Neurologic Complications of Diabetes

  • Gerald A. Charnogursky
  • Nicholas V. Emanuele
  • Mary Ann Emanuele
Neurology of Systemic Disease (J Biller, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Neurology of Systemic Disease

Abstract

Neuropathy as a complication of diabetes is common and presents in a wide variety of clinical scenarios. Often the work-up is one of exclusion tempered with monitoring the response of symptoms to treatment options. The collaboration of a neurologist is often crucial to determining the best course of action for the patient. This review will address proposed pathogenic mechanisms and potential therapeutic interventions, both pharmacologic and nonpharmacologic.

Keywords

Pathogenesis Diabetic neuropathy Painful peripheral neuropathy Diabetic autonomic neuropathy Diabetic cardiovascular neuropathy Diabetic gastroparesis Therapeutic treatment diabetic neuropathy 

Terms

IGF

Insulin-like growth factors

NADPH

Nicotinamide adenine dinucleotide phosphate hydrogen

NIS

Neuropathy Impairment Score

RAGE

Receptor for Advanced Glycation end products

TRP

Transient receptor potential channel

Notes

Compliance with Ethics Guidelines

Conflict of Interest

Gerald A. Charnogursky, Nicholas V. Emanuele, and Mary Ann Emanuele declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Galer B, Gianas A, Jensen M. Painful diabetic polyneuropathy: epidemiology, pain description, and quality of life. Diabetes Res Clin Pract. 2000;47:123–8.PubMedGoogle Scholar
  2. 2.
    Ziegler D, Gries F, Spuler M, et al. The epidemiology of diabetic neuropathy. Diabetic Cardiovascular Autonomic Neuropathy Multicenter Study Group. J Diabetes Complicat. 1992;6:49–57.PubMedGoogle Scholar
  3. 3.
    Cohen J, Jeffers B, Faldut D, et al. Risks for sensorimotor peripheral neuropathy and autonomic neuropathy in non-insulin-dependent diabetes mellitus (NIDDM). Muscle Nerve. 1998;21:72–80.PubMedGoogle Scholar
  4. 4.
    Genuth S. Insights from the diabetes control and complications trial/epidemiology of diabetes interventions and complications study on the use of intensive glycemic treatment to reduce the risk of complications of type 1 diabetes. Endocr Pract. 2006;12 Suppl 1:34–41.PubMedGoogle Scholar
  5. 5.
    Diabetes Control and Complications Trial Research Group. The effect of intensive diabetes therapy on the development and progression of neuropathy. Ann Intern Med. 1995;122:561–8.Google Scholar
  6. 6.
    Tesfaye S, Chaturvedi N, Eaton SE, et al. EURODIAB Prospective Complications Study Group. Vascular risk factors and diabetic neuropathy. Vascular risk factors and diabetic neuropathy. N Engl J Med. 2005;352:341–52.Google Scholar
  7. 7.
    Ziegler D, Rathmann W, Dickhaus T, Meisinger C, Mielck A, KORA Study Group. Neuropathic pain in diabetes, prediabetes and normal glucose tolerance: the MONICA/KORA Augsburg Surveys S2 and S3. Pain Med. 2009;10:393–400.PubMedGoogle Scholar
  8. 8.
    Van Acker K, Bouhassira D, De Bacquer D, et al. Prevalence and impact on quality of life of peripheral neuropathy with or without neuropathic pain in type 1 and type 2 diabetic patients attending hospital outpatients clinics. Diabetes Metab. 2009;35:206–13.PubMedGoogle Scholar
  9. 9.
    Ziegler D, Rathmann W, Meisinger C, Dickhaus T, Mielck A, KORA Study Group. Prevalence and risk factors of neuropathic pain in survivors of myocardial infarction with pre-diabetes and diabetes. The KORA Myocardial Infarction Registry. Eur J Pain. 2009;13:582–7.PubMedGoogle Scholar
  10. 10.
    Newrick P, Wilson A, Jakubowski J, et al. Sural nerve oxygen tension in diabetes. Br Med J. 1986;293:1053–4.Google Scholar
  11. 11.
    Sugimoto K, Yasujima M, Yagihashi S. Role of advanced glycation end products (AGEs) in diabetic neuropathy. Curr Pharm Des. 2008;14:953–61.PubMedGoogle Scholar
  12. 12.
    Singh R, Barden A, Mori T, et al. Advanced glycation end products: a review. Diabetologia. 2001;44:129–46.PubMedGoogle Scholar
  13. 13.
    Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414:813–20.PubMedGoogle Scholar
  14. 14.
