and CON groups were found (Table 1). 3.2. Neurophysiological parameters from baseline to the end of the 4-year study 3.2.1. NCV parameters We found significant differences on D (delta) in NCV for both peroneal and sural motor nerve between the EXE and CON groups during the study period ( Pb.001, 95% CI= 0.53 to 2.26; Pb.001, 95% CI= 4.48 to 1.71, respectively; Fig. 1). Peroneal motor NCV significantly increased in the EXE group ( Pb.05, 95% CI= 0.37 to 3.22) and insignificantly decreased in the CON group. For sural sensory NCV, there was no significant increase in the EXE group (95% CI=1.53 to 5.11), while a significant decrease in the CON group ( Pb.05, 95% CI=1.21 to 4.26) was found. No significant difference in both peroneal and sural DL and NAPA between the two groups was observed (Table 2). 3.2.2. PDN development during the 4-year study The percentage of diabetic patients who developed motor neuropathy during the 4 years of the study was
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Fig. 3. Malleulus and Hallux VPT at baseline and after 4 years on the control and exercise groups; *Pb.05.
significantly higher in the CON than the EXE group (17.0% vs. 0.0%, Pb.05, OR= 0.07; 95% CI=0.003– 0.77). Similarly, the percentage of diabetic patients that developed sensory neuropathy during the 4 years of the study was significantly higher in the CON than the EXE group (29.8% vs. 6.5%, Pb.05, OR= 0.16; 95% CI=0.004 –1.3). In addition, the percentage of diabetic patients who developed increased VPT (25 V) during the study was statistically significantly higher in the CON than the EXE group (21.3% vs. 12.9%, Pb.05, OR=0.554; 95% CI= 0.04– 0.97; Fig. 2). 3.2.3. VPT parameters Change on Hallux VPT from baseline to the end of the study was significantly different between the EXE and CON groups ( Pb.05); no significant change in Malleolus VPT between the two groups occurred (Fig. 3). No significant differences on NCV and VPT parameters between Types 1 and 2 diabetic patients during the study were observed.
4. Discussion Our study shows, for the first time, that long-term aerobic exercise training can modify the natural history of peripheral diabetic neuropathy or even prevent its onset. In fact, we found that a prescribed aerobic exercise regimen, although of mild intensity, can positively influence and modify both motor and sensory neuromuscular parameters in diabetic patients. The treatment of DPN has traditionally focused on the control of hyperglycemia. The impact of an intensive glycemic control on DPN has been widely evaluated (Azad et al., 1999; Balducci et al., 2004; Castaneda et al., 2002; Dahl-Jorgensen et al., 1986; DCCT Research Group, 1995; Dunston et al., 2002; Goldhaber-Fiebert et al., 2003; Maiorana et al., 2002; Vinik, 1999), but with controversial results. In fact, some studies showed substantial improve-
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ments on peroneal NCV in Type 1 diabetic patients (Muller-Felber et al., 1993; Muller-Felber et al., 1991; Navarro, Sutherland, & Kennedy, 1997), whereas others failed to demonstrate significant changes in the progression of somatic or autonomic neuropathy (Azad et al., 1999; Ruiz, 2004). Our study can provide original information of potential interest. First, this is the first long-term follow up study on the effect of aerobic exercise training on the development of DPN, because only short-term studies were previously performed (Richardson et al., 2001). We evaluated the progression of neurophysiological parameters for each year of the 4-year study period. Second, we studied diabetic patients without baseline signs or symptoms of DPN. This study design allowed us to evaluate the DPN development in two groups of diabetic patients with the same baseline neurological condition. Third, we prescribed mild submaximal aerobic exercise training, as well as brisk walking, to evaluate physical exercise easily reproducible and reliable within the lifestyle of diabetic patients. Our data seem to indicate the effectiveness of a submaximal and reliable exercise on DPN. Fourth, no difference at baseline on age, duration of diabetes, BMI, waist circumference, glycemic control, smoking, alcohol intake, blood pressure, and nephropathy between the study and control groups occurred. We believe that this latter point could allow us to evaluate the effect of exercise on DPN without the confounding role of the most important risk factors. In fact, it is well known that DPN is associated with poor glycemic control, obesity, dyslipidemia, retinopathy, microalbuminuria, and smoking (Boulton et al., 2004). The absence of statistically significant changes on BMI, waist circumference, and metabolic profile could suggest a possible direct and local effect of exercise on peripheral nerves in our diabetic patients. This partially unexpected finding could be due to the mild intensity of the training and to the fact that no modifications on participants’ dietary habitus have been applied in this study. However, these data should be interpreted with caution. Finally, this study included the expertise of a highly specialized metabolic fitness assistant who supervised on the technical aspects of the proposed exercise and took good care of the patients. The presence of this professional figure could explain the good compliance of the patients. Several exercise-induced vascular and metabolic changes could be invoked to explain the effects of training on DPN development. Human and experimental studies suggest that short-term exercise stimulates endotheliumdependent vasodilatation. Higher vascular endothelial growth factor (VEGF) expression during short-term exercise has been proposed to play a role in endoneurial blood flow increase (Gustafsson, Puntschart, Kaijser, Jansson, & Sundberg, 1999). Exercise may also improve abnormal perfusion and plasma viscosity facilitating oxygen delivery (Terjung, Mathien, Erney, & Ogilvie, 1988; FuchsjagerMayrl et al., 2002). It is known that exercise training
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exposes the vessels to repeated episodes of hyperemia. The elevated shear stress from the increased blood flow of aerobic exercise augments vasodilatation over the long term by increasing the vascular expression of nitric oxide synthase and by enhancing the release of nitric oxide (NO; Fukai et al., 2000; Maiorana, O’Driscoll, Taylor, & Green, 2003; McAllister, Hirai, & Musch, 1995; Niebauer & Cooke, 1996). The increase of NO synthesis or bioavailability may be useful in preventing diabetes-induced changes in the polyol pathway (Ramana, Chandra, Srivastava, Bhatnagar, & Srivastava, 2003). Exercise-induced nerve function changes could be also related to an improvement of Na/K ATPase activity. In fact, training has been reported to increase the concentration of Na/K ATPase in rat muscle cells (Kjeldsen, Richter, Galbo, Lortie, & Clausen, 1986). In addition, K (ATP) channel openers have been shown to provide marked beneficial effects on nerve perfusion and function in experimental diabetic neuropathy (Hohman, Cotter, & Cameron, 2000). In conclusion, this study suggests, for the first time, that long-term prescribed and supervised aerobic exercise training may modify the natural history of DPN or even delay its onset. Mild aerobic exercise training, like brisk walking, could be an effective and reasonable treatment tool to prevent the onset or modify the natural history of DPN.
5. Study limitations Our data are promising, but further studies on a larger population are necessary to confirm these findings. No conclusions on the possible exercise-related mechanisms inducing a delayed development of DPN can be drawn from this study.
Acknowledgments The authors thank Gianluca Balducci, Lorella Senigagliesi, and the participants, for their contribution to these studies. We also express our gratitude to Philippa Mungra in the preparation of the manuscript.
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