Exercise training can modify the natural history of diabetic peripheral neuropathy

Article Outline

• Abstract
• 1. Introduction
• 2. Study design
  • 2.1. Inclusion criteria
  • 2.2. Exclusion criteria
  • 2.3. Participants
  • 2.4. Methods
    • 2.4.1. Neurophysiological measurements
    • 2.4.2. Anthropometric measurements
    • 2.4.3. Dual energy X-ray absorptiometry (DEXA) measurements
    • 2.4.4. Exercise testing
    • 2.4.5. Blood pressure measurements
    • 2.4.6. Lifestyle habits
    • 2.4.7. Analytic procedures
  • 2.5. Statistical analysis
• 3. Results
  • 3.1. Clinical parameters
  • 3.2. Neurophysiological parameters from baseline to the end of the 4-year study
    • 3.2.1. NCV parameters
    • 3.2.2. PDN development during the 4-year study
    • 3.2.3. VPT parameters
• 4. Discussion
• 5. Study limitations
• Acknowledgments
• References
• Copyright

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; 49±15.5 years old; body mass index (BMI)=27.9±4.7], 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; 52.9±13.4 years old; BMI=30.9±8.4). 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 Δ (delta) in NCV for both peroneal and sural motor nerve between the EXE and CON groups during the study period (P<.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%, P<.05, and 29.8% vs. 6.45%, P<.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%, P<.05). Change on Hallux VPT from baseline to the end of the study was significantly different between the EXE and CON groups (P<.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.

Keywords: Diabetic peripheral neuropathy, Exercise training

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1. Introduction 

Diabetic peripheral neuropathy (DPN) is a common complication and quality-of-life damaging factor in diabetic patients (Boulton et al., 2004, 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). 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 et al., 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 et al., 2004, Goldhaber-Fiebert et al., 2003).

Nevertheless, very few data on the effectiveness of exercise treatment on DPN have been reported (Richardson et al., 2001, Tesfaye et al., 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 long-term exercise training on the development of peripheral neuropathy in both Types 1 and 2 diabetic patients.

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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:

2.2. Exclusion criteria 

Patients carrying at least one of the following conditions were excluded from the study:

2.3. Participants 

Seventy-eight diabetic patients (39 f, 39 m; age=51.3±14.3 years, duration of diabetes=8.79±6.2 years) who met the inclusion criteria were enrolled and randomized in two treatment groups:

2.4. Methods 

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 μV 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, Hanssen, Sandvik, Berg, & Dahl-Jorgensen, 2003).

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 et al., 1998, Young et al., 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).

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.

Fat mass (FM, %) and free fat mass (FFM, kg) calculations were performed using a whole body densitometer (Hologic QDR 2000 plus, Hologic).

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 (VO_{2 max}) was measured used a 1-mile track walk (Kline, Porcari, & Rippe, 1987).

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.

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 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.

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 μg/min in two consecutive samples.

Plasma glucose was determined by the glucose oxidase method [Autoanalyzer, Beckman Coulter, Fullerton, CA; coefficient of variation (CV), 1.9±0.2%]. Plasma total cholesterol (CV, 3.4±0.2%), triglycerides (CV, 3.1±0.5%), and creatinine (CV, 1±0.4%) concentrations were measured using enzymatic kits (Ortho-Clinical Diagnostic, Milan, Italy).

2.5. Statistical analysis 

All the results are expressed as means±S.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 P<.05 indicated statistical significance. Statistical analysis was made by StatView, Version 4.5 (Abacus Concept, Berkeley, CA, USA).

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3. Results 

We obtained an excellent compliance, and all patients completed the study and attended >90% of the prescribed program sessions. No adverse effects throughout the entire study were observed.

3.1. Clinical parameters 

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).

Table 1. Patients' clinical characteristics at baseline and at the end of the 4-years study

Data are mean±S.D.