    Pacher P, Obrosova I, Mabley J, et al. Role of nitroative stress and peroxynitrite in the pathogenesis of diabetic complications. Emerging new therapeutical strategies. Curr Med Chem. 2005;12:267–72.PubMedCentralPubMedGoogle Scholar
  15. 15.
    Kennedy J, Zochodne DW. Impaired peripheral nerve regeneration in diabetes mellitus. J Peripher Nerv Syst. 2005;10:144–57.PubMedGoogle Scholar
  16. 16.
    Brussee V, Cunningham F, Zochodne D. Direct insulin signaling of neurons reverses diabetic neuropathy. Diabetes. 2004;53:1824–30.PubMedGoogle Scholar
  17. 17.•
    Tesfaye S, Boulton AJM, Dickenson AH. Mechanisms and management of diabetic painful distal symmetrical polyneuropathy. Diabetes Care. 2013;36:2456–65. An in-depth, comprehensive, and current review of the pathogenisis and therapeutic options of painful neuropathy due to diabetes. This article is written by the leading authorities in the area and is well-referenced with the highest caliber of science in the literature. PubMedCentralPubMedGoogle Scholar
  18. 18.
    Charnogursky GA, Lee H, Lopez N. Diabetic neuropathy in neurologic aspects of systemic disease part II. In: Handbook of Clinical Neurology (Series Editors: Aminoff MJ, Boller F, and Swaab DF) Volume Editors: Jose Biller and Jose M. Ferro: Aminoff MJ, Ois Boller F, Swaab DF, et al. Volume 120, 3rd series. Edinburgh: Elsevier Publishing; 2014. p. 773–87.Google Scholar
  19. 19.
    Tesfaye S, Boulton AJM, Dyck PJ, Toronto Diabetic Neuropathy Expert Group, et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010;33:2285–93.PubMedCentralPubMedGoogle Scholar
  20. 20.
    Zelman DC, Brandenburg NA, Gore M. Sleep impairment in patients with painful diabetic peripheral neuropathy. Clin J Pain. 2006;2:681–5.Google Scholar
  21. 21.
    Gore M, Brandenburg NA, Dukes E, Hoffman DL, Tai KS, Stacey B. Pain severity in diabetic peripheral neuropathy is associated with patient functioning, symptom levels of anxiety and depression, and sleep. J Pain Symptom Manag. 2005;30:374–85.Google Scholar
  22. 22.
    Boulton AJM, Armstrong WD, Scarpello JHB, Ward JD. The natural history of painful diabetic neuropathyda 4-year study. Postgrad Med. 1983;59:556–9.Google Scholar
  23. 23.
    Benbow SJ, Chan AW, Bowsher D, MacFarlane IA, Williams G. A prospective study of painful symptoms, small-fibre function and peripheral vascular disease in chronic painful diabetic neuropathy. Diabet Med. 1994;11:17–21.PubMedGoogle Scholar
  24. 24.
    England J, Gronseth G, Franklin G, et al. Practice parameter: evaluation of distal symmetric polyneuropathy: role of laboratory and genetic testing (an evidence-based review): report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation. Neurology. 2009;72:185–92.PubMedGoogle Scholar
  25. 25.
    Tesfaye S, Kempler P. Painful diabetic neuropathy. Diabetologia. 2005;48:805–7.PubMedGoogle Scholar
  26. 26.
    Martin C, Albers J, Herman W, The DCCT/EDIC research group, et al. Neuropathy among the diabetes control and complications trial cohort 8 years after trial completion. Diabetes Care. 2006;29:340–4.PubMedCentralPubMedGoogle Scholar
  27. 27.
    Albers J, Herman W, Pop-Busai R, et al. Effect of prior intensive insulin treatment during the Diabetes Control and Complications Trial (DCCT) on peripheral neuropathy in type 1 diabetes during the Epidemiology of Diabetes Interventions and Complications (EDIC) study. Diabetes Care. 2010;33:1090–6.PubMedCentralPubMedGoogle Scholar
  28. 28.
    Mehra S, Tavakoli M, Kallinikos P, et al. Corneal confocal microscopy detects early nerve regeneration after pancreas transplantation in patients with type 1 diabetes. Diabetes Care. 2007;30:2608–12.PubMedGoogle Scholar
  29. 29.
    Holman R, Paul S, Bethel M, Matthews D, Neil H. 10 Year follow-up of intensive diabetes control in type 2 dm. N Engl J Med. 2008;359:1577–89.Google Scholar
  30. 30.
    Patel A, MacMahon S, Chalmers J, et al. The ADVANCE Collaborative Group intensive blood glucose control and vascular outcomes in patients with type 2 dm. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–72.PubMedGoogle Scholar
  31. 31.
    Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129–39.PubMedGoogle Scholar
  32. 32.
