J Korean Diabetes.  2018 Sep;19(3):160-167. 10.4093/jkd.2018.19.3.160.

Diagnosis and Management of Diabetic Autonomic Neuropathy

• Kim CH

• KMID: 2421297
• DOI: http://doi.org/10.4093/jkd.2018.19.3.160

Abstract

Diabetic autonomic neuropathy (DAN) is a serious and common complication of diabetes, although it is often overlooked. Abnormal autonomic function tests are often found in peoples with diabetic peripheral neuropathy. Autonomic neuropathies affect the autonomic neurons (parasympathetic, sympathetic, or both) and are associated with a variety of site-specific symptoms. The symptoms and signs of DAN should be elicited carefully during the medical history and physical examination. Major clinical manifestations of DAN include hypoglycemia unawareness, resting tachycardia, orthostatic hypotension, gastroparesis, constipation, diarrhea, fecal incontinence, erectile dysfunction, neurogenic bladder, and sudomotor dysfunction with either increased or decreased sweating. When a patient has signs and symptoms of DAN, various autonomic function tests should be performed. Recognition and management of DAN may improve symptoms, reduce sequelae, and improve quality of life. Clinically relevant diabetic autonomic neuropathies such as cardiovascular, gastrointestinal, genitourinary, and sudomotor dysfunction should be considered in the optimal care of patients with diabetes. The present review summarizes the latest knowledge regarding clinical presentation, diagnosis, and management of DAN.

Keyword

Autonomic neuropathy; Diabetic neuropathy

MeSH Terms

Constipation
Diabetic Neuropathies*
Diagnosis*
Diarrhea
Erectile Dysfunction
Fecal Incontinence
Gastroparesis
Humans
Hypoglycemia
Hypotension, Orthostatic
Male
Neurons
Peripheral Nervous System Diseases
Physical Examination
Quality of Life
Sweat
Sweating
Tachycardia
Urinary Bladder, Neurogenic

Reference

References

1. Spallone V, Ziegler D, Freeman R, Bernardi L, Frontoni S, Pop-Busui R, Stevens M, Kempler P, Hilsted J, Tesfaye S, Low P, Valensi P. Toronto Consensus Panel on Diabetic Neuropathy. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev. 2011; 27:639–53.

2. Low PA, Benrud-Larson LM, Sletten DM, Opfer-Gehrking TL, Weigand SD, O'Brien PC, Suarez GA, Dyck PJ. Autonomic symptoms and diabetic neuropathy: a population-based study. Diabetes Care. 2004; 27:2942–7.

3. Martin CL, Albers JW, Pop-Busui R. DCCT/EDIC Research Group. Neuropathy and related findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care. 2014; 37:31–8.

4. Pop-Busui R, Low PA, Waberski BH, Martin CL, Albers JW, Feldman EL, Sommer C, Cleary PA, Lachin JM, Herman WH. DCCT/EDIC Research Group. 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; 119:2886–93.

5. Tesfaye S, Stevens LK, Stephenson JM, Fuller JH, Plater M, Ionescu-Tirgoviste C, Nuber A, Pozza G, Ward JD. Prevalence of diabetic neuropathy and its relation to glycaemic control and potential risk factors: the EURODIAB IDDM Complications Study. Diabetologia. 1996; 39:1377–84.

6. Maser RE, Mitchell BD, Vinik AI, Freeman R. The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: a metaanalysis. Diabetes Care. 2003; 26:1895–901.

7. Lykke JA, Tarnow L, Parving HH, Hilsted J. A combined abnormality in heart rate variation and QT corrected interval is a strong predictor of cardiovascular death in type 1 diabetes. Scand J Clin Lab Invest. 2008; 68:654–9.

8. Lonn EM, Rambihar S, Gao P, Custodis FF, Silwa K, Teo KK, Yusuf S, Böhm M. Heart rate is associated with increased risk of major cardiovascular events, cardiovascular and all-cause death in patients with stable chronic cardiovascular disease: an analysis of ONTARGET/TRANSCEND. Clin Res Cardiol. 2014; 103:149–59.

9. Pop-Busui R, Evans GW, Gerstein HC, Fonseca V, Fleg JL, Hoogwerf BJ, Genuth S, Grimm RH, Corson MA, Prineas R. Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of cardiac autonomic dysfunction on mortality risk in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Diabetes Care. 2010; 33:1578–84.

10. Astrup AS, Tarnow L, Rossing P, Hansen BV, Hilsted J, Parving HH. Cardiac autonomic neuropathy predicts cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy. Diabetes Care. 2006; 29:334–9.

11. Orlov S, Cherney DZ, Pop-Busui R, Lovblom LE, Ficociello LH, Smiles AM, Warram JH, Krolewski AS, Perkins BA. Cardiac autonomic neuropathy and early progressive renal decline in patients with nonmacroalbuminuric type 1 diabetes. Clin J Am Soc Nephrol. 2015; 10:1136–44.

12. Wheelock KM, Jaiswal M, Martin CL, Fufaa GD, Weli EJ, Lemley KV, Yee B, Feldman E, Brosius FC 3rd, Knowler WC, Nelson RG, Pop-Busui R. Cardiovascular autonomic neuropathy associates with nephropathy lesions in American Indians with type 2 diabetes. J Diabetes Complications. 2016; 30:873–9.

