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Balducci2006 PDF
Balducci2006 PDF
Balducci2006 PDF
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.
1056-8727/06/$ – see front matter D 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.jdiacomp.2005.07.005
S. Balducci et al. / Journal of Diabetes and Its Complications 20 (2006) 216 – 223 217
Although no definitive treatment for DPN has been was tested in the metabolic fitness center with heart
established yet, several studies have shown that intensive rate monitoring.
therapy and optimal glycemic control can significantly
reduce DPN (Azad et al., 1999; Dahl-Jorgensen et al.,
2.2. Exclusion criteria
1986; DCCT Research Group, 1995). Promising treatment
for DPN include metabolic treatments, autoimmune thera-
Patients carrying at least one of the following conditions
pies, and nerve growth factors (Vinik, 1999). Recent studies
were excluded from the study:
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., 1. Physical and electrodiagnostic evidence of DPN,
2002; Dunston et al., 2002; Maiorana, O’Driscoll, Goodman, according to the reported criteria (Feldman et al.,
Taylor, & Green, 2002). The beneficial effects of a regular 1994).
exercise on glycemic control, insulin sensitivity, lipid Exclusion criteria based on physical examination. The
abnormalities, and hypertension in diabetic patients have presence of DPN was evaluated with the Michigan
been previously described (Balducci, Leonetti, Di Mario, Neuropathy Screening Instrument (MNSI). MNSI con-
& Fallucca, 2004; Goldhaber-Fiebert, Goldhaber-Fiebert, sisted of an inspection of the foot, examination of the
Tristan, & Nathan, 2003). Achilles reflexes, and evaluation of the vibratory thresh-
Nevertheless, very few data on the effectiveness of old (VPT). Vibration perception was considered reduced
exercise treatment on DPN have been reported (Richardson, when the patients said that they did not feel any
Sandman, & Vela, 2001; Tesfaye, Harris, Wilson, & Ward, vibration, while the operator perceives the vibrations at
1992). Prescribed and supervised long-term exercise pro- the index of their own hand for another 10 s. If the final
grams may influence neuromuscular parameters in diabetic score was of 2.5 or more (MNSI positivity), the patient
patients, thereby inducing adaptive changes in the neuro- was excluded from the study.
muscular system in response to exercise training. Exclusion criteria based on electrodiagnostic exami-
In this study, we sought to examine the effects of a long- nation:
term exercise training on the development of peripheral (a) Sural response: absent or decreased amplitude
neuropathy in both Types 1 and 2 diabetic patients. (b6 AV) with a normal or minimally prolonged
distal latency (DL; b3 ms) stimulating 14 cm
from the recording site posterior to the lateral
2. Study design Malleolus. If the sural response was absent bila-
terally, the motor responses were not performed.
This was a 4-year prospective randomized intervention (b) Peroneal responses: absent or decreased in
study. Types 1 and 2 diabetic patients, from 500 consecutive amplitude (b 2 mV for peroneal), with a normal
diabetic patients admitted in our Department, without signs DL (b 6.2 ms stimulating 9 cm from recording
and symptoms of DPN and able to have a 1.6-km-distance sites over the extensor digitorum brevis).
walk were enrolled in this study. Patients who did not accept 2. A history or evidence on physical examination of
to perform the proposed exercise program were excluded significant central nervous system dysfunction (i.e.,
from the study. The enrolled participants were subsequently hemiparesis, myelopathy, and cerebellar ataxia).
randomized in two groups and followed up for each year of 3. Significant musculoskeletal deformity [i.e., amputa-
the study. All patients had their usual diet during the study tion, scoliosis, abnormality of range of motion
period. The dietary regimen was based on the Mediterranean (ROM)] that would prevent participation (b908 of
diet. In addition, no significant changes in pharmacological humeral abduction, inability to grip, b108 of com-
treatment for diabetes, lipid, and blood-pressure-lowering bined ankle inversion/eversion).
drugs during the study were applied. This study was con- 4. Lower extremity arthritis or pain that limits exercise.
ducted in accordance with the Declaration of Helsinki guide- 5. A history or clinical evidence of severe cardiovas-
lines. Each participant gave an informed consent before the cular diseases that limit or contraindicate the exercise.
study began. 6. A history or evidence on physical examination of
vestibular dysfunction.
