Diabetic autonomic neuropathy is a barrier to achieving glycemic control

Diabetic autonomic neuropathy is the second most common form of damage to the nervous system in diabetes mellitus as a result of disorders of the central and/or peripheral parts of the autonomic nervous system. On average, its frequency of occurrence is about 40%, and 60% or more with an increase in the duration of diabetes over than 10 years. Diabetic autonomic neuropathy is characterized by polysyndromism of clinical manifestations. In this regard, a number of forms of diabetic autonomic neuropathy are distinguished both in the form of an isolated violation of the function of organs and systems, and with their combined defeat. In the pathogenesis of autonomic neuropathy, vascular and metabolic changes common to the development of diabetic polyneuropathy play an important role. The most significant risk factors for the development of diabetic autonomic neuropathy are the patient's age, duration of diabetes mellitus, and a higher average HbA1c. The development and progression of diabetic autonomic neuropathy depends on glycemic control, but its forms such as gastrointestinal and impaired recognition of hypoglycemia (asymptomatic hypoglycemia) can cause poor compensation for diabetes. This article discusses the various clinical manifestations of gastrointestinal autonomic neuropathy. Attention is drawn to the fact that the clinical picture is often nonspecific and asymptomatic, which complicates timely diagnosis. The gastrointestinal form of diabetic autonomic neuropathy leads to limited performance, social maladaptation of patients, dramatically reduces the quality of life of patients with diabetes mellitus. In clinical practice, the doctor must remember that it can significantly affect the achievement of glycemic control, as a result of a violation of the digestion and passage of food, as well as a violation of the pharmacokinetics of hypoglycemic drugs. Impaired recognition of hypoglycemia also makes it difficult to compensate well. These complications require a personalized approach to the patient from the doctor, and strict and frequent self-control of glycemia with the help of a modern glucometer from the patient to maintain optimal glycemic control and prevent possible hypoglycemic conditions.

1. Dedov I.I., Shestakova M.V., Majorov A.Yu. (ed.). Standarts of specialized diabet care. 9th ed. (revised). Sakharnii Diabet = Diabetes Mellitus. 2019;22(1):1-144. (In Russ.) doi: 10.14341/DM221S1.

2. Dedov I.I., Shestakova M.V., Galstyan G.R. The prevalence of type 2 diabetes mellitus in the adult population of Russia (NATION study). Sakharnyy diabet = Diabetes mellitus. 2016;19(2):104-112. (In Russ.) doi: 10.14341/DM2004116-17.

3. Ametov A.S., Lysenko M.A. Neuropathy And Prediabetes: This Clock Starts Ticking Early. Farmateka. 2012;(16):11-15. (In Russ.) Available at: https://pharmateca.ru/ru/archive/article/8597.

4. Kotov S.V., Rudakova I.G., Isakova E.V., Volchenkova T.V Diabetic neuropathy: a variety of clinical forms (lecture). RMZH. Meditsinskoe obozrenie. = RMJ. Russian Medical Review. 2017;(11):822-830. (In Russ.) Available at: https://www.rusmedreview.com/articles/nevrologiya/Diabeticheskaya_neyropatiya_raznoobrazie_klinicheskih_form_lekciya/.

5. Statsenko M.E., Turkina S.V. Diabetic autonomous cardiac neuropathy in patients with type 2 Diabetes mellitus: focus on unresolved problems. Arhiv'' vnutrennej mediciny = The Russian Archives of Internal Medicine. 2013;(3):57-62. (In Russ.) doi: 10.20514/2226-6704-2013-0-3-57-62.

6. Chyun D.A., Melkus G.D., Katten D.M., Price W.J., Davey J.A., Grey N., Heller G., Wackers F.J. The Association of Psychological Factors, Physical Activity, Neuropathy, and Quality of Life in Type 2 Diabetes. Biol Res Nurs. 2006;7(4):279-288. doi: 10.1177/1099800405285748.

7. Voulgari C., Psallas M., Kokkinos A., Argiana V., Katsilambros N., Tentolouris N. The association between cardiac autonomic neuropathy with metabolic and other factors in subjects with type 1 and type 2 diabetes. J Diabetes and Its Complications. 2011;25(3):159-167. doi: 10.1016/j.jdiaco-mp.2010.06.001.

8. Cankurtaran V., Ozates S., Ozler S. Association of pupil responses with severity of erectile dysfunction in diabetes mellitus. Indian J Ophthalmol. 2019;67(8):1314-1319. doi: 10.4103/ijo.IJO_220_19.

9. Chew S.K., Taouk Y., Xie J., Nicolaou T.E., Wang J.J., Wong T.Y., Lamoureux E.L. Relationship between diabetic retinopathy, diabetic macular edema and erectile dysfunction in type 2 diabetics. Clin Exp Ophthalmol. 2013;41(7):683-689. doi: 10.1111/ceo.12099.

10. Kotov S.V., Kalinin A.P., Rudakova I.G. Diabetic neuropathy. 2nd ed. Moscow: Meditsinskoye informatsionnoye agentstvo; 2011. 439 p. (In Russ.)