    The Action To Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–59.Google Scholar
  33. 33.•
    Bril V, England J, Franklin GM, American Academy of Neurology; American Association of Neuromuscular and Electrodiagnostic Medicine; American Academy of Physical Medicine and Rehabilitation, et al. Evidence-based guideline: treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2011;76:1758–65. The most recently published guidelines suggested by the major organizations that deal with treatment of diabetic neuropathy for neurologists. It incorporates the leading studies in the area that are well-validated. PubMedCentralPubMedGoogle Scholar
  34. 34.•
    Tesfaye S, Vileikyte L, Rayman G, Toronto Expert Panel on Diabetic Neuropathy, et al. Painful diabetic assessment and management. Diabetes Metab Res Rev. 2011;27:629–38. An insightful overview of leading experts on the appropriate evaluation of the patient with diabetes and painful neuropathy. Although this is expert opinion, it reflects the views of the clear authorities in diabetic neuropathy. PubMedGoogle Scholar
  35. 35.
    Kajdasz DK, Iyengar S, Desaiah D, et al. Duloxetine for the management of diabetic peripheral neuropathic pain: evidence-based findings from post hoc analysis of three multicenter, randomized, double-blind, placebo-controlled, parallel-group studies. Clin Ther. 2007;29(Suppl):2536–46.PubMedGoogle Scholar
  36. 36.
    Rowbotham MC, Goli V, Kunz NR, Lei D. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study. Pain. 2004;110:697–706.PubMedGoogle Scholar
  37. 37.
    Backonja MM, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA. 1998;280:1831–6.PubMedGoogle Scholar
  38. 38.
    Backonja M, Glanzman R. Gabapentin dosing for neuropathic pain: evidence from randomized, placebo controlled clinical trials. Clin Ther. 2003;25:81–104.PubMedGoogle Scholar
  39. 39.
    Sandercock D, Cramer M, Wu J, et al. Gabapentin extended release for the treatment of painful diabetic neuropathy. Diabetes Care. 2009;32:e20.PubMedGoogle Scholar
  40. 40.
    Freeman R, Durso-DeCruz E, Emir B. Efficacy, safety, and tolerability of pregabalin treatment for painful diabetic peripheral neuropathy. Diabetes Care. 2008;31:1448–54.PubMedCentralPubMedGoogle Scholar
  41. 41.
    Ziegler D, Low P, Litchy W, et al. Efficacy and safety of antioxidant treatment with alcohol bipolar casted over 4 years in diabetic polyneuropathy. The NATHAN1 trial. Diabetes Care. 2011;34:2054–60.PubMedCentralPubMedGoogle Scholar
  42. 42.
    Zhang W, Wan Po A. The effectiveness of topically applied capsaicin: a meta-analysis. Eur J Clin Pharmacol. 1994;45:517–22.Google Scholar
  43. 43.
    Backonja M, Wallace M, Blonsky E, et al. NGX-4010, a high-concentration capsaicin patch, for the treatment of post herpetic neuralgia: a randomized, double-blind study. Lancet Neurol. 2008;7:1102–12.Google Scholar
  44. 44.
    Ziegler D. Current concepts in the management of diabetic polyneuropathy. Curr Diabetes Rev. 2011;7:208–20.PubMedGoogle Scholar
  45. 45.
    Bansal D, Bhansali A, Hota D, Chakrabarti A, Dutta P. Amitriptyline vs pregabalin in painful diabetic neuropathy: a randomized double blind clinical trial. Diabet Med. 2009;26:1019–26.PubMedGoogle Scholar
  46. 46.
    Kaur H, Hota D, Bhansali A, Dutta P, Bansal D, Chakrabarti A. A comparative evaluation of amitriptyline and duloxetine in painful diabetic neuropathy: a randomized, double-blind, cross-over clinical trial. Diabetes Care. 2011;34:818–22.PubMedCentralPubMedGoogle Scholar
  47. 47.
    Quilici S, Chancellor J, Löthgren M, et al. Meta-analysis of duloxetine vs pregabalin and gabapentin in the treatment of diabetic peripheral neuropathic pain. BMC Neurol. 2009;9:6–11.PubMedCentralPubMedGoogle Scholar
  48. 48.
    Gilron I, Bailey JM, Tu D, Holden RR, Jackson AC, Houlden RL. Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial. Lancet. 2009;374:1252–61.PubMedGoogle Scholar
  49. 49.
    Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, Houlden RL. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med. 2005;352:1324–34.PubMedGoogle Scholar
  50. 50.
