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Semin Neurol 2003; 23(4): 365-372
DOI: 10.1055/s-2004-817720
Copyright © 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Diabetic Autonomic Neuropathy

Aaron I. Vinik1 , Roy Freeman2 , Tomris Erbas1
  • 1Strelitz Diabetes Research Institutes, Eastern Virginia Medical School, Norfolk, Virginia
  • 2Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
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Publication History

Publication Date:
15 April 2004 (online)

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ABSTRACT

Diabetic autonomic neuropathy is the most common and troublesome complication of diabetes mellitus. Although involvement of the autonomic nervous system is generally diffuse, symptoms may be confined to a single target organ or organ system. Complications of diabetic autonomic neuropathy contribute greatly to the morbidity, mortality, and reduced quality of life of the person with diabetes and are the major source of increased costs of caring for the diabetic patient. Factors in the pathogenesis of these complications are altered metabolism, vascular insufficiency, loss of growth factor trophism, and autoimmune destruction of nerves in a visceral and cutaneous distribution. The clinical manifestations and the complications of diabetic autonomic neuropathy are reviewed. Future therapeutic strategies that are developed from a better understanding of the pathogenetic processes underlying this disorder can be directed at the cause rather than the manifestations. There are studies in progress that suggest that autonomic nerves can be induced to regenerate, and the future for patients with diabetic autonomic neuropathy is brighter.

KEYWORDS

Diabetes mellitus - autonomic neuropathy - cardiovascular autonomic neuropathy - gastrointestinal autonomic neuropathy - erectile dysfunction - neurogenic bladder

