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.

  • Review Article
  • Published:

Neuropathy in prediabetes: does the clock start ticking early?

Nature Reviews Endocrinology volume 7, pages 682–690 (2011)Cite this article

Subjects

Abstract

Between 25% and 62% of patients with idiopathic peripheral neuropathy are reported to have prediabetes, and among individuals with prediabetes 11–25% are thought to have peripheral neuropathy, and 13–21% have neuropathic pain. Population-based studies suggest a gradient for the prevalence of neuropathy, being highest in patients with manifest diabetes mellitus, followed by individuals with impaired glucose tolerance then impaired fasting glucose and least in those with normoglycemia. The most sensitive test to assess glucose metabolism status is the oral glucose tolerance test. Pathogenesis involves hyperglycemia, microvascular abnormalities, dyslipidemia and the metabolic syndrome. Individuals with prediabetes have less severe neuropathy than those with manifest diabetes mellitus. Sensory modalities are more frequently affected than motor modalities, but impairment of small nerve fibers could be the earliest detectable sign. Diagnosis should rely on careful clinical examination, with emphasis on the evaluation of small fibers. An oral glucose tolerance test should be performed in patients with idiopathic neuropathy. The only treatment with any efficacy is lifestyle modification to improve control of hyperglycemia and cardiovascular risk factors, but long-term efficacy of this approach has not been established. This Review summarizes the current evidence on the association between prediabetes and neuropathy.

Key Points

  • A substantial proportion of individuals with prediabetes has neuropathy and vice versa

  • People with prediabetes generally have less severe neuropathy than those with overt diabetes mellitus

  • The most sensitive test to assess glucose metabolism is the oral glucose tolerance test, which should be performed in patients with idiopathic neuropathy

  • The main underlying mechanisms implicated in the pathogenesis of neuropathy are hyperglycemia, microvascular abnormalities, dyslipidemia and the metabolic syndrome

  • Treatment involves lifestyle modification to improve control of hyperglycemia and cardiovascular risk factors, but its long-term efficacy is uncertain

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Similar content being viewed by others

Article 13 June 2019

Eva L. Feldman, Brian C. Callaghan, … Vijay Viswanathan

References

  1. Forouhi, N. G. et al. Diabetes prevalence in England, 2001—estimates from an epidemiological model. Diabet. Med. 23, 189–197 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Yang, W. et al. Prevalence of diabetes among men and women in China. N. Engl. J. Med. 362, 1090–1101 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. Boulton, A. J. et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care. 28, 956–962 (2005).

    Article  PubMed  Google Scholar 

  4. Vinik, A. I. & Ziegler, D. Diabetic cardiovascular autonomic neuropathy. Circulation 115, 387–397 (2007).

    Article  PubMed  Google Scholar 

  5. Smith, A. G. & Singleton, J. R. Idiopathic neuropathy, prediabetes and the metabolic syndrome. J. Neurol. Sci. 242, 9–14 (2006).

    Article  Google Scholar 

  6. Rota, E. et al. Electrophysiological findings of peripheral neuropathy in newly diagnosed type II diabetes mellitus. J. Peripher. Nerv. Syst. 10, 348–353 (2005).

    Article  PubMed  Google Scholar 

  7. Rota, E. et al. Clinical and electrophysiological correlations in type 2 diabetes mellitus at diagnosis. Diabetes Res. Clin. Pract. 76, 152–154 (2007).

    Article  PubMed  Google Scholar 

  8. Dyck, P. J., Dyck, P. J., Klein, C. J. & Weigand, S. D. Does impaired glucose metabolism cause polyneuropathy? Review of previous studies and design of a prospective controlled population-based study. Muscle Nerve 36, 536–541 (2007).