    Tesfaye S, Wilhelm S, Lledo A, et al. Duloxetine and pregabalin: high-dose monotherapy or their combination? The “COMBO-DN study” - a multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain. Pain. 2013;154:2616–25.Google Scholar
  51. 51.
    Low P, Nickander K, Tritcshler H. The role of oxidative stress and antioxidant treatment in experimental diabetic neuropathy. Diabetes. 1997;46:S38–42.PubMedGoogle Scholar
  52. 52.
    Ziegler D, Hanefeld M, Ruhnau K. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month multicenter randomized controlled trial (ALADIN III study). Diabetes Care. 1999;22:1296–301.PubMedGoogle Scholar
  53. 53.
    Ziegler D, Nowak H, Kempler P. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis. Diabet Med. 2004;21:114–21.PubMedGoogle Scholar
  54. 54.
    Reljanovic M, Reichel G, Rett K, et al. Treatment of diabetic polyneuropathy with antioxidant thioctic acid (a-lipoic acid): a two-year multi-center randomized double-blind placebo-controlled trial (ALADIN II). Alpha Lipoic Acid in Diabetic Neuropathy. Free Radic Res. 1999;31:171–9.PubMedGoogle Scholar
  55. 55.
    Ziegler D. Oral treatment with α-Lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care. 2006;29:2365–70.PubMedGoogle Scholar
  56. 56.
    Ziegler D, Low PA, Litchy WJ, Boulton AJ, et al. Efficacy and safety of antioxidant treatment with α-Lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial. Diabetes Care. 2011;34:2054–60.Google Scholar
  57. 57.
    Bril V, Hirose T, Tomioka S, et al. Ranirestat for the management of diabetic sensorimotor polyneuropathy. Diabetes Care. 2009;32:1256–60.PubMedCentralPubMedGoogle Scholar
  58. 58.
    Vinik A, Bril V, Kempler P, et al. Treatment of symptomatic diabetic peripheral neuropathy with the protein kinase C b-inhibitor ruboxistaurin mesylate during a 1-year, randomized, placebo-controlled, double-blind clinical trial. Clin Ther. 2005;27:1164–80.PubMedGoogle Scholar
  59. 59.
    Quattrini C, Jeziorska M, Boulton A, et al. Reduced vascular endothelial growth factor expression and intraepidermal nerve fiber loss in human diabetic neuropathy. Diabetes Care. 2008;31:140–5.PubMedGoogle Scholar
  60. 60.
    Ropper A, Gorson K, Gooch C, et al. Vascular endothelial growth factor gene transfer for diabetic polyneuropathy: a randomized, double-blinded trial. Ann Neurol. 2009;65:386–93.PubMedGoogle Scholar
  61. 61.
    Van Etten R, de Koning F, Verhaar M, et al. NO dependent vasodilation in patients with type II non-insulin-dependent diabetes mellitus is restored by acute administration of folate. Diabetologia. 2002;45:1004–10.PubMedGoogle Scholar
  62. 62.
    Verhaar M, Stroes E, Rabelink T. Folates and cardiovascular disease. Arterioscler Thromb Vasc Biol. 2002;22:6–11.PubMedGoogle Scholar
  63. 63.
    Wile D, Toth C. Association of metformin, elevated homocysteine, and methylmalonic acid levels and clinically worsened diabetic peripheral neuropathy. Diabetes Care. 2010;33:156–61.PubMedCentralPubMedGoogle Scholar
  64. 64.
    Walker M, Morris L, Cheng D. Improvement of cutaneous sensitivity in diabetic peripheral neuropathy with combination L-methylfolate, methylcobalamin and pyridoxal 5-phosphate. Rev Neurol Dis. 2010;7:132–9.PubMedGoogle Scholar
  65. 65.
    Mata M, Hao S, Fink D. Applications of gene therapy to the treatment of chronic pain. Curr Gene Ther. 2008;8:42–8.PubMedCentralPubMedGoogle Scholar
  66. 66.
    Gilden DH. Clinical practice. Bell’s palsy. N Engl J Med. 2004;351:1323–31.PubMedGoogle Scholar
  67. 67.
    Pecket P, Schattner A. Concurrent Bell’s palsy and diabetes mellitus: a diabetic mononeuropathy? J Neurol Neurosurg Psychiatry. 1982;45:652–5.PubMedCentralPubMedGoogle Scholar
  68. 68.
    Dyck P, Kratz K, Karnes J, et al. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study. Neurology. 1993;43:817–24.PubMedGoogle Scholar
  69. 69.
    Gulliford M, Latinovic R, Charlton J, et al. Increased incidence of carpal tunnel syndrome up to 10 years before diagnosis of diabetes. Diabetes Care. 2006;29:1929–30.PubMedGoogle Scholar
  70. 70.
    Stamboulis E, Vassilopoulos D, Kalfakis N. Symptomatic focal mononeuropathies in diabetic patients: increased or not? J Neurol. 2005;252:448–52.PubMedGoogle Scholar