11. Galstyan G.R. Diabetic neuropathy. In: Dedov I.I., Shestakova M.V. (ed.). Diabetes mellitus: acute and chronic complications. Moscow: Meditsinskoye informatsionnoye agentstvo; 2011, pp. 353-365. (In Russ.) Available at: https://elibrary.ru/item.asp?id=18911411.

12. Belova A.N., Kudykin M.N., Sheiko G.E. Diabetic peripheral neuropathy: epidemiology, pathogenesis, clinic, diagnostics, treatment. Rossiyskiy mediko-biologicheskiy vestnik imeni akademika I.P. Pavlova = I.P. Pavlov Russian Medical Biological Herald. 2016;24(4):139-51. (In Russ.) doi: 10.23888/PAVLOVJ20164139-151.

13. Kotov A.S. Diabetic polyneuropathy: a literature review. Effektivnaya farma-koterapiya. Ehndokrinologiya = Effective pharmacotherapy. Endocrinology. 2011;(5):44-8. (In Russ.) Available at: h https://umedp.ru/articles/diabet-icheskaya_polinevropatiya_obzor_literatury.html.

14. Pop-Busui R., Low P.A., Waberski B.H., Martin C.L., Albers J.W., Feldman E.L. 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(22):2886-2893. doi: 10.1161/CIRCULATIONAHA.108.837369.

15. Pop-Busui R., Braffett B.H., Zinman B., Martin C., White N.H., William H.H., et al. Cardiovascular autonomic neuropathy and cardiovascular outcomes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. Diabetes Care. 2017;40(1):94-100. doi: 10.2337/dc16-1397.

16. Braffett B.H., Gubitosi-Klug R.A., Albers J.W., Feldman E.L., Martin C.L., White N.H. et al. DCCT/EDIC Research Group. Risk Factors for Diabetic Peripheral Neuropathy and Cardiovascular Autonomic Neuropathy in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study. Diabetes. 2020;69(5):1000-1010. doi: 10.2337/db19-1046.

17. Chernikov A.A., Severina A.S., Shamkhalova M.S., Shestakova M.V. The role of «metabolic memory» mechanisms in the development and progression of vascular complications of diabetes mellitus. Sakharnyy diabet = Diabetes Mellitus. 2017;20(2):126-134. (In Russ.) doi: 10.14341/7674.

18. Kempler P., Tesfaye S., Chaturvedi N., Stevens L.K., Webb D.J. et al. EURODIAB IDDM Complications Study Group. Autonomic neuropathy is associated with increased cardiovascular risk factors: the EURODIAB IDDM Complications Study. Diabet Med. 2002;19(11):900-909. doi: 10.1046/j.1464-5491.2002.00821.x.

19. Semikova D.A., Belova N.V., Grishina D.A., Antonova K.V., Suponeva N.A. Diabetic smallfiber neuropathy. Effektivnaya farmakoterapiya. Endokrinologiya. = Effective pharmacotherapy. Endocrinology. 2018;(5-6):32-38. (In Russ.) Available at: https://umedp.ru/articles/diabeticheskaya_tonkovolokonnaya_polineyropatiya.html.

20. Korei A.E., Istenes I., Papanas N., Kempler P. Smallfiber neuropathy: a diabetic microvascular complication of special clinical, diagnostic, and prognostic importance. Angiology. 2016;67(1):49-57. doi: 10.1177/0003319715583595.

21. Biryukova E.V. Complications in diabetes mellitus: diabetic neuropathy focus. Meditsinskiy sovet = Medical Council. 2018;(4):48-52. (In Russ.) Available at: doi: 10.21518/2079-701X-2018-4-48-52.

22. Dimova R., Tankova T., Guergueltcheva V., Tournevc I., Chakarova N., Grozeva G., Dakovska L. Risk factors for autonomic and somatic nerve dysfunction in different stages of glucose tolerance. J Diabetes Complications. 2017;31(3):537-543. doi: 10.1016/j.jdiacomp.2016.11.002.

23. Vinik A.I., Maser R.E., Mitchell B.D., Freeman R. Diabetic Autonomic Neuropathy. Diabetes Care. 2003;26(5):1553-1579. doi: 10.2337/diac-are.26.5.1553.

24. Pop-Busui R., Boulton A.J., Feldman E.L., Bril V., Freeman R., Malik R.A., Sosenko J.M., Ziegler D. Diabetic neuropathy: a position statement by the American Diabetes Association. Diabetes Care. 2017;40(1):136-154. doi: 10.2337/dc16-2042.

25. Horvath VJ., Vittal H., Lorincz A., Chen H., Almeida-Porada G., Redelman D., Ordog T. Reduced stem cell factor links smooth myopathy and loss of interstitial cells of cajal in murine diabetic gastroparesis. Gastroenterology. 2006;130(3):759-770. doi: 10.1053/j.gastro.2005.12.027.

