Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Diabetic neuropathies: clinical manifestations and current treatment options

Nature Clinical Practice Endocrinology & Metabolism volume 2, pages 269–281 (2006)Cite this article

Abstract

Diabetic neuropathies are a heterogeneous group of disorders that include a wide range of abnormalities. They can be focal or diffuse, proximal or distal, affecting both peripheral and autonomic nervous systems, causing morbidity with significant impact on the quality of life of the person with diabetes, and can result in early death. Distal symmetric polyneuropathy, the most common form of diabetic neuropathy, usually involves small and large nerve fibers. Small-nerve-fiber neuropathy often presents with pain but without objective signs or electrophysiologic evidence of nerve damage, and is recognized as a component of the impaired glucose tolerance and metabolic syndromes. The greatest risk resulting from small-fiber neuropathy is foot ulceration and subsequent gangrene and amputation. Large-nerve-fiber neuropathies produce numbness, ataxia and uncoordination, impairing activities of daily living and causing falls and fractures. A careful history and detailed physical examination are essential for the diagnosis. Symptomatic therapy has become available and newer and better treatment modalities, based on etiologic factors, are being explored with potential for significant impact on morbidity and mortality. Preventive strategies and patient education still remain key factors in reducing complication rates and mortality.

Key Points

  • Diabetic neuropathies are among the commonest, long-term complications of diabetes although often are not recognized by physicians

  • A thorough history and detailed physical examination, with the aid of simple tests that can be done in the clinic, are essential for the diagnosis

  • Management of the disease is complex and the key to success depends, in part, on discovering the underlying pathological processes in each particular clinical presentation

  • There has been increasing understanding of the pathogenesis of diabetic neuropathies over the last decades and new therapies are emerging that hold promise for the treatment of this disease

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: A simplified view of the peripheral nervous system
Figure 2: Cutaneous nerve fibers that stain positive for the neuronal antigen protein gene product 9.5 (PGP 9.5) in metabolic syndrome and diabetes
Figure 3: A diagnostic algorithm for assessment of neurologic deficit and classification of neuropathic syndromes
Figure 4: Pathogenesis of diabetic neuropathies
Figure 5: Different mechanisms of pain and possible treatments
Figure 6: Schematic representation of the generation of pain

References

  1. Caputo GM et al. (1994) Assessment and management of foot disease in patients with diabetes. N Engl J Med 331: 854–860

    CAS  PubMed  Google Scholar 

  2. Vinik E et al. (2005) The development and validation of the Norfolk QOL-DN, a new measure of patients' perception of the effects of diabetes and diabetic neuropathy. Diabetes Technol Ther 7: 497–508

    PubMed  Google Scholar 

  3. Vinik AI (2004) Advances in diabetes for the millennium: new treatments for diabetic neuropathies. MedGenMed 6 (3 Suppl): 13

    PubMed  PubMed Central  Google Scholar 

  4. Boulton A et al. (2004) Diabetic somatic neuropathies. Diabetes Care 27: 1458–1486

    PubMed  Google Scholar 

  5. Dyck PJ (2003) Severity and staging of diabetic polyneuropathy. In Textbook of Diabetic Neuropathy, 170–175 (Eds Gries FA et al.) Stuttgart: Thieme

    Google Scholar 

  6. Thomas PK (1997) Classification, differential diagnosis and staging of diabetic peripheral neuropathy. Diabetes 46 (Suppl 2): S54–S57

    CAS  PubMed  Google Scholar 

  7. Boulton AJ et al. (2005) Position statement: diabetic neuropathies. Diabetes Care 28: 956–962

    PubMed  Google Scholar 

  8. Vinik A and Mehrabyan A (2004) Diabetic neuropathies. Med Clin North Am 88: 947–999

    CAS  PubMed  Google Scholar 

  9. Oyibo SO et al. (2002) The relationship between blood glucose excursions and painful diabetic peripheral neuropathy: a pilot study. Diabet Med 19: 870–873

    CAS  PubMed  Google Scholar 

  10. Tesfaye S et al. (1996) Arterio-venous shunting and proliferating new vessels in acute painful neuropathy of rapid glycemic control (insulin neuritis). Diabetologia 39: 329–335

    CAS  PubMed  Google Scholar 

  11. Sinnreich M et al. (2005) Diabetic neuropathies. Classification, clinical features, and pathophysiological basis. Neurologist 11: 63–79

    PubMed  Google Scholar 

  12. Harris M et al. (1993) Symptoms of sensory neuropathy in adults with NIDDM in the US population. Diabetes Care 16: 1446–1452