  71. 71.
    Stewart JD. Diabetic truncal neuropathy: topography of the sensory deficit. Ann Neurol. 1989;25:233–8.PubMedGoogle Scholar
  72. 72.
    Kikta DG, Breuer AC, Wilbourn AJ. Thoracic root pain in diabetes: the spectrum of clinical and electromyographic findings. Ann Neurol. 1982;11:80–5.PubMedGoogle Scholar
  73. 73.
    Barohn R, Sahenk Z, Warmolts J, et al. The Bruns–Garland syndrome (diabetic amyotrophy). Revisited 100 years later. Arch Neurol. 1991;48:1130–5.PubMedGoogle Scholar
  74. 74.
    Feldman E, Stevens M, Thomas P, et al. A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care. 1994;17:1281–9.PubMedGoogle Scholar
  75. 75.
    Kincaid J, Price K, Jimenez M, et al. Correlation of vibratory quantitative sensory testing and nerve conduction studies in patients with diabetes. Muscle Nerve. 2007;36:821–7.PubMedGoogle Scholar
  76. 76.
    Oyer D, Saxon D, Shah A. Quantitative assessment of diabetic peripheral neuropathy with use of the clanging tuning fork test. Endocr Pract. 2007;13:5–10.PubMedGoogle Scholar
  77. 77.
    Dyck P, Kratz K, Lehman K, et al. The Rochester Diabetic Neuropathy Study: design, criteria for types of neuropathy, selection bias, and reproducibility of neuropathic tests. Neurology. 1991;41:799–807.PubMedGoogle Scholar
  78. 78.
    Dyck P, Karnes J, O’Brien P, et al. The Rochester Diabetic Neuropathy Study: re-assessment of tests and criteria for diagnosis and staged severity. Neurology. 1992;42:1164–70.PubMedGoogle Scholar
  79. 79.
    Liatis S, Marinou K, Tentolouris N, et al. Usefulness of a new indicator test for the diagnosis of peripheral and autonomic neuropathy in patients with diabetes mellitus. Diabet Med. 2007;24:1375–80.PubMedGoogle Scholar
  80. 80.
    Tavakoli M, Quattrini C, Abbot D. Corneal confocal microscopy. A novel noninvasive test to diagnose and stratify the severity of human diabetic neuropathy. Diabetes Care. 2010;22:1792–7.Google Scholar
  81. 81.
    Pambianco G, Costacou T, Ellis D, et al. The 30-year natural history of type 1 diabetes complications: the Pittsburgh Epidemiology of Diabetes Complications Study experience. Diabetes. 2006;55:1463–72.PubMedGoogle Scholar
  82. 82.
    The effect of intensive diabetes therapy on measures of autonomic nervous system function in the Diabetes Control and Complications Trial (DCCT). Diabetologia. 1998;41:416–25.Google Scholar
  83. 83.
    Pop-Busui R, Low PA, Waberski BH, et al. Effects of prior intensive insulin therapy on cardiac autonomic nervous system function in type 1 diabetes mellitus: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study (DCCT/EDIC). Circulation. 2009;119:2886–92.PubMedCentralPubMedGoogle Scholar
  84. 84.
    Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358:580–5.PubMedGoogle Scholar
  85. 85.
    Vinik AI, Ziegler D. Diabetic cardiovascular autonomic neuropathy. Circulation. 2007;115:387–92.PubMedGoogle Scholar
  86. 86.
    Bernardi L, Ricordi L, Lazzari P, et al. Impaired circadian modulation of sympathovagal activity in diabetes. A possible explanation for altered temporal onset of cardiovascular disease. Circulation. 1992;86:1443–50.PubMedGoogle Scholar
  87. 87.
    Aronson D, Weinrauch LA, D'Elia JA, et al. Circadian patterns of heart rate variability, fibrinolytic activity, and hemostatic factors in type I diabetes mellitus with cardiac autonomic neuropathy. Am J Cardiol. 1999;84:449–53.PubMedGoogle Scholar
  88. 88.
    Hornung RS, Mahler RF, Raftery EB. Ambulatory blood pressure and heart rate in diabetic patients: an assessment of autonomic function. Diabet Med. 1989;6:579–83.PubMedGoogle Scholar
  89. 89.
    Istenes I, Keresztes K, Hermányi Z, et al. Relationship between autonomic neuropathy and hypertension—are we underestimating the problem? Diabet Med. 2008;25:863–8.PubMedGoogle Scholar
  90. 90.
    Stevens MJ, Edmonds ME, Mathias CJ, Watkins PJ. Disabling postural hypotension complicating diabetic autonomic neuropathy. Diabet Med. 1991;8:870–4.PubMedGoogle Scholar
  91. 91.
    Jansen RW, Lipsitz LA. Postprandial hypotension: epidemiology, pathophysiology, and clinical management. Ann Intern Med. 1995;122:286–91.PubMedGoogle Scholar