13. Ziegler D, Keller J, Maier C, Pannek J. German Diabetes Association. Diabetic neuropathy. Exp Clin Endocrinol Diabetes. 2014; 122:406–15.

14. 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; 93:1043–65.

15. Pop-Busui R. Cardiac autonomic neuropathy in diabetes: a clinical perspective. Diabetes Care. 2010; 33:434–41.

16. The Consensus Committee of the American Autonomic Society and the American Academy of Neurology. Consensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. Neurology. 1996; 46:1470.

17. Vinik AI, Ziegler D. Diabetic cardiovascular autonomic neuropathy. Circulation. 2007; 115:387–97.

18. Freeman R. Clinical practice. Neurogenic orthostatic hypotension. N Engl J Med. 2008; 358:615–24.

19. Low PA, Tomalia VA. Orthostatic hypotension: mechanisms, causes, management. J Clin Neurol. 2015; 11:220–6.

20. Low PA, Gilden JL, Freeman R, Sheng KN, McElligott MA. Midodrine Study Group. Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized, double-blind multicenter study. JAMA. 1997; 277:1046–51.

21. Bharucha AE. Epidemiology and natural history of gastroparesis. Gastroenterol Clin North Am. 2015; 44:9–19.

22. Choung RS, Locke GR 3rd, Schleck CD, Zinsmeister AR, Melton LJ 3rd, Talley NJ. Risk of gastroparesis in subjects with type 1 and 2 diabetes in the general population. Am J Gastroenterol. 2012; 107:82–8.

23. Camilleri M. Clinical practice. Diabetic gastroparesis. N Engl J Med. 2007; 356:820–9.

24. Bytzer P, Talley NJ, Leemon M, Young LJ, Jones MP, Horowitz M. Prevalence of gastrointestinal symptoms associated with diabetes mellitus: a population-based survey of 15,000 adults. Arch Intern Med. 2001; 161:1989–96.

25. Schirra J, Nicolaus M, Roggel R, Katschinski M, Storr M, Woerle HJ, Göke B. Endogenous glucagon-like peptide 1 controls endocrine pancreatic secretion and antro-pyloroduodenal motility in humans. Gut. 2006; 55:243–51.

26. Murphy DB, Sutton JA, Prescott LF, Murphy MB. Opioid-induced delay in gastric emptying: a peripheral mechanism in humans. Anesthesiology. 1997; 87:765–70.

27. Schvarcz E, Palmér M, Aman J, Lindkvist B, Beckman KW. Hypoglycaemia increases the gastric emptying rate in patients with type 1 diabetes mellitus. Diabet Med. 1993; 10:660–3.

28. Schvarcz E, Palmér M, Aman J, Horowitz M, Stridsberg M, Berne C. Physiological hyperglycemia slows gastric emptying in normal subjects and patients with insulindependent diabetes mellitus. Gastroenterology. 1997; 113:60–6.

29. Pop-Busui R, Stevens M. Autonomic neuropathy in diabetes. Umpierrez GE, editor. American Diabetes Association. Therapy for diabetes mellitus and related disorders. 6th ed.Alexandria: American Diabetes Association;2014. p. 834–63.

30. Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol. 1994; 151:54–61.

31. Giugliano F, Maiorino M, Bellastella G, Gicchino M, Giugliano D, Esposito K. Determinants of erectile dysfunction in type 2 diabetes. Int J Impot Res. 2010; 22:204–9.

32. Saigal CS, Wessells H, Pace J, Schonlau M, Wilt TJ. Urologic Diseases in America Project. Predictors and prevalence of erectile dysfunction in a racially diverse population. Arch Intern Med. 2006; 166:207–12.

33. Van Den Eeden SK, Sarma AV, Rutledge BN, Cleary PA, Kusek JW, Nyberg LM, McVary KT, Wessells H. Diabetes Control and Complications Trial/Epidemiology of Diabetes Research Group. 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.

34. Wessells H, Penson DF, Cleary P, Rutledge BN, Lachin JM, NcVary KT, Schade DS, Sarma AV. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Effect of intensive glycemic therapy on erectile function in men with type 1 diabetes. J Urol. 2011; 185:1828–34.

35. Ueda T, Yoshimura N, Yoshida O. Diabetic cystopathy: relationship to autonomic neuropathy detected by sympathetic skin response. J Urol. 1997; 157:580–4.

36. Pontiroli AE, Cortelazzi D, Morabito A. Female sexual dysfunction and diabetes: a systematic review and metaanalysis. J Sex Med. 2013; 10:1044–51.

37. Smith AG, Lessard M, Reyna S, Doudova M, Singleton JR. The diagnostic utility of Sudoscan for distal symmetric peripheral neuropathy. J Diabetes Complications. 2014; 28:511–6.

38. Shaw JE, Parker R, Hollis S, Gokal R, Boulton AJ. Gustatory sweating in diabetes mellitus. Diabet Med. 1996; 13:1033–7.

39. Shaw JE, Abbott CA, Tindle K, Hollis S, Boulton AJ. A randomised controlled trial of topical glycopyrrolate, the first specific treatment for diabetic gustatory sweating. Diabetologia. 1997; 40:299–301.