REFERENCES

  • 1 Vinik A I, Maser R E, Mitchell B D, Freeman R. Diabetic autonomic neuropathy.  Diabetes Care . 2003;  26 1553-1579
    CrossrefPubMedGoogle Scholar
  • 2 Freeman R. Diabetic autonomic neuropathy: an overview. In: Veves A, ed. Clinical Management of Diabetic Neuropathy Totowa, NJ: Humana Press 1998: 181-208
    Google Scholar
  • 3 Vinik A I, Erbas T. Recognizing and treating diabetic autonomic neuropathy.  Cleve Clin J Med . 2001;  68 928-944
    PubMedGoogle Scholar
  • 4 Vinik A I, Erbas T, Pfeifer M A, Feldman E L, Stevens M J, Russell J W. Diabetic autonomic neuropathy. In: Porte D, Sherwin RS, Baron A, eds. Ellenberg & Rifkin's Diabetes Mellitus 6th ed. New York: McGraw Hill; 2003: 789-804
    Google Scholar
  • 5 Ewing D J, Clarke B F. Diabetic autonomic neuropathy: present insights and future prospects.  Diabetes Care . 1986;  9 648-665
    PubMedGoogle Scholar
  • 6 Ziegler D. Cardiovascular autonomic neuropathy: clinical manifestations and measurement.  Diabetes Reviews . 1999;  7 300-315
    PubMedGoogle Scholar
  • 7 Pfeifer M A, Weinberg C R, Cook D L. et al . Autonomic neural dysfunction in recently diagnosed diabetic subjects.  Diabetes Care . 1984;  7 447-453
    PubMedGoogle Scholar
  • 8 Dyck P J, Kratz K M, Karnes J L. 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;  43 817-824
    CrossrefPubMedGoogle Scholar
  • 9 Neil H A, Thompson A V, John S, McCarthy S T, Mann J I. Diabetic autonomic neuropathy: the prevalence of impaired heart rate variability in a geographically defined population.  Diabet Med . 1989;  6 20-24
    CrossrefPubMedGoogle Scholar
  • 10 Ziegler D, Gries F A, Spuler M, Lessmann F. Diabetic Cardiovascular Autonomic Neuropathy Multicenter Study Group: the epidemiology of diabetic neuropathy.  J Diabetes Complications . 1992;  6 49-57
    CrossrefPubMedGoogle Scholar
  • 11 Greene D A, Lattimer S A, Sima A A. Are disturbances of sorbitol, phosphoinositide, and Na+-K+-ATPase regulation involved in pathogenesis of diabetic neuropathy?.  Diabetes . 1988;  37 688-693
    PubMedGoogle Scholar
  • 12 Cameron N E, Cotter M A. Metabolic and vascular factors in the pathogenesis of diabetic neuropathy.  Diabetes . 1997;  46(S2) S31-S37
    PubMedGoogle Scholar
  • 13 Low P A, Nickander K K, Tritschler H J. The roles of oxidative stress and antioxidant treatment in experimental diabetic neuropathy.  Diabetes . 1997;  46 (suppl 2) S38-S42
    CrossrefPubMedGoogle Scholar
  • 14 Hoeldtke R D, Bryner K D, McNeill D R. et al . Nitrosative stress, uric acid, and peripheral nerve function in early type 1 diabetes.  Diabetes . 2002;  51 2817-2825
    PubMedGoogle Scholar
  • 15 Vinik A I, Erbas T, Tae S, Stansberry K, Scanelli J A, Pittenger G L. Dermal neurovascular dysfunction in type 2 diabetes.  Diabetes Care . 2001;  24 1468-1475
    PubMedGoogle Scholar
  • 16 Pittenger G L, Malik R A, Burcus N, Boulton A J, Vinik A I. Specific fiber deficits in sensorimotor diabetic polyneuropathy correspond to cytotoxicity against neuroblastoma cells of sera from patients with diabetes.  Diabetes Care . 1999;  22 1839-1844
    PubMedGoogle Scholar
  • 17 Apfel S C, Arezzo J C, Brownlee M, Federoff H, Kessler J A. Nerve growth factor administration protects against experimental diabetic sensory neuropathy.  Brain Res . 1994;  634 7-12
    CrossrefPubMedGoogle Scholar
  • 18 Horrobin D F. Essential fatty acids in the management of impaired nerve function in diabetes.  Diabetes . 1997;  46 (suppl 2) S90-S93
    PubMedGoogle Scholar
  • 19 Vincenti A M, Brownlee M, Russell J W. Oxidative stress and programmed cell death in diabetic neuropathy.  Ann N Y Acad Sci . 2002;  959 368-383
    PubMedGoogle Scholar
  • 20 Pacher P, Liaudet L, Soriano F G, Mabley J G, Szabo E, Szabo C. The role of poly(ADP-ribose) polymerase activation in the development of myocardial and endothelial dysfunction in diabetes.  Diabetes . 2002;  51 514-521