  92. 92.
    Mathias CJ. Effect of food intake on cardiovascular control in patients with impaired autonomic function. J Neurosci Methods. 1990;34:193–7.PubMedGoogle Scholar
  93. 93.
    Winkler AS, Landau S, Watkins PJ. Erythropoietin treatment of postural hypotension in anemic type 1 diabetic patients with autonomic neuropathy: a case study of four patients. Diabetes Care. 2001;24:1121–5.PubMedGoogle Scholar
  94. 94.
    Ziegler D. Cardiovascular autonomic neuropathy: clinical manifestations and measurement. Diabetes Rev. 1999;7:342–9.Google Scholar
  95. 95.
    Maser RE, Mitchell BD, Vinik AI, Freeman R. The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: a meta-analysis. Diabetes Care. 2003;26:1895–90.PubMedGoogle Scholar
  96. 96.
    Pop-Busui R, Evans GW, Gerstein HC, et al. Effects of cardiac autonomic dysfunction on mortality risk in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Diabetes Care. 2010;33:1578–83.PubMedCentralPubMedGoogle Scholar
  97. 97.
    O'Brien IA, McFadden JP, Corrall RJ. The influence of autonomic neuropathy on mortality in insulin-dependent diabetes. Q J Med. 1991;79:495–9.PubMedGoogle Scholar
  98. 98.
    Navarro X, Kennedy WR, Sutherland DE. Autonomic neuropathy and survival in diabetes mellitus: effects of pancreas transplantation. Diabetologia. 1991;34 Suppl 1:S108.PubMedGoogle Scholar
  99. 99.
    Rathmann W, Ziegler D, Jahnke M, et al. Mortality in diabetic patients with cardiovascular autonomic neuropathy. Diabet Med. 1993;10:820–5.PubMedGoogle Scholar
  100. 100.
    Sampson MJ, Wilson S, Karagiannis P, et al. Progression of diabetic autonomic neuropathy over a decade in insulin-dependent diabetics. Q J Med. 1990;75:635–41.PubMedGoogle Scholar
  101. 101.
    Ewing DJ, Campbell IW, Clarke BF. The natural history of diabetic autonomic neuropathy. Q J Med. 1980;49:95–101.PubMedGoogle Scholar
  102. 102.
    Watkins PJ, Mackay JD. Cardiac denervation in diabetic neuropathy. Ann Intern Med. 1980;92:304–9.PubMedGoogle Scholar
  103. 103.
    Soedamah-Muthu SS, Chaturvedi N, Witte DR, et al. Relationship between risk factors and mortality in type 1 diabetic patients in Europe: the EURODIAB Prospective Complications Study (PCS). Diabetes Care. 2008;31:1360–7.PubMedCentralPubMedGoogle Scholar
  104. 104.
    Wackers FJ, Young LH, Inzucchi SE, et al. Detection of silent myocardial ischemia in asymptomatic diabetic subjects: the DIAD study. Diabetes Care. 2004;27:1954–9.PubMedGoogle Scholar
  105. 105.
    Valensi P, Sachs RN, Harfouche B, et al. Predictive value of cardiac autonomic neuropathy in diabetic patients with or without silent myocardial ischemia. Diabetes Care. 2001;24:339–44.PubMedGoogle Scholar
  106. 106.
    Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diabetes Care. 2003;26:1553–8.PubMedGoogle Scholar
  107. 107.
    Cohen JA, Estacio RO, Lundgren RA, et al. Diabetic autonomic neuropathy is associated with an increased incidence of strokes. Auton Neurosci. 2003;108:73–7.PubMedGoogle Scholar
  108. 108.
    Page MM, Watkins PJ. Cardiorespiratory arrest and diabetic autonomic neuropathy. Lancet. 1978;1:14–8.PubMedGoogle Scholar
  109. 109.
    Rees PJ, Prior JG, Cochrane GM, Clark TJ. Sleep apnoea in diabetic patients with autonomic neuropathy. J R Soc Med. 1981;74:192–6.PubMedCentralPubMedGoogle Scholar
  110. 110.
    Ficker JH, Dertinger SH, Siegfried W, et al. Obstructive sleep apnoea and diabetes mellitus: the role of cardiovascular autonomic neuropathy. Eur Respir J. 1998;11:14–8.PubMedGoogle Scholar
  111. 111.
    Neumann C, Martinez D, Schmid H. Nocturnal oxygen desaturation in diabetic patients with severe autonomic neuropathy. Diabetes Res Clin Pract. 1995;28:97–101.PubMedGoogle Scholar
  112. 112.
    Bottini P, Dottorini ML, Cristina Cordoni M, et al. Sleep-disordered breathing in nonobese diabetic subjects with autonomic neuropathy. Eur Respir J. 2003;22:654–7.PubMedGoogle Scholar
  113. 113.
    Wieling W, Borst C, van Dongen Torman MA, et al. Relationship between impaired parasympathetic and sympathetic cardiovascular control in diabetes mellitus. Diabetologia. 1983;24:422–36.PubMedGoogle Scholar