    Article  CAS  PubMed  Google Scholar 

  9. Smith, A. G. & Singleton, J. R. Impaired glucose tolerance and neuropathy. Neurologist 14, 23–29 (2008).

    Article  PubMed  Google Scholar 

  10. Novella, S. P., Inzucchi, S. E. & Goldstein, J. M. The frequency of undiagnosed diabetes and impaired glucose tolerance in patients with idiopathic sensory neuropathy. Muscle Nerve 24, 1229–1231 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Singleton, J. R., Smith, A. G. & Bromberg, M. B. Painful sensory polyneuropathy associated with impaired glucose tolerance. Muscle Nerve 24, 1225–1228 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Sumner, C. J., Sheth, S., Griffin, J. W., Cornblath, D. R. & Polydefkis, M. The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology 60, 108–111 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Smith, A. G. & Singleton, J. R. The diagnostic yield of a standardized approach to idiopathic sensory-predominant neuropathy. Arch. Intern. Med. 164, 1021–1025 (2004).

    Article  PubMed  Google Scholar 

  14. Singleton, J. R., Smith, A. G. & Bromberg, M. B. Increased prevalence of impaired glucose tolerance in patients with painful sensory neuropathy. Diabetes Care 24, 1448–1453 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Hoffman-Snyder, C., Smith, B. E., Ross, M. A., Hernandez, J. & Bosch, E. P. Value of the oral glucose tolerance test in the evaluation of chronic idiopathic axonal polyneuropathy. Arch. Neurol. 63, 1075–1079 (2006).

    Article  PubMed  Google Scholar 

  16. Franklin, G. M., Kahn, L. B., Baxter, J., Marshall, J. A. & Hamman, R. F. Sensory neuropathy in non-insulin-dependent diabetes mellitus. The San Luis Valley Diabetes Study. Am. J. Epidemiol. 131, 633–643 (1990).

    Article  CAS  PubMed  Google Scholar 

  17. Ziegler, D. et al. Prevalence of polyneuropathy in pre-diabetes and diabetes is associated with abdominal obesity and macroangiopathy: the MONICA/KORA Augsburg Surveys S2 and S3. Diabetes Care 31, 464–469 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Ziegler, D. et al. Neuropathic pain in diabetes, prediabetes and normal glucose tolerance: the MONICA/KORA Augsburg Surveys S2 and S3. Pain Med. 10, 393–400 (2009).

    Article  PubMed  Google Scholar 

  19. Ziegler, D. et al. 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 13, 582–587 (2009).

    Article  PubMed  Google Scholar 

  20. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 26 (Suppl. 1), S5–S20 (2003).

  21. [No authors listed] Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 20, 1183–1197 (1997).

  22. Borch-Johnsen, K. et al. Creating a pandemic of prediabetes: the proposed new diagnostic criteria for impaired fasting glycaemia. Diabetologia 47, 1396–1402 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. International Expert Committee. International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 32, 1327–1334 (2009).

  24. DECODE Study Group, the European Diabetes Epidemiology Group. Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria. Arch. Intern. Med. 161, 397–405 (2001).

  25. Qiao, Q. et al. Two-hour glucose is a better risk predictor for incident coronary heart disease and cardiovascular mortality than fasting glucose. Eur. Heart J. 23, 1267–1275 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Hyvärinen, M. et al. Hyperglycemia and stroke mortality: comparison between fasting and 2-h glucose criteria. Diabetes Care 32, 348–354 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Ning, F. et al. Cardiovascular disease mortality in Europeans in relation to fasting and 2-h plasma glucose levels within a normoglycaemic range. Diabetes Care 33, 2211–2216 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Colagiuri, S. Glycemic Thresholds for Diabetes-Specific Retinopathy: Implications for diagnostic criteria for diabetes. Diabetes Care 34, 145–150 (2011).

    Article  PubMed  Google Scholar 

  29. Sosenko, J. M., Kato, M. & Goldberg, R. B. Sensory function and albumin excretion according to diagnostic criteria for diabetes. Diabetes Care 27, 1716–1720 (2004).

    Article  PubMed  Google Scholar 

  30. Smith, A. G. et al. Lifestyle intervention for pre-diabetic neuropathy. Diabetes Care 29, 1294–1299 (2006).

    Article  PubMed  Google Scholar 

  31. Singleton, J. R. et al. Diet and exercise counseling alone does not prevent long term neuropathy progression in IGT neuropathy [abstract]. Neurology 68, a410 (2007).