    PubMedGoogle Scholar
  • 21 Du X, Matsumura T, Edelstein D. et al . Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells.  J Clin Invest . 2003;  112 1049-1057
    CrossrefPubMedGoogle Scholar
  • 22 Ziegler D, Gries F A, Muhlen H, Rathmann W, Spuler M, Lessmann F. Prevalence and clinical correlates of cardiovascular autonomic and peripheral diabetic neuropathy in patients attending diabetes center. The DiaCAN Multicenter Study Group.  Diabetes Metab . 1993;  19 143-151
    PubMedGoogle Scholar
  • 23 Maser R E, Mitchell B D, Vinik A I, Freeman R. The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: a meta-analysis.  Diabetes Care . 2003;  26 1895-1901
    CrossrefPubMedGoogle Scholar
  • 24 Kahn J, Zola B, Juni J, Vinik A I. Decreased exercise heart rate in diabetic subjects with cardiac autonomic neuropathy.  Diabetes Care . 1986;  9 389-394
    PubMedGoogle Scholar
  • 25 Ewing D J, Boland O, Neilson J M, Cho C G, Clarke B F. Autonomic neuropathy, QT interval lengthening, and unexpected deaths in male diabetic patients.  Diabetologia . 1991;  34 182-185
    CrossrefPubMedGoogle Scholar
  • 26 Valensi P, Sachs R N, Harfouche B. et al . Predictive value of cardiac autonomic neuropathy in diabetic patients with or without silent myocardial ischemia.  Diabetes Care . 2001;  24 339-343
    CrossrefPubMedGoogle Scholar
  • 27 Milan Study on Atherosclerosis and Diabetes. (MiSAD) Group: prevalence of unrecognized silent myocardial ischemia and its association with atherosclerotic risk factors in noninsulin-dependent diabetes mellitus.  Am J Cardiol . 1997;  79 134-139
    CrossrefPubMedGoogle Scholar
  • 28 Miettinen H, Lehto S, Salomaa V. et al . Impact of diabetes on mortality after the first myocardial infarction: The FINMONICA Myocardial Infarction Register Study Group.  Diabetes Care . 1998;  21 69-75
    PubMedGoogle Scholar
  • 29 Ewing D J, Martyn C N, Young R J, Clarke B F. The value of cardiovascular autonomic function tests: 10 years experience in diabetes.  Diabetes Care . 1985;  8 491-498
    CrossrefPubMedGoogle Scholar
  • 30 Freeman R, Saul P, Roberts M, Berger R D, Broadbridge C, Cohen R. Spectral analysis of heart rate in diabetic autonomic neuropathy.  Arch Neurol . 1991;  48 185-190
    PubMedGoogle Scholar
  • 31 Risk M, Bril V, Broadbridge C, Cohen A. Heart rate variability measurement in diabetic neuropathy: review of methods.  Diabetes Technol Ther . 2001;  3 63-76
    CrossrefPubMedGoogle Scholar
  • 32 Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability: standards of measurement, physiological interpretation and clinical use.  Circulation . 1996;  93 1043-1065
    Google Scholar
  • 33 Kilo S, Berghoff M, Hilz M, Freeman R. Neural and endothelial control of the microcirculation in diabetic peripheral neuropathy.  Neurology . 2000;  54 1246-1252
    PubMedGoogle Scholar
  • 34 Stansberry K B, Hill M A, Shapiro S A, McNitt P M, Bhatt B A, Vinik A I. Impairment of peripheral blood flow responses in diabetes resembles an enhanced aging effect.  Diabetes Care . 1997;  20 1711-1716
    PubMedGoogle Scholar
  • 35 Stansberry K B, Peppard H R, Babyak L M, Popp G, McNitt P M, Vinik A I. Primary nociceptive afferents mediate the blood flow dysfunction in non-glabrous (hairy) skin of type 2 diabetes: a new model for the pathogenesis of microvascular dysfunction.  Diabetes Care . 1999;  22 1549-1554
    PubMedGoogle Scholar
  • 36 Vinik A I, Erbas T, Park T S, Pierce K K, Stansberry K B. Methods for evaluation of peripheral neurovascular dysfunction.  Diabetes Technol Ther . 2001;  3 29-50
    CrossrefPubMedGoogle Scholar
  • 37 Maleki D, Locke III R G, Camilleri M. et al . Gastrointestinal tract symptoms among persons with diabetes mellitus in the community.  Arch Intern Med . 2000;  160 2808-2816