    CAS  PubMed  Google Scholar 

  13. Singleton JR et al. (2001) Painful sensory polyneuropathy associated with impaired glucose tolerance. Muscle Nerve 24: 1225–1228

    CAS  PubMed  Google Scholar 

  14. Singleton JR et al. (2001) Increased prevalence of impaired glucose tolerance in patients with painful sensory neuropathy. Diabetes Care 24: 1448–1453

    CAS  PubMed  Google Scholar 

  15. Sumner C et al. (2003) The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology 60: 108–111

    CAS  PubMed  Google Scholar 

  16. Cavanagh PR et al. (1993) Ulceration, unsteadiness, and uncertainty: the biomechanical consequences of diabetes mellitus. J Biomech 26 (Suppl 1): 23–40

    PubMed  Google Scholar 

  17. Katoulis EC et al. (1997) Gait abnormalities in diabetic neuropathy. Diabetes Care 20: 1904–1907

    CAS  PubMed  Google Scholar 

  18. Dyck PJ et al. (1993) 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 43: 817–824

    CAS  PubMed  Google Scholar 

  19. Dyck PJ (1988) Detection, characterization and staging of polyneuropathy: assessed in diabetics. Muscle Nerve 11: 21–32

    CAS  PubMed  Google Scholar 

  20. Vinik AI et al. (1995) Quantitative measurement of cutaneous perception in diabetic neuropathy. Muscle Nerve 18: 574–584

    CAS  PubMed  Google Scholar 

  21. Abbott CA et al. (2002) The North-West Diabetes Foot Care Study: incidence of, and risk factors for, new diabetic foot ulceration in a community-based patient cohort. Diabet Med 19: 377–384

    CAS  PubMed  Google Scholar 

  22. Dyck PJ et al. (1997) Approaches to improve epidemiological studies of diabetic neuropathy: insights from the Rochester Diabetic Neuropathy Study. Diabetes 46 (Suppl 2): S5–S8

    CAS  PubMed  Google Scholar 

  23. Yarnitsky D and Sprecher E (1994) Thermal testing: normative data and repeatability for various test algorithms. J Neurol Sci 125: 39–45

    CAS  PubMed  Google Scholar 

  24. Anonymous (1988) Consensus Statement. Report and recommendations of the San Antonio conference on diabetic neuropathy. American Diabetes Association American Academy of Neurology. Diabetes Care 11: 592–597

  25. Anonymous (1995) Peripheral Nerve Society. Diabetic polyneuropathy in controlled clinical trials: consensus report of the Peripheral Nerve Society. Ann Neurol 38: 478–482

  26. Partanen J et al. (1995) Natural history of peripheral neuropathy in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 333: 89–94

    CAS  PubMed  Google Scholar 

  27. DCCT Research Group (1995) The effect of intensive diabetes therapy on the development and progression of neuropathy. Ann Intern Med 122: 561–568

  28. Vinik A et al. (2004) Focal entrapment neuropathies in diabetes. Diabetes Care 27: 1783–1788

    PubMed  Google Scholar 

  29. Kennedy WR et al. (1996) Quantitation of epidermal nerves in diabetic neuropathy. Neurology 47: 1042–1048

    CAS  PubMed  Google Scholar 

  30. Polydefkis M et al. (2001) Skin biopsy as a tool to assess distal small fiber innervation in diabetic neuropathy. Diabetes Technol Ther 3: 23–28

    CAS  PubMed  Google Scholar 

  31. Pittenger G et al. (2004) Intraepidermal nerve fibers are indicators of small fiber neuropathy in both diabetic and non-diabetic patients. Diabetes Care 27: 1974–1979

    PubMed  Google Scholar 

  32. Vileikyte L et al. (2003) The development and validation of a neuropathy- and foot ulcer-specific quality of life instrument. Diabetes Care 26: 2549–2555

    PubMed  Google Scholar 

  33. Maser RE et al. (2003) The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: a meta-analysis. Diabetes Care 26: 1895–1901

    PubMed  Google Scholar 

  34. Ziegler D et al. (1992) The epidemiology of diabetic neuropathy. Diabetic Cardiovascular Autonomic Neuropathy Multicenter Study Group. J Diabetes Complications 6: 49–57

    CAS  PubMed  Google Scholar 

  35. Vinik AI et al. (2003) Diabetic autonomic neuropathy. Diabetes Care 26: 1553–1579

    PubMed  Google Scholar 

  36. Ziegler D and Gries FA (1997) α-Lipoic acid in the treatment of diabetic peripheral and cardiac autonomic neuropathy. Diabetes 46 (Suppl 2): S62–S66