    Google Scholar 

  32. Hughes, R. A. et al. A controlled investigation of the cause of chronic idiopathic axonal polyneuropathy. Brain 127, 1723–1730 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Harris, M. I. et al. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in, U. S. adults. The Third National Health and Nutrition Examination Survey, 1988–1994. Diabetes Care 21, 518–524 (1998).

    Article  CAS  PubMed  Google Scholar 

  34. Nebuchennykh, M., Løseth, S., Jorde, R. & Mellgren, S. I. Idiopathic polyneuropathy and impaired glucose metabolism in a Norwegian patient series. Eur. J. Neurol. 15, 810–816 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Centers for Disease Control and Prevention (CDC). Prevalence of diabetes and impaired fasting glucose in adults—United States, 1999–2000. MMWR Morb. Mortal. Wkly Rep. 52, 833–837 (2003).

  36. Russell, J. W. & Feldman, E. L. Impaired glucose tolerance--does it cause neuropathy? Muscle Nerve 24, 1109–1112 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Kissel, J. T. Peripheral neuropathy with impaired glucose tolerance: a sweet smell of success? Arch. Neurol. 63, 1055–1056 (2006).

    Article  PubMed  Google Scholar 

  38. Feldman, E. L., Stevens, M. J., Thomas, P. K., Brown, M. B., Canal, N. & Greene, D. A. A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care 17, 1281–1289 (1994).

    Article  CAS  PubMed  Google Scholar 

  39. Moghtaderi, A., Bakhshipour, A. & Rashidi, H. Validation of Michigan neuropathy screening instrument for diabetic peripheral neuropathy. Clin. Neurol. Neurosurg. 108, 477–481 (2006).

    Article  PubMed  Google Scholar 

  40. de Neeling, J. N., Beks, P. J., Bertelsmann, F. W., Heine, R. J. & Bouter, L. M. Peripheral somatic nerve function in relation to glucose tolerance in an elderly Caucasian population: the Hoorn study. Diabet. Med. 13, 960–966 (1996).

    Article  CAS  PubMed  Google Scholar 

  41. Grandinetti, A. et al. Impaired glucose tolerance is associated with postganglionic sudomotor impairment. Clin. Auton. Res. 17, 231–233 (2007).

    Article  PubMed  Google Scholar 

  42. Isak, B., Oflazoglu, B., Tanridag, T., Yitmen, I. & Us, O. Evaluation of peripheral and autonomic neuropathy among patients with newly diagnosed impaired glucose tolerance. Diabetes Metab. Res. Rev. 24, 563–569 (2008).

    Article  PubMed  Google Scholar 

  43. Fujimoto, W. Y. et al. Prevalence of complications among second-generation Japanese-American men with diabetes, impaired glucose tolerance, or normal glucose tolerance. Diabetes 36, 730–739 (1987).

    Article  CAS  PubMed  Google Scholar 

  44. Shaw, J. E. et al. Diabetic neuropathy in Mauritius: prevalence and risk factors. Diabetes Res. Clin. Pract. 42, 131–139 (1998).

    Article  CAS  PubMed  Google Scholar 

  45. Barr, E. L. et al. Is peripheral neuropathy associated with retinopathy and albuminuria in individuals with impaired glucose metabolism? The 1999–2000 AusDiab. Diabetes Care 29, 1114–1116 (2006).

    Article  PubMed  Google Scholar 

  46. Eriksson, K. F. et al. Diabetes mellitus but not impaired glucose tolerance is associated with dysfunction in peripheral nerves. Diabet. Med. 11, 279–285 (1994).

    Article  CAS  PubMed  Google Scholar 

  47. Mäntyselkä, P., Miettola, J., Niskanen, L. & Kumpusalo, E. Glucose regulation and chronic pain at multiple sites. Rheumatology (Oxford) 47, 1235–1238 (2008).

    Article  CAS  Google Scholar 

  48. Mäntyselkä, P., Miettola, J., Niskanen, L. & Kumpusalo, E. Chronic pain, impaired glucose tolerance and diabetes: a community-based study. Pain 137, 34–40 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. Ziegler, D. et al. Prediction of mortality using measures of cardiac autonomic dysfunction in the diabetic and nondiabetic population: the MONICA/KORA Augsburg Cohort Study. Diabetes Care 31, 556–561 (2008).