2.1. Inclusion criteria 7. A history of angina or angina-equivalent symptoms
(i.e., nausea, diaphoresis, and shortness of breath with
The following inclusion criteria were implemented: exercise).
8. Symptomatic postural hypotension defined as a fall in
! Type 2 and/or Type 1 diabetes blood pressure (i.e., N20 mm Hg for systolic or
! No signs or symptoms of DPN N10 mm Hg for diastolic blood pressure) in response
! Ability to walk a 1.6-km distance without assistance or to postural change, from supine to standing (Position
with a device. The ability to complete this walk-distance paper, 1996).
218 S. Balducci et al. / Journal of Diabetes and Its Complications 20 (2006) 216 – 223
2.3. Participants
Table 2
Neurological parameters at baseline and for each year of the study
CON EXE
Baseline 1 year 2 years 3 years 4 years Baseline 1 year 2 years 3 years 4 years
n 47 47 31 31
VPT
VPT Malleolus (mV) 18.6F8.5 18.9F7.1 19.6F7.2 20.5F8.9 21.4F9.60 17.9F6.20 18F6.6 18.4F6.21 18.0F7.1 17.9F6.90
VPT Hallux (mV) 14.2F6.7 14.9F6.2 16F7.4 16.2F9.1 16.7F9.23 14.1F4.00 14.1F5.1 14.0F4.6 13.6F4.3 13.6F7.00T
Patients with 0 (0%) 1 (2.1%) 2 (4.3%) 6 (12.8%) 10 (21.2%) 0 (0.0%) 0 (0.0%) 1 (3.2%) 3 (9.7%) 4 (12.9%)T
VPT altered
Data are meansFS.D.
T Pb.05.
TT Pb.001.
Large-fiber sensory nerve function was quantified by 2.4.3. Dual energy X-ray absorptiometry (DEXA)
VPT at the Hallux and Malleolus by means of a measurements
Biothesiometer (Horwell, Nottingham, U.K.). We defined Fat mass (FM, %) and free fat mass (FFM, kg) cal-
reduced vibration detection to be a VPT test score of 25 V culations were performed using a whole body densitometer
(Abbott, Vileikyte, Williamson, Carrington, & Boulton, (Hologic QDR 2000 plus, Hologic).
1998; Young, Breddy, Veves, & Boulton, 1994).
Participants were tested in a quiet environment in closed 2.4.4. Exercise testing
room with constant temperature. The Biothesiometer was All participants were started on a walking program on a
applied to the skin surface but held lightly so that almost treadmill Technogym at baseline and for each year
its full weight was on the foot to ensure that the pressure throughout the 4 years of the study after instruction by a
was always the same during testing. The vibration qualified physical education instructor on suitable clothing,
amplitude was increased until the participants could feel shoes, and other precautions. The patients were fitted
vibration at the site that was being tested. The patients with a heart rate feature strapped to the chest, for heart
were instructed not to respond to sensation perceived in rate monitoring. Maximal aerobic capacity (VO2 max)
other parts of the foot or leg. If vibration was perceived in
was measured used a 1-mile track walk (Kline, Porcari, &
the tested area, this was indicated by the patients by a
Rippe, 1987).
verbal response. The values of VPT were determined as the
mean of three measurements (Davis, Jones, Walsh, &
Byrne, 1997). 2.4.5. Blood pressure measurements
Blood pressure was measured using a standard manual
2.4.2. Anthropometric measurements mercury sphygmomanometer for at least three measurements
Weight (to the nearest 0.1 kg) and height (to the nearest in a seated position, after at least 15 min of rest, according to
0.5 cm) were measured while the participants were fasting the NIH guidelines.