    CAS  PubMed  Google Scholar 

  37. Athyros VG et al. (1998) Long-term effect of converting enzyme inhibition on circadian sympathetic and parasympathetic modulation in patients with diabetic autonomic neuropathy. Acta Cardiol 53: 201–209

    CAS  PubMed  Google Scholar 

  38. Gaede P et al. (1999) Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomized study. Lancet 353: 617–622

    CAS  PubMed  Google Scholar 

  39. Wilbourn AJ (1999) Diabetic entrapment and compression neuropathies. In Diabetic Neuropathy, 481–508 (Eds Dyck PJ and Thomas PK) Philadelphia: Saunders

    Google Scholar 

  40. Watanabe K et al. (1990) Characteristics of cranial nerve palsies in diabetic patients. Diabetes Res Clin Pract 10: 19–27

    CAS  PubMed  Google Scholar 

  41. Perkins B et al. (2002) Carpal tunnel syndrome in patients with diabetic polyneuropathy. Diabetes Care 25: 565–569

    PubMed  Google Scholar 

  42. Dyck PJ and Windebank AJ (2002) Diabetic and nondiabetic lumbosacral radiculoplexus neuropathy: new insights into pathophysiology and treatment. Muscle Nerve 25: 477–491

    PubMed  Google Scholar 

  43. Sharma K et al. (2002) Demyelinating neuropathy in diabetes mellitus. Arch Neurol 59: 758–765

    PubMed  Google Scholar 

  44. Krendel DA et al. (1997) Autoimmune diabetic neuropathy. Neurol Clin 15: 959–971

    CAS  PubMed  Google Scholar 

  45. Ayyar DR and Sharma KR (2004) Chronic inflammatory demyelinating polyradiculoneuropathy in diabetes mellitus. Curr Diab Rep 4: 409–412

    PubMed  Google Scholar 

  46. DCCT Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin dependent diabetes mellitus. N Engl J Med 329: 977–986

  47. UK Prospective Diabetes Study Group (1998) Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 317: 703–713

  48. UK Prospective Diabetes Study (UKPDS) Group (1998) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352: 854–865

  49. Gaede P et al. (2003) Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 348: 383–393

    PubMed  Google Scholar 

  50. Tesfaye S et al. (2005) Vascular risk factors and diabetic neuropathy. N Engl J Med 352: 341–350

    CAS  PubMed  Google Scholar 

  51. Ziegler D et al. (2004) Oxidative stress and antioxidant defense in relation to the severity of diabetic polyneuropathy and cardiovascular autonomic neuropathy. Diabetes Care 27: 2178–2183

    CAS  PubMed  Google Scholar 

  52. Vincent AM et al. (2004) Oxidative stress in the pathogenesis of diabetic neuropathy. Endocr Rev 25: 612–628

    CAS  PubMed  Google Scholar 

  53. Bril V and Buchanan RA (2004) Aldose reductase inhibition by AS-3201 in sural nerve from patients with diabetic sensorimotor polyneuropathy. Diabetes Care 27: 2369–2375

    CAS  PubMed  Google Scholar 

  54. Keen H et al. (1993) Treatment of diabetic neuropathy with γ-linolenic acid. The γ-Linolenic Acid Multicenter Trial Group. Diabetes Care 16: 8–15

    CAS  PubMed  Google Scholar 

  55. Ziegler D et al. (2004) Treatment of symptomatic diabetic polyneuropathy with the antioxidant α-lipoic acid: a meta-analysis. Diabet Med 21: 114–121

    CAS  PubMed  Google Scholar 

  56. Vinik A et al. (2005) Sural sensory nerve action potential identifies diabetic peripheral neuropathy responders to therapy. Muscle Nerve 32: 619–625

    PubMed  Google Scholar 

  57. Vinik A et al. (2005) Treatment of symptomatic diabetic peripheral neuropathy with protein kinase CB inhibitor ruboxistaurin mesylate during a 1-year, randomized, placebo-controlled, double-blind clinical trial. Clin Ther 27: 1164–1180

    CAS  PubMed  Google Scholar 

  58. Pittenger G and Vinik A (2003) Nerve growth factor and diabetic neuropathy Exp Diabesity Res 4: 271–285

    PubMed  PubMed Central  Google Scholar 

  59. Vinik AI (1999) Treatment of diabetic polyneuropathy (DPN) with recombinant human nerve growth factor (rhNGF). In National Diabetes Association, 59th Scientific Sessions: 1999, June 19–22; San Diego, CA, 48: 0232:A54

    Google Scholar 

  60. Rivard A et al. (1999) Rescue of diabetes-related impairment of angiogenesis by intramuscular gene therapy with adeno-VEGF. Am J Pathol 154: 355–363