3.2. Neurophysiological parameters from baseline to the end of the 4-year study 

We found significant differences on Δ (delta) in NCV for both peroneal and sural motor nerve between the EXE and CON groups during the study period (P<.001, 95% CI=−0.53 to 2.26; P<.001, 95% CI=−4.48 to −1.71, respectively; Fig. 1).

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• Fig. 1. 

  Change in NCV (ΔNCV) from baseline to the end of the study; ^⁎⁎P<.001.

Peroneal motor NCV significantly increased in the EXE group (P<.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 (P<.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).

Table 2. Neurological parameters at baseline and for each year of the study

Data are means±S.D.

The percentage of diabetic patients who developed motor neuropathy during the 4 years of the study was significantly higher in the CON than the EXE group (17.0% vs. 0.0%, P<.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%, P<.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%, P<.05, OR=0.554; 95% CI=0.04– 0.97; Fig. 2).

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• Fig. 2. 

  Percentage of patients developing (A) motor neuropathy, (B) sensory neuropathy, and (C) VPT ≥25 V during 4 years of follow-up in the (– –) control and (—) exercise group.

Change on Hallux VPT from baseline to the end of the study was significantly different between the EXE and CON groups (P<.05); no significant change in Malleolus VPT between the two groups occurred (Fig. 3).

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• Fig. 3. 

  Malleulus and Hallux VPT at baseline and after 4 years on the control and exercise groups; *P<.05.

No significant differences on NCV and VPT parameters between Types 1 and 2 diabetic patients during the study were observed.

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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, 1989), but with controversial results. In fact, some studies showed substantial improvements on peroneal NCV in Type 1 diabetic patients (Muller-Felber et al., 1993, Muller-Felber et al., 1991, Navarro et al., 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 endothelium-dependent 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 et al., 1988, Fuchsjager-Mayrl et al., 2002). It is known that exercise training 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 et al., 2003, McAllister et al., 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.

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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.

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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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References 