and wearing only their undergarments. BMI was calculated
as body weight divided by height squared. Minimum waist 2.4.6. Lifestyle habits
circumference (W, in centimeters; minimum circumference Information about smoking habits, use of medication,
between the lower rib margin and the iliac crest, midwaist) and alcohol was obtained through questionnaires. The
was measured while the participants were standing with Minnesota Leisure Time Physical Activity Questionnaire
their heels together. was used to obtain information on the average frequency
220 S. Balducci et al. / Journal of Diabetes and Its Complications 20 (2006) 216 – 223
3. Results
and duration of participation for a specific list of physical 3.2.1. NCV parameters
activities. Sedentary lifestyle was defined as performing no We found significant differences on D (delta) in NCV for
vigorous activity and performing no light to moderate both peroneal and sural motor nerve between the EXE and
activity during the past 1 week, 1 month, 3 months, and 1 year CON groups during the study period ( Pb.001, 95%
preceding the survey. CI= 0.53 to 2.26; Pb.001, 95% CI= 4.48 to 1.71,
respectively; Fig. 1).
2.4.7. Analytic procedures Peroneal motor NCV significantly increased in the EXE
Glycosylated hemoglobin (HbA1c) and microalbuminuria group ( Pb.05, 95% CI= 0.37 to 3.22) and insignificantly
were measured using monoclonal antibody method (DCA decreased in the CON group. For sural sensory NCV, there
2000+Analyzer, Milan, Italy). Overnight urine collections was no significant increase in the EXE group (95% CI=1.53
for microalbuminuria detection were performed. Micro- to 5.11), while a significant decrease in the CON group
albuminuria was defined as urinary albumin excretion ( Pb.05, 95% CI=1.21 to 4.26) was found. No significant
between 20 and 200 Ag/min in two consecutive samples. difference in both peroneal and sural DL and NAPA
Plasma glucose was determined by the glucose oxidase between the two groups was observed (Table 2).
method [Autoanalyzer, Beckman Coulter, Fullerton, CA;
coefficient of variation (CV), 1.9F0.2%]. Plasma total 3.2.2. PDN development during the 4-year study
cholesterol (CV, 3.4F0.2%), triglycerides (CV, 3.1F The percentage of diabetic patients who developed
0.5%), and creatinine (CV, 1F0.4%) concentrations were motor neuropathy during the 4 years of the study was
S. Balducci et al. / Journal of Diabetes and Its Complications 20 (2006) 216 – 223 221
exposes the vessels to repeated episodes of hyperemia. The on metabolic profiles in type 2 diabetic patients? Diabetes Care, 27,
841 – 842.
elevated shear stress from the increased blood flow of
Boulton, A. J. (1998). Lowering the risk of neuropathy, foot ulcers and
aerobic exercise augments vasodilatation over the long term amputations. Diabetic Medicine, 15 (Suppl. 4), S57 – S59.
by increasing the vascular expression of nitric oxide Boulton, A. J. M., Malik, R. A., Arezzo, J. C., & Sosenko, J. M. (2004).
synthase and by enhancing the release of nitric oxide (NO; Diabetic somatic neuropathies. Diabetes Care, 27, 1458 – 1486.
Fukai et al., 2000; Maiorana, O’Driscoll, Taylor, & Green, Castaneda, C., Layne, J. E., Munoz-Orians, L., Gordon, P. L., Walsmith, J.,
2003; McAllister, Hirai, & Musch, 1995; Niebauer & Cooke, Foldvari, M., Roubenoff, R., Tucker, K. L., & Nelson, M. E. (2002). A
randomized controlled trial of resistance exercise training to improve
1996). The increase of NO synthesis or bioavailability may glycemic control in older adults with type 2 diabetes. Diabetes Care,
be useful in preventing diabetes-induced changes in the 25, 2335 – 2341.