26. Ordog T., Hayashi Y., Gibbons S.J. Cellular pathogenesis of diabetic gastro-enteropathy. Minerva Gastroenterol Dietol. 2009;55(3):315-343. Available at: https://mayoclinic.pure.elsevier.com/en/publications/cellular-pathogenesis-of-diabetic-gastroenteropathy.

27. Kurniawan A.H., Suwandi B.H., Kholili U. Diabetic Gastroenteropathy: A Complication of Diabetes Mellitus. Acta Med Indones. 2019;51(3):263-271. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31699951.

28. Meldgaard T., Keller J., Olesen A.E., Olesen S.S., Krogh K., Borre M. et al. Pathophysiology and management of diabetic gastroenteropathy. Therap Adv Gastroenterol. 2019;12:1-17. doi: 10.1177/1756284819852047.

29. Bharucha A.E., Camilleri M., Forstrom L., Zinsmeister A.R. Relationship between clinical features and gastric emptying disturbances in diabetes mellitus. Clin Endocrinol (Oxf). 2008;70(3):415-420. doi: 10.1111/j.1365-2265.2008.03351.x.

30. Hyett B., Martinez F.J., Gill B.M., Mehra S., Lembo A., Kelly C.P., Leffler D.A. Delayed radionucleotide gastric emptying studies predict morbidity in diabetics with symptoms of gastroparesis. Gastroenterology. 2009;137(2):445-452. doi: 10.1053/j.gastro.2009.04.055.

31. Iltz J.L., Baker D.E., Setter S.M., Keith Campbell R. Exenatide: an incretin mimetic for the treatment of type 2 diabetes mellitus. Clin Ther. 2006;28(5):652-665. doi: 10.1016/j.clinthera.2006.05.006.

32. Kostitska I.O. Prospects of exenatide in the treatment of diabetic gastro-paresis. Mir Mediciny i Biologii = World of Medicine and Biology. 2016;(3):113-118. (In Russ.) Available at: https://womab.com.ua/smb-2016-03/6215.

33. Filippov Yu. Gastroenterological disorders in diabetic neuropathy. Vrach = Doctor. 2011;(4):96-101. (In Russ.) Available at: https://elibrary.ru/item.asp?id=15635038.

34. Avdeev V.G. Diabetic enteropathy. Farmateka. 2010;(3):46-49. (In Russ.) Available at: https://pharmateca.ru/ru/archive/article/7736.

35. Codario R.A. Type 2 diabetes, pre-diabetes, and the metabolic syndrome: the primary care guide to diagnosis and management. 2nd ed. Humana Press Inc.; 2010. 384 p. doi: 10.1007/978-1-60327-441-8.

36. Osipenko M.F., Vorontsova Ye.S., Zhuk Ye.A. Gastroenterological symptoms in type 2 diabetes. Eksperimental'naya i klinicheskaya gastroenterologiya = Experimental and Clinical Gastroenterology. 2015;(3):84-89. (In Russ.) Available at: https://elibrary.ru/item.asp?id=233423355.

37. Shul'pekova Yu.O. Gastroenterological manifestations of autonomic diabetic neuropathy. RMZH. Bolezni organov pishchevareniya = RMJ. Digestive Apparatus Diseases. 2011;(17):1111-1118. (In Russ.) Available at: https://www.gastroscan.ru/literature/authors/6794.

38. Kunitsyna M.A., Kashkina Ye.I., Semikina T.M. The dynamics of the formation of diabetic autonomic neuropathy and gallbladder disease in patients with type 2 diabetes. Medicinskij al'manah. = Medical Almanac. 2018;(1):67-71. (In Russ.) Available at: https://elibrary.ru/item.asp?id=32827414.

39. Zhukova Ye.V., Kunitsyna M.A., Kashkina Ye.I., Semikina T.M. Formation an Atypical Clinical Pictureof Chronic Cholecystitis in Patients Suffering From Type 2 Diabetes Mellitus Burdened with Diabetic Autonomic Neuropathy. Trudnyj pacient = Difficult Patient. 2018;16(3):37-40. (In Russ.) Available at: http://t-pacient.ru/wp-content/uploads/2018/04/7.pdf.

40. Galstyan G.R., Starostina E.G., Yakhno N.N., Gurieva I.V., Churyukanov M.V., Strokov I.A., Tokmakova A.Y., Kukushkin M.L., Martynov A.I., Shestakova M.V. Diagnosis and rational treatment of painful diabetic peripheral neuropathy: an interdisciplinary expert consensus. Sakharnyy diabet = Diabetes Mellitus. 2019;22(4):305-327. (In Russ.) doi: 10.14341/DM9625.

41. Frier B.M. Impaired Awareness of Hypoglycemia. In: Frier B.M., Heller S.R., McCrimmon R.J. (ed.). Hypoglycemia. 3rd ed. Hoboken: John Wiley& Sons; 2014, pp. 114-144.

42. Klimontov V.V. Impaired hypoglycemia awareness in diabetes: epidemiology, mechanisms and therapeutic approaches. Sakharnyy diabet = Diabetes Mellitus. 2018;21(6):513-523. (In Russ.) doi: 10.14341/DM9597.