    Article  PubMed  Google Scholar 

  50. [No authors listed] Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation 93, 1043–1065 (1996).

  51. Beijers, H. J. et al. Microalbuminuria and cardiovascular autonomic dysfunction are independently associated with cardiovascular mortality: evidence for distinct pathways: the Hoorn Study. Diabetes Care 32, 1698–1703 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Putz, Z. et al. Noninvasive evaluation of neural impairment in subjects with impaired glucose tolerance. Diabetes Care 32, 181–183 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Diakakis, G. F. et al. Myocardial sympathetic innervation in patients with impaired glucose tolerance: relationship to subclinical inflammation. Cardiovasc. Pathol. 17, 172–177 (2008).

    Article  CAS  PubMed  Google Scholar 

  54. Elming, M. B., Hornum, M., Feldt-Rasmussen, B. & Mathiesen, E. R. Cardiac autonomic neuropathy in patients with uraemia is not related to pre-diabetes. Dan. Med. Bull. 58, A4244 (2011).

    PubMed  Google Scholar 

  55. Gerritsen, J. et al. Glucose tolerance and other determinants of cardiovascular autonomic function: the Hoorn Study. Diabetologia 43, 561–570 (2000).

    Article  CAS  PubMed  Google Scholar 

  56. Singh, J. P. et al. Association of hyperglycemia with reduced heart rate variability: The Framingham Heart Study. Am. J. Cardiol. 86, 309–312 (2000).

    Article  CAS  PubMed  Google Scholar 

  57. Schroeder, E. B. et al. Diabetes, glucose, insulin, and heart rate variability: the Atherosclerosis Risk in Communities (ARIC) study. Diabetes Care 28, 668–674 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Wu, J. S. et al. Epidemiological evidence of altered cardiac autonomic function in subjects with impaired glucose tolerance but not isolated impaired fasting glucose. J. Clin. Endocrinol. Metab. 92, 3885–3889 (2007).

    Article  CAS  PubMed  Google Scholar 

  59. Wu, J. S. et al. Epidemiological evidence of altered cardiac autonomic function in overweight but not underweight subjects. Int. J. Obes. (Lond.) 32, 788–794 (2008).

    Article  Google Scholar 

  60. Stein, P. K. et al. The relationship of heart rate and heart rate variability to non-diabetic fasting glucose levels and the metabolic syndrome: the Cardiovascular Health Study. Diabet. Med. 24, 855–863 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Perciaccante, A., Fiorentini, A., Paris, A., Serra, P. & Tubani, L. Circadian rhythm of the autonomic nervous system in insulin resistant subjects with normoglycemia, impaired fasting glycemia, impaired glucose tolerance, type 2 diabetes mellitus. BMC Cardiovasc. Disord. 6, 19 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Carnethon, M. R. et al. The association among autonomic nervous system function, incident diabetes, and intervention arm in the Diabetes Prevention Program. Diabetes Care. 29, 914–919 (2006).

    Article  PubMed  Google Scholar 

  63. Yagihashi, S., Mizukami, H. & Sugimoto, K. Mechanism of diabetic neuropathy: Where are we now and where to go? Journal of Diabetes Investigation 2, 18–32 (2011).

    Article  CAS  PubMed  Google Scholar 

  64. Sugimoto, K., Murakawa, Y. & Sima, A. A. Diabetic neuropathy—a continuing enigma. Diabetes Metab. Res. Rev. 16, 408–433 (2000).

    Article  CAS  PubMed  Google Scholar 

  65. Dobretsov, M., Romanovsky, D. & Stimers, J. R. Early diabetic neuropathy: triggers and mechanisms. World J. Gastroenterol. 13, 175–191 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Russell, J. W., Sullivan, K. A., Windebank, A. J., Herrmann, D. N. & Feldman, E. L. Neurons undergo apoptosis in animal and cell culture models of diabetes. Neurobiol. Dis. 6, 347–363 (1999).