polyol pathway (Ramana, Chandra, Srivastava, Bhatnagar, Dahl-Jorgensen, K., Brinchmann-Hansen, O., Hanssen, K. F., Ganes, T.,
& Srivastava, 2003). Exercise-induced nerve function Kierulf, P., Smeland, E., Sandvik, L., & Aagenaes, O. (1986). Effect of
near normoglycaemia for two years on progression of early diabetic
changes could be also related to an improvement of Na/K
retinopathy, nephropathy, and neuropathy: The Oslo study. British
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increase the concentration of Na/K ATPase in rat muscle Davis, E. A., Jones, T. W., Walsh, P., & Byrne, G. C. (1997). The use of the
cells (Kjeldsen, Richter, Galbo, Lortie, & Clausen, 1986). In biothesiometer to detect neuropathy in children and adolescents with
addition, K (ATP) channel openers have been shown to IDDM. Diabetes Care, 20, 1448 – 1453.
provide marked beneficial effects on nerve perfusion and DCCT Research Group. (1995). The effect of intensive diabetes therapy on
the development and progression of neuropathy. Annals of Internal
function in experimental diabetic neuropathy (Hohman, Medicine, 122, 561 – 568.
Cotter, & Cameron, 2000). Dunston, D. W., Daly, R. M., Owen, N., Jolley, D., De Courten, M., Shaw,
In conclusion, this study suggests, for the first time, that J., & Zimmet, P. (2002). High-intensity resistance training improves
long-term prescribed and supervised aerobic exercise train- glycemic control in older patients with type 2 diabetes. Diabetes Care,
ing may modify the natural history of DPN or even delay its 25, 1729 – 1736.
Falck, B., Andreassen, S., Groth, T., Lang, H., Melander, M., Nurmi, A.,
onset. Mild aerobic exercise training, like brisk walking, Rosenfalck, A., Stalberg, E., & Suojanen, M. (1991). The development
could be an effective and reasonable treatment tool to of a multicenter database for reference values in clinical neuro-
prevent the onset or modify the natural history of DPN. physiology—Principles and examples. Computer Methods and Pro-
grams in Biomedicine, 34, 145 – 162.
Feldman, E. L., Stevens, M. J., Thomas, P. K., Brown, M. B., Canal, N., &
Greene, D. A. (1994). A practical two-step quantitative clinical and
5. Study limitations electrophysiological assessment for the diagnosis and staging of
diabetic neuropathy. Diabetes Care, 17, 1281 – 1289.
Our data are promising, but further studies on a larger Fuchsjager-Mayrl, G., Pleiner, J., Wiesinger, G. F., Sieder, A. E., Quittan,
population are necessary to confirm these findings. No M., Nuhr, M. J., Francesconi, C., Seit, H. P., Francesconi, M.,
conclusions on the possible exercise-related mechanisms Schmetterer, L., & Wolzt, M. (2002). Exercise training improves
vascular endothelial function in patients with type 1 diabetes. Diabetes
inducing a delayed development of DPN can be drawn from
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superoxide dismutase by nitric oxide and exercise training. Journal of
Acknowledgments Clinical Investigation, 105, 1631 – 1639.
Goldhaber-Fiebert, J. D., Goldhaber-Fiebert, S. N., Tristan, M. L., &
Nathan, D. M. (2003). Randomized controlled community-based
The authors thank Gianluca Balducci, Lorella Seniga- nutrition and exercise intervention improves glycemia and cardiovas-
gliesi, and the participants, for their contribution to these cular risk factors in type 2 diabetic patients in rural Costa Rica. Diabetes
studies. We also express our gratitude to Philippa Mungra in Care, 26, 24 – 29.
the preparation of the manuscript. Gustafsson, T., Puntschart, A., Kaijser, L., Jansson, E., & Sundberg, C. J.
(1999). Exercise-induced expression of angiogenesis-related transcrip-
tion and growth factors in human skeletal muscle. American Journal of
Physiology, 276, H679 – H685.
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