1. Abbott L, Vileikyte S, Williamson AL, Carrington AJ. Multicenter study of the incidence of and predictive risk factors for diabetic neuropathic foot ulceration. Diabetes Care. 1998;21:1071–1075
   • View In Article
   • MEDLINE
   • CrossRef
2. Azad N, Emanuele NV, Abraira C, Henderson WG, Colwell J, Levin SR, et al. The effects of intensive glycemic control on neuropathy in the VA cooperative study on type II diabetes mellitus (VA CSDM). Journal of Diabetes and Its Complications. 1999;13:307–313
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (444 KB)
   • CrossRef
3. Balducci S, Leonetti F, Di Mario U, Fallucca F. Is a long-term aerobic plus resistance training program feasible for and effective on metabolic profiles in type 2 diabetic patients?. Diabetes Care. 2004;27:841–842
   • View In Article
   • MEDLINE
   • CrossRef
4. Boulton AJ. Lowering the risk of neuropathy, foot ulcers and amputations. Diabetic Medicine. 1998;15(Suppl. 4):S57–S59
   • View In Article
5. Boulton AJM, Malik RA, Arezzo JC, Sosenko JM. Diabetic somatic neuropathies. Diabetes Care. 2004;27:1458–1486
   • View In Article
   • MEDLINE
   • CrossRef
6. Castaneda C, Layne JE, Munoz-Orians L, Gordon PL, Walsmith J, Foldvari M, et al. A randomized controlled trial of resistance exercise training to improve glycemic control in older adults with type 2 diabetes. Diabetes Care. 2002;25:2335–2341
   • View In Article
   • MEDLINE
   • CrossRef
7. Dahl-Jorgensen K, Brinchmann-Hansen O, Hanssen KF, Ganes T, Kierulf P, Smeland E, et al. Effect of near normoglycaemia for two years on progression of early diabetic retinopathy, nephropathy, and neuropathy: The Oslo study. British Medical Journal. 1986;8:1195–1199
   • View In Article
8. Davis EA, Jones TW, Walsh P, Byrne GC. The use of the biothesiometer to detect neuropathy in children and adolescents with IDDM. Diabetes Care. 1997;20:1448–1453
   • View In Article
   • MEDLINE
9. DCCT Research Group. The effect of intensive diabetes therapy on the development and progression of neuropathy. Annals of Internal Medicine. 1995;122:561–568
   • View In Article
   • MEDLINE
10. Dunston DW, Daly RM, Owen N, Jolley D, De Courten M, Shaw J, et al. High-intensity resistance training improves glycemic control in older patients with type 2 diabetes. Diabetes Care. 2002;25:1729–1736
    • View In Article
    • MEDLINE
    • CrossRef
11. Falck B, Andreassen S, Groth T, Lang H, Melander M, Nurmi A, et al. The development of a multicenter database for reference values in clinical neurophysiology—Principles and examples. Computer Methods and Programs in Biomedicine. 1991;34:145–162
    • View In Article
    • MEDLINE
    • CrossRef
12. Feldman EL, Stevens MJ, Thomas PK, Brown MB, Canal N, Greene DA. A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care. 1994;17:1281–1289
    • View In Article
    • MEDLINE
13. Fuchsjager-Mayrl G, Pleiner J, Wiesinger GF, Sieder AE, Quittan M, Nuhr MJ, et al. Exercise training improves vascular endothelial function in patients with type 1 diabetes. Diabetes Care. 2002;25:1795–1801
    • View In Article
    • MEDLINE
    • CrossRef
14. Fukai T, Siegfried MR, Ushio-Fukai M, Cheng Y, Kojda G, Harrison DG. Regulation of the vascular extracellular superoxide dismutase by nitric oxide and exercise training. Journal of Clinical Investigation. 2000;105:1631–1639
    • View In Article
15. Goldhaber-Fiebert JD, Goldhaber-Fiebert SN, Tristan ML, Nathan DM. Randomized controlled community-based nutrition and exercise intervention improves glycemia and cardiovascular risk factors in type 2 diabetic patients in rural Costa Rica. Diabetes Care. 2003;26:24–29
    • View In Article
    • MEDLINE
    • CrossRef
16. Gustafsson T, Puntschart A, Kaijser L, Jansson E, Sundberg CJ. Exercise-induced expression of angiogenesis-related transcription and growth factors in human skeletal muscle. American Journal of Physiology. 1999;276:H679–H685
    • View In Article
17. Hohman TC, Cotter MA, Cameron NE. ATP-sensitive K(+) channel effects on nerve function, Na(+), K(+) ATPase, and glutathione in diabetic rats. European Journal of Pharmacology. 2000;2:335–341
    • View In Article
18. Kjeldsen K, Richter EA, Galbo H, Lortie G, Clausen T. Training increases the concentration of [3H]ouabain-binding sites in rat skeletal muscle. Biochimica Et Biophysica Acta. 1986;11(860):708–712
    • View In Article