  114. 114.
    Spallone V, Ziegler D, Freeman R, et al. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev. 2011;10:1002.Google Scholar
  115. 115.
    Bernardi L, Spallone V, Stevens M, et al. Investigation methods for cardiac autonomic function in human research studies. Diabetes Metab Res Rev. 2011;27:654–64.Google Scholar
  116. 116.
    American Academy of Neurology. Assessment: clinical autonomic testing report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 1996;46:873–80.Google Scholar
  117. 117.
    Tesfaye S, Boulton AJ, Dyck PJ, et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010;33:2285–91.PubMedCentralPubMedGoogle Scholar
  118. 118.
    Low PA, Benrud-Larson LM, Sletten DM, et al. Autonomic symptoms and diabetic neuropathy: a population-based study. Diabetes Care. 2004;27:2942–6.PubMedGoogle Scholar
  119. 119.
    Valensi P, Pariès J, Attali JR, French Group for Research and Study of Diabetic Neuropathy. Cardiac autonomic neuropathy in diabetic patients: influence of diabetes duration, obesity, and microangiopathic complications—the French multicenter study. Metabolism. 2003;52:815–22.PubMedGoogle Scholar
  120. 120.
    Witte DR, Tesfaye S, Chaturvedi N, et al. Risk factors for cardiac autonomic neuropathy in type 1 diabetes mellitus. Diabetologia. 2005;48:164–9.PubMedGoogle Scholar
  121. 121.
    Allman KC, Stevens MJ, Wieland DM, et al. Noninvasive assessment of cardiac diabetic neuropathy by carbon-11 hydroxyephedrine and positron emission tomography. J Am Coll Cardiol. 1993;22:1425–9.PubMedGoogle Scholar
  122. 122.
    Kreiner G, Wolzt M, Fasching P, et al. Myocardial m-[123I]iodobenzylguanidine scintigraphy for the assessment of adrenergic cardiac innervation in patients with IDDM. Comparison with cardiovascular reflex tests and relationship to left ventricular function. Diabetes. 1995;44:543–6.PubMedGoogle Scholar
  123. 123.
    Langer A, Freeman MR, Josse RG, Armstrong PW. Metaiodobenzylguanidine imaging in diabetes mellitus: assessment of cardiac sympathetic denervation and its relation to autonomic dysfunction and silent myocardial ischemia. J Am Coll Cardiol. 1995;25:610–4.PubMedGoogle Scholar
  124. 124.
    Pop-Busui R, Kirkwood I, Schmid H, et al. Sympathetic dysfunction in type 1 diabetes: association with impaired myocardial blood flow reserve and diastolic dysfunction. J Am Coll Cardiol. 2004;44:2368–72.PubMedGoogle Scholar
  125. 125.
    Boulton AJ, Vinik AI, Arezzo JC, American Diabetes Association, et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care. 2005;28:956–62.PubMedGoogle Scholar
  126. 126.
    Howorka K, Pumprla J, Haber P, et al. Effects of physical training on heart rate variability in diabetic patients with various degrees of cardiovascular autonomic neuropathy. Cardiovasc Res. 1997;34:206–11.PubMedGoogle Scholar
  127. 127.
    Pagkalos M, Koutlianos N, Kouidi E, et al. Heart rate variability modifications following exercise training in type 2 diabetic patients with definite cardiac autonomic neuropathy. Br J Sports Med. 2008;42:47.PubMedGoogle Scholar
  128. 128.
    Bannister R, Mathias CJ. Management of postural hypotension. In: Bannister R, editor. Autonomic failure. A textbook of clinical disorders of the autonomic nervous system. 2nd ed. Oxford: Oxford University Press; 1988. p. 569–80.Google Scholar
  129. 129.
    Ten Harkel AD, van Lieshout JJ, Wieling W. Effects of leg muscle pumping and tensing on orthostatic arterial pressure: a study in normal subjects and patients with autonomic failure. Clin Sci (Lond). 1994;87:553–6.Google Scholar
  130. 130.
    Fouad-Tarazi FM, Okabe M, Goren H. Alpha sympathomimetic treatment of autonomic insufficiency with orthostatic hypotension. Am J Med. 1995;99:604–8.PubMedGoogle Scholar
  131. 131.
    Grubb BP, Samoil D, Kosinski D, et al. Fluoxetine hydrochloride for the treatment of severe refractory orthostatic hypotension. Am J Med. 1994;97:366–70.PubMedGoogle Scholar
  132. 132.
    Singer W, Sandroni P, Opfer-Gehrking T, et al. Pyridostigmine treatment trial in heneurogenic orthostatic hypotension. Arch Neurol. 2006;63:513–7.PubMedGoogle Scholar
  133. 133.