    Article  CAS  PubMed  Google Scholar 

  67. Edwards, J. L. et al. Diabetes regulates mitochondrial biogenesis and fission in mouse neurons. Diabetologia 53, 160–169 (2010).

    Article  CAS  PubMed  Google Scholar 

  68. Burchiel, K. J., Russell, L. C., Lee, R. P. & Sima, A. A. Spontaneous activity of primary afferent neurons in diabetic BB/Wistar rats. A possible mechanism of chronic diabetic neuropathic pain. Diabetes 34, 1210–1213 (1985).

    Article  CAS  PubMed  Google Scholar 

  69. Garcia Soriano, F. et al. Diabetic endothelial dysfunction: the role of poly(ADP-ribose) polymerase activation. Nat. Med. 7, 108–113 (2001).

    Article  CAS  PubMed  Google Scholar 

  70. Heine, R. J., Balkau, B., Ceriello, A., Del Prato, S., Horton, E. S. & Taskinen, M. R. What does postprandial hyperglycaemia mean? Diabet. Med. 21, 208–213 (2004).

    Article  CAS  PubMed  Google Scholar 

  71. Su, Y. et al. The relationship between endothelial dysfunction and oxidative stress in diabetes and prediabetes. Int. J. Clin. Pract. 62, 877–882 (2008).

    Article  CAS  PubMed  Google Scholar 

  72. Thrainsdottir, S. et al. Endoneurial capillary abnormalities presage deterioration of glucose tolerance and accompany peripheral neuropathy in man. Diabetes 52, 2615–2622 (2003).

    Article  CAS  PubMed  Google Scholar 

  73. Caballero, A. E. et al. Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes. Diabetes 48, 1856–1862 (1999).

    Article  CAS  PubMed  Google Scholar 

  74. Green, A. Q., Krishnan, S., Finucane, F. M. & Rayman, G. Altered C-fiber function as an indicator of early peripheral neuropathy in individuals with impaired glucose tolerance. Diabetes Care 33, 174–176 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Watcho, P., Stavniichuk, R., Ribnicky, D. M., Raskin, I. & Obrosova, I. G. High-fat diet-induced neuropathy of prediabetes and obesity: effect of PMI-5011, an ethanolic extract of Artemisia dracunculus L. Mediators Inflamm. 2010, 268547 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Stavniichuk, R. et al. Role of 12/15-lipoxygenase in nitrosative stress and peripheral prediabetic and diabetic neuropathies. Free Radic. Biol. Med. 49, 1036–1045 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Vincent, A. M. et al. Dyslipidemia-induced neuropathy in mice: the role of oxLDL/LOX-1. Diabetes 58, 2376–2385 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  79. Vincent, A. M., Hinder, L. M., Pop-Busui, R. & Feldman, E. L. Hyperlipidemia: a new therapeutic target for diabetic neuropathy. J. Peripher. Nerv. Syst. 14, 257–267 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Herman, R. M. et al. Prevalence of somatic small fiber neuropathy in obesity. Int. J. Obes. (Lond.). 31, 226–235 (2007).

    Article  CAS  Google Scholar 

  81. Smith, A. G., Rose, K. & Singleton, J. R. Idiopathic neuropathy patients are at high risk for metabolic syndrome. J. Neurol. Sci. 273, 25–28 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Pittenger, G. L. et al. Small fiber neuropathy is associated with the metabolic syndrome. Metab. Syndr. Relat. Disord. 3, 113–121 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Singleton, J. R., Smith, A. G., Russell, J. W. & Feldman, E. L. Microvascular complications of impaired glucose tolerance. Diabetes 52, 2867–2873 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. Rezania, K., Soliven, B., Rezai, K. A. & Roos, R. P. Impaired glucose tolerance and metabolic syndrome in idiopathic polyneuropathy: The role of pain and depression. Med. Hypotheses 76, 538–542 (2011).

    Article  CAS  PubMed  Google Scholar 

  85. Smith, A. G., Ramachandran, P., Tripp, S. & Singleton, J. R. Epidermal nerve innervation in impaired glucose tolerance and diabetes-associated neuropathy. Neurology 57, 1701–1704 (2001).