    CrossrefPubMedGoogle Scholar
  • 38 Kong M F, Horowitz M, Jones K L, Wishart J M, Harding P E. Natural history of diabetic gastroparesis.  Diabetes Care . 1999;  22 503-507
    CrossrefPubMedGoogle Scholar
  • 39 Vinik A, Erbas T, Stansberry K. Gastrointestinal, genitourinary, and neurovascular disturbances in diabetes.  Diabetes Reviews . 1999;  7 358-378
    PubMedGoogle Scholar
  • 40 Lysy J, Israeli E, Goldin E. The prevalence of chronic diarrhea among diabetic patients.  Am J Gastroenterol . 1999;  94 2165-2170
    CrossrefPubMedGoogle Scholar
  • 41 Bacon C G, Hu F B, Giovannucci E, Glasser D B, Mittleman M A, Rimm E B. Association of type and duration of diabetes with erectile dysfunction in a large cohort of men.  Diabetes Care . 2002;  25 1458-1463
    CrossrefPubMedGoogle Scholar
  • 42 Richardson D, Vinik A. Etiology and treatment of erectile failure in diabetes mellitus.  Curr Diab Rep . 2002;  2 501-509
    PubMedGoogle Scholar
  • 43 Bradley W E. Diagnosis of urinary bladder dysfunction in diabetes mellitus.  Ann Intern Med . 1980;  92 323-326
    PubMedGoogle Scholar
  • 44 Shaw J E, Parker R, Hollis S, Gokal R, Boulton A J. Gustatory sweating in diabetes mellitus.  Diabet Med . 1996;  13 1033-1037
    CrossrefPubMedGoogle Scholar
  • 45 Cryer P E. Hypoglycemia-associated autonomic failure in diabetes.  Am J Physiol Endocrinol Metab . 2001;  281 E1115-E1121
    PubMedGoogle Scholar
  • 46 DCCT Research Group. The effect of intensive diabetes therapy on measures of autonomic nervous system function in the Diabetes Control and Complications Trial (DCCT).  Diabetologia . 1998;  41 416-423
    CrossrefPubMedGoogle Scholar
  • 47 Gaede P, Vedel P, Parving H H, Pedersen O. Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomised study.  Lancet . 1999;  353 617-622
    CrossrefPubMedGoogle Scholar
  • 48 Ziegler D, Reljanovic M, Mehnert H, Gries F A. Alpha-lipoic acid in the treatment of diabetic polyneuropathy in Germany: current evidence from clinical trials.  Exp Clin Endocrinol Diabetes . 1999;  107 421-430
    PubMedGoogle Scholar
  • 49 Ebbehoj E, Poulsen P L, Hansen K W, Knudsen S T, Molgaard H, Mogensen C E. Effects on heart rate variability of metoprolol supplementary to on going ACE-inhibitor treatment in type I diabetic patients with abnormal albuminuria.  Diabetologia . 2002;  45 965-975
    CrossrefPubMedGoogle Scholar
  • 50 Kontopoulos A G, Athyros V G, Didangelos T P. et al . Effect of chronic quinapril administration on heart rate variability in patients with diabetic autonomic neuropathy.  Diabetes Care . 1997;  20 355-361
    PubMedGoogle Scholar
  • 51 Malik R A, Williamson S, Abbott C. et al . Effect of angiotensin-converting-enzyme (ACE) inhibitor trandolapril on human diabetic neuropathy: randomised double-blind controlled trial.  Lancet . 1998;  352 1978-1981
    CrossrefPubMedGoogle Scholar
  • 52 Erbas T, Varoglu E, Erbas B, Tastekin G, Akalin S. Comparison of metoclopramide and erythromycin in the treatment of diabetic gastroparesis.  Diabetes Care . 1993;  16 1511-1514
    PubMedGoogle Scholar
  • 53 Janssens J, Peeters T L, Vantrappen G. et al . Improvement of gastric emptying in diabetic gastroparesis by erythromycin. Preliminary studies.  N Engl J Med . 1990;  322 1028-1031
    PubMedGoogle Scholar
  • 54 Shaw J E, Abbott C A, Tindle K, Hollis S, Boulton A J. A randomized controlled trial of topical glycopyrrolate, the first specific treatment for diabetic gustatory sweating.  Diabetologia . 1997;  40 299-301
    CrossrefPubMedGoogle Scholar
  • 55 Restivo D A, Lanza S, Patti F. et al . Improvement of diabetic autonomic gustatory sweating by botulinum toxin type A.  Neurology . 2002;  59 1971-1973
    PubMedGoogle Scholar
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