    Shibao C, Okamoto L, Gamboa A, et al. Comparative efficacy of yohimbine against pyridostigmine for the treatment of orthostatic hypotension in autonomic failure. Hypertension. 2010;56:847–50.PubMedCentralPubMedGoogle Scholar
  134. 134.
    Hoeldtke R, Streeten D. Treatment of orthostatic hypotension with erythropoietin. N Engl J Med. 1993;329:611–15.Google Scholar
  135. 135.
    Wilkins RW, Kolb LC. Vasomotor disturbance in peripheral neuritis. Am J Med Sci. 1941;202:216–21.Google Scholar
  136. 136.
    Stevens MJ, Edmonds ME, Douglas SL, Watkins PJ. Influence of neuropathy on the microvascular response to local heating in the human diabetic foot. Clin Sci (Lond). 1991;80:249–53.Google Scholar
  137. 137.
    Tentolouris N, Marinou K, Kokotis P, et al. Sudomotor dysfunction is associated with foot ulceration in diabetes. Diabet Med. 2009;26:302–6.PubMedGoogle Scholar
  138. 138.
    Aso Y, Fujiwara Y, Inukai T, Takemura Y. Power spectral analysis of heart rate variation in diabetic patients with neuropathic foot ulceration. Diabetes Care. 1998;21:1173–8.PubMedGoogle Scholar
  139. 139.
    Shahani BT, Halperin JJ, Boulu P, Cohen J. Sympathetic skin response—a method of assessing unmyelinated axon dysfunction in peripheral neuropathies. J Neurol Neurosurg Psychiatry. 1984;47:536–40.PubMedCentralPubMedGoogle Scholar
  140. 140.
    Ziegler D, Papanas N, Roden M, GDC Study Group. Neuropad: evaluation of three cut-off points of sudomotor dysfunction for early detection of polyneuropathy in recently diagnosed diabetes. Diabet Med. 2011;28:1412–8.PubMedGoogle Scholar
  141. 141.
    Quattrini C, Tavakoli M, Jeziorska M, et al. Surrogate markers of small fiber damage in human diabetic neuropathy. Diabetes. 2007;56:2148–52.PubMedGoogle Scholar
  142. 142.
    Edmonds ME, Roberts VC, Watkins PJ. Blood flow in the diabetic neuropathic foot. Diabetologia. 1982;22:9–13.PubMedGoogle Scholar
  143. 143.
    Jude EB, Selby PL, Burgess J, et al. Bisphosphonates in the treatment of Charcot neuroarthropathy: a double-blind randomised controlled trial. Diabetologia. 2001;44:2032–7.PubMedGoogle Scholar
  144. 144.
    Parkman HP, Hasler WL, Fisher RS, American Gastroenterological Association. American Gastroenterological Association medical position statement: diagnosis and treatment of gastroparesis. Gastroenterology. 2004;127:1589–97.PubMedGoogle Scholar
  145. 145.
    Maganti K, Onyemere K, Jones M. Oral erythromycin and symptomatic relief in gastroparesis: a systematic review. Am J Gastroenterol. 2003;98:259–63.PubMedGoogle Scholar
  146. 146.
    Inman BA, Sauver JL, Jacobson DJ, et al. A population-based, longitudinal study of erectile dysfunction and future coronary artery disease. Mayo Clin Proc. 2009;84:108–15.PubMedCentralPubMedGoogle Scholar
  147. 147.
    Brown JS, Wessells H, Chancellor MB, et al. Urologic complications of diabetes. Diabetes Care. 2005;28:177–81.PubMedGoogle Scholar
  148. 148.
    Van Den Eeden SK, Sarma AV, Rutledge BN, et al. Effect of intensive glycemic control and diabetes complications on lower urinary tract symptoms in men with type 1 diabetes: Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. Diabetes Care. 2009;32:664–70.Google Scholar
  149. 149.
    Sarma AV, Kanaya A, Nyberg LM, et al. Risk factors for urinary incontinence among women with type 1 diabetes: findings from the epidemiology of diabetes interventions and complications study. Urology. 2009;73:1203–8.PubMedCentralPubMedGoogle Scholar
  150. 150.
    Rendell MS, Rajfer J, Wicker PA, Smith MD. Sildenafil for treatment of erectile dysfunction in men with diabetes: a randomized controlled trial. Sildenafil Diabetes Study Group. JAMA. 1999;281:421–6.PubMedGoogle Scholar
  151. 151.
    Meyer C, Grossmann R, Mitrakou A, et al. Effects of autonomic neuropathy on counterregulation and awareness of hypoglycemia in type 1 diabetic patients. Diabetes Care. 1998;21:1960–6.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Gerald A. Charnogursky
    • 1
  • Nicholas V. Emanuele
    • 1
  • Mary Ann Emanuele
    • 1
  1. 1.Division of Endocrinology and MetabolismLoyola University Medical CenterMaywoodUSA

Personalised recommendations