19. Kline GM, Porcari JP, Rippe JM. Estimation of Vo_2max from a one-mile track walk, gender, age and body weight. Medicine and Science in Sports and Exercise. 1987;19:253–259
    • View In Article
    • MEDLINE
20. Larsen JR, Sjoholm H, Hanssen KF, Sandvik L, Berg TJ, Dahl-Jorgensen K. Optimal blood glucose control during 18 years preserves peripheral nerve function in patients with 30 years' duration of type 1 diabetes. Diabetes Care. 2003;26:2400–2404
    • View In Article
    • MEDLINE
    • CrossRef
21. In:  Liveson JA,  Ma DM editor. Laboratory reference for clinical neurophysiology. Philadelphia: FA Davis; 1992;p. 278–317
    • View In Article
22. Maiorana A, O'Driscoll G, Goodman C, Taylor R, Green D. Combined aerobic and resistance exercise improves glycemic control and fitness in type 2 diabetes. Diabetes Research and Clinical Practice. 2002;56:115–123
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (115 KB)
    • CrossRef
23. Maiorana A, O'Driscoll G, Taylor R, Green D. Exercise and the nitric oxide vasodilator system. Sports Medicine. 2003;33:1013–1035
    • View In Article
24. McAllister RM, Hirai T, Musch TI. Contribution of endothelium-derived nitric oxide (EDNO) to the skeletal muscle blood flow response to exercise. Medicine and Science in Sports and Exercise. 1995;27:1145–1151
    • View In Article
    • MEDLINE
25. Muller-Felber W, Landgraf R, Scheuer R, Wagner S, Reimers CD, Nusser J, et al. Diabetic neuropathy 3 years after successful pancreas and kidney transplantation. Diabetes. 1993, Oct.;42(10):1482–1486
    • View In Article
    • MEDLINE
26. Muller-Felber W, Landgraf R, Wagner S, Mair N, Nusser J, Landgraf-Leurs MM, et al. Follow-up study of sensory-motor polyneuropathy in type 1 (insulin-dependent) diabetic subjects after graft rejection. Diabetologia. 1991;(Suppl. 1):S113–S117
    • View In Article
27. Navarro X, Sutherland DE, Kennedy WR. Long-term effects of pancreatic transplantation on diabetic neuropathy. Annals of Neurology. 1997;42:727–736
    • View In Article
    • MEDLINE
    • CrossRef
28. Niebauer J, Cooke JP. Cardiovascular effects of exercise: Role of endothelial shear stress. Journal of the American College of Cardiology. 1996;28:1652–1660
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (121 KB)
    • CrossRef
29. Poncelet AN. Diabetic polyneuropathy. Risk factors, patterns of presentation, diagnosis, and treatment. Geriatrics. 2003;58:16–18
    • View In Article
    • MEDLINE
30. Position paper. The Consensus Committee of the American Autonomic Society and the American Academy of Neurology. Journal of Autonomic Nervous System. 1996;58:123–124
    • View In Article
31. Ramana KV, Chandra D, Srivastava S, Bhatnagar A, Srivastava SK. Nitric oxide regulates the polyol pathway of glucose metabolism in vascular smooth muscle cells. Federation of American Societies for Experimental Biology. 2003;17:417–425
    • View In Article
32. Richardson JK, Sandman D, Vela S. A focused exercise regimen improves clinical measures of balance in patients with peripheral neuropathy. Archives of Physical Medicine and Rehabilitation. 2001;82:205–209
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (44 KB)
    • CrossRef
33. Ruiz J. Intensive care of type 2 diabetes: What does the STENO 2 study teach us?. Revue Medicale De La Suisse Romande. 2004;124:125–127
    • View In Article
    • MEDLINE
34. Terjung RL, Mathien GM, Erney TP, Ogilvie RW. Peripheral adaptations to low blood flow in muscle during exercise. The American Journal of Cardiology. 1988;62:15E–19E
    • View In Article
    • MEDLINE
    • CrossRef
35. Tesfaye S, Harris ND, Wilson RM, Ward JD. Exercise-induced conduction velocity increment: A marker of impaired peripheral nerve blood flow in diabetic neuropathy. Diabetologia. 1992;35:155–159
    • View In Article
    • MEDLINE
    • CrossRef
36. Vinik AI. Diabetic neuropathy: Pathogenesis and therapy. The American Journal of Medicine. 1999;107(2B):17S–26S
    • View In Article
    • MEDLINE
37. Vinik AI, Erbas T, Stansberry KB, Pittenger GL. Small fiber neuropathy and neurovascular disturbances in diabetes mellitus. Experimental and Clinical Endocrinology and Diabetes. 2001;109(Suppl. 2):S451–S473
    • View In Article
38. Young MJ, Breddy JL, Veves A, Boulton AJM. The prediction of diabetic foot ulceration using vibration perception thresholds: A prospective study. Diabetes Care. 1994;17:557–560
    • View In Article
    • MEDLINE