    Article  CAS  PubMed  Google Scholar 

  86. Haanpää, M. L. et al. Assessment of neuropathic pain in primary care. Am. J. Med. 122 (Suppl. 10), S13–S21 (2009).

    Article  PubMed  Google Scholar 

  87. Al-Shekhlee, A., Chelimsky, T. C. & Preston, D. C. Review: Small-fiber neuropathy. Neurologist 8, 237–253 (2002).

    Article  PubMed  Google Scholar 

  88. Chéliout-Héraut, F. et al. Exploration of small fibers for testing diabetic neuropathies. Joint Bone Spine 72, 412–415 (2005).

    Article  PubMed  Google Scholar 

  89. Tesfaye, S. et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care 33, 2285–2293 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Smith, A. G. & Bromberg, M. B. A rational diagnostic approach to peripheral neuropathy. J. Clin. Neuromuscul. Dis. 4, 190–198 (2003).

    Article  PubMed  Google Scholar 

  91. Hays, A. P. Utility of skin biopsy to evaluate peripheral neuropathy. Curr. Neurol. Neurosci. Rep. 10, 101–107 (2010).

    Article  PubMed  Google Scholar 

  92. Lauria, G. et al. Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study. J. Peripher. Nerv. Syst. 15, 202–207 (2010).

    Article  PubMed  Google Scholar 

  93. Peltier, A. et al. Reliability of quantitative sudomotor axon reflex testing and quantitative sensory testing in neuropathy of impaired glucose regulation. Muscle Nerve 39, 529–535 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Quattrini, C. et al. Surrogate markers of small fiber damage in human diabetic neuropathy. Diabetes 56, 2148–2154 (2007).

    Article  CAS  PubMed  Google Scholar 

  95. Tavakoli, M. et al. Corneal confocal microscopy: a novel means to detect nerve fibre damage in idiopathic small fibre neuropathy. Exp. Neurol. 223, 245–250 (2010).

    Article  PubMed  Google Scholar 

  96. Gong, Q. et al. Long-term effects of a randomised trial of a 6-year lifestyle intervention in impaired glucose tolerance on diabetes-related microvascular complications: the China Da Qing Diabetes Prevention Outcome Study. Diabetologia 54, 300–307 (2011).

    Article  CAS  PubMed  Google Scholar 

  97. Gaede, P., Vedel, P., Larsen, N., Jensen, G. V., Parving, H. H. & Pedersen, O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N. Engl. J. Med. 348, 383–393 (2003).

    Article  PubMed  Google Scholar 

  98. Boyd, A. L., Barlow, P. M., Pittenger, G. L., Simmons, K. F. & Vinik, A. I. Topiramate improves neurovascular function, epidermal nerve fiber morphology, and metabolism in patients with type 2 diabetes mellitus. Diabetes Metab. Syndr. Obes. 3, 431–437 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute for Clinical Diabetology, German Diabetes Center at the Heinrich Heine University, Leibniz Center for Diabetes Research,

    Nikolaos Papanas & Dan Ziegler

  2. Department of Metabolic Diseases, University Hospital, Auf'm Hennekamp 65, D–40225, Düsseldorf, Germany

    Nikolaos Papanas & Dan Ziegler

  3. Strelitz Diabetes Center for Endocrine and Metabolic Disorders and Neuroendocrine Unit, Eastern Virginia Medical School, 855 West Brambleton Avenue, Norfolk, 23510, VA, USA

    Aaron I. Vinik

Authors
  1. Nikolaos Papanas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aaron I. Vinik
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dan Ziegler
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

N. Papanas and D. Ziegler researched the data for the article and contributed equally to writing the article. All authors provided a substantial contribution to discussions of the content and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Dan Ziegler.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Papanas, N., Vinik, A. & Ziegler, D. Neuropathy in prediabetes: does the clock start ticking early?. Nat Rev Endocrinol 7, 682–690 (2011). https://doi.org/10.1038/nrendo.2011.113

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2011.113

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