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Milicevic Z et al. (1997) Anti-ganglioside GM1 antibody and distal symmetric “diabetic polyneuropathy” with dominant motor features. Diabetologia 40: 1364–1365

    CAS  PubMed  Google Scholar 

  62. Vinik AI et al. (2005) Antibodies to neuronal structures: innocent bystanders or neurotoxins? Diabetes Care 28: 2067–2072

    PubMed  Google Scholar 

  63. Granberg V et al. (2005) Autoantibodies to autonomic nerves associated with cardiac and peripheral autonomic neuropathy. Diabetes Care 28: 1959–1964

    PubMed  Google Scholar 

  64. Krendel DA et al. (1995) Successful treatment of neuropathies in patients with diabetes mellitus. Arch Neurol 52: 1053–1061

    CAS  PubMed  Google Scholar 

  65. Rains C and Bryson HM (1995) Topical capsaicin. A review of its pharmacological properties and therapeutic potential in post-herpetic neuralgia, diabetic neuropathy and osteoarthritis. Drugs Aging 7: 317–328

    CAS  PubMed  Google Scholar 

  66. Goldstein DJ et al. (2005) Duloxetine vs. placebo in patients with painful diabetic neuropathy. Pain 116: 109–118

    CAS  PubMed  Google Scholar 

  67. Rosenstock J et al. (2004) Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain 110: 628–638

    CAS  PubMed  Google Scholar 

  68. Said G et al. (1998) Uncommon early-onset neuropathy in diabetic patients. J Neurol 245: 61–68

    CAS  PubMed  Google Scholar 

  69. Harati Y et al. (1998) Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology 50: 1842–1846

    CAS  PubMed  Google Scholar 

  70. Dworkin RH et al. (2003) Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol 60: 1524–1534

    PubMed  Google Scholar 

  71. Sindrup S et al. (1990) The selective serotonin reuptake inhibitor paroxetine is effective in treatment of diabetic neuropathy symptoms. Pain 42: 135–144

    CAS  PubMed  Google Scholar 

  72. Goldstein DJ et al. (2005) Duloxetine vs. placebo in patients with painful diabetic neuropathy. Pain 116: 109–118

    CAS  PubMed  Google Scholar 

  73. Backonja M et al. (1998) Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA 280: 1831–1836

    CAS  PubMed  Google Scholar 

  74. DeToledo JC et al. (1997) Changes in body weight with chronic, high-dose gabapentin therapy. Ther Drug Monit 19: 394–396

    CAS  PubMed  Google Scholar 

  75. Raskin P et al. (2004) Topiramate vs placebo in painful diabetic neuropathy: analgesic and metabolic effects. Neurology 63: 865–873

    CAS  PubMed  Google Scholar 

  76. Vinik A (2005) Use of antiepileptic drugs in the treatment of chronic painful diabetic neuropathy. J Clin Endocrinol Metab 90: 4936–4945

    CAS  PubMed  Google Scholar 

  77. Cavanagh PR et al. (1992) Problems with gait and posture in neuropathic patients with insulin-dependent diabetes mellitus. Diabet Med 9: 469–474

    CAS  PubMed  Google Scholar 

  78. Liu-Ambrose T et al. (2004) Resistance and agility training reduce fall risk in women aged 75 to 85 with low bone mass: a 6-month randomized, controlled trial. J Am Geriatr Soc 52: 657–665

    PubMed  PubMed Central  Google Scholar 

  79. Jude EB et al. (2001) Biphosphonates in the treatment of Charcot neuroarthropathy: a double-blind randomized controlled trial. Diabetologia 44: 2032–2037

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Our work is supported by the American Diabetes Association, NIH, the Department of Housing and Urban Development, the Diabetes Institutes Foundation, the Commonwealth Health Research Board and various industrial companies (Astra Zeneca, Takeda, Pliva, Dainippon, Eli Lilly & Company).

Author information

Authors and Affiliations

  1. Internal Medicine, Pathology, Neurobiology and the Director of Research,

    Aaron Vinik, Jagdeesh Ullal, Henri K Parson & Carolina M Casellini

  2. Neurovascular Unit, at the Strelitz Diabetes Institutes, Norfolk, VA, USA

    Aaron Vinik, Jagdeesh Ullal, Henri K Parson & Carolina M Casellini

Authors
  1. Aaron Vinik
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jagdeesh Ullal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Henri K Parson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carolina M Casellini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Aaron Vinik.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Vinik, A., Ullal, J., Parson, H. et al. Diabetic neuropathies: clinical manifestations and current treatment options. Nat Rev Endocrinol 2, 269–281 (2006). https://doi.org/10.1038/ncpendmet0142

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpendmet0142

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing