Diabetes mellitus as a result of neuroimmunoendocrine disorders

The review article presents an analysis of domestic and foreign scientific literature devoted to the study of neuroimmune disorders leading to the development of diabetes mellitus. It has been established that the nervous, immune and endocrine systems act as a regulatory triad that maintains the constancy of the organism and dysfunctional changes in one of the systems, lead to changes in others, which is accompanied by the launch of various pathological processes. The unity of the regulatory triad is explained by the structural and functional features of the hypothalamic-pituitary system, the dysregulation of which can act as a triggering mechanism for the development of both nervous and endocrine and immune pathologies, while the initial link in the pathology of each system can be dysregulation disorders in other integrative systems. Thus, disturbances in the melanocortin and dopamine signaling systems, as well as immune-mediated destruction of insulin-producing cells in the pancreas, can lead to diabetes. The cause of the development of diabetes mellitus is also considered an immune pathology, accompanied by a violation of cytokine regulation, namely the predominance of pro-inflammatory cytokines, such as IL-1β, IL-2, TNF-α, etc. In turn, diabetes mellitus can cause disorders from the nervous (neuropathy), immune (decreased body resistance), blood circulation (angiopathy), as well as other body systems. Based on the data of the World Health Organization about an excessively high increase in the incidence of diabetes mellitus, the aggravating development of comorbid pathologies, as a result of leading to disability of the population, a detailed study of the mechanisms of the development of this disease is necessary in order to further search for new means of correcting pathological conditions.

immune system, nervous system, endocrine system, neuroimmunoendocrinology, diabetes mellitus

1. Alekseev L.P., Dedov I.I., Khaitov R.M., Boldyreva M.N., Trofimov D.Yu., Peterkova V.A., Kuraeva T.L., Abramov D.D. Immunogenetics of type 1 diabetes - from basic research to the clinic. Annals of the Russian academy of medical sciences. 2012;67(1):75-80 (in Russ.). DOI: 10.15690/vramn.v67i1.114

2. Beloglazov V.A., Kochukova G.N., Alekseeva A.A. The interaction of the main regulatory systems of the body. Crimean journal of internal diseases. 2007;2(2-9):24-30 (in Russ.).

3. Ivanov V.V., Shakhristova E.V., Stepovaya E.A., Litvyakov N.V., Perekucha N.A., Nosareva O.L., Fedorova T.S., Novitskiy V.V. Oxidative stress in the pathogenesis of type 1 diabetes: the role of adipocyte xanthine oxidase. Bulletin of Siberian Medicine. 2017;16(4):134-143 (in Russ.). DOI: 10.20538/1682-0363-2017-4-134-143

4. Kryzhanovsky G.N. Disregulatory pathology. Pathological physiology and experimental therapy. 2002;3:1-29 (in Russ.).

5. Kryzhanovsky G.N., Magaeva S.V. Pathophysiology of neuroimmune interactions. Patogenez. 2010;8(1):4-9 (in Russ.).

6. Kuznetsov E.V., Zhukova L.A., Pakhomova E.A., Gulamov A.A. Endocrine deseases as medical-social prolem of today. Sovremennye problemy nauki i obrazovaniya. 2017;4:62 (in Russ.). URL: http://science-education.ru/ru/article/view?id=26662

7. Kurumchina O.B., Shnayder N.A., Petrova M.M., Kirichkova G.A. Genetic aspects of diabetes mellitus. Bulletin of Novosibirsk State University. Series: Biology, Clinical Medicine. 2009;7(1):129-135 (in Russ.)

8. Mazur L.P. State of the α-factor system of tumor necrosis in type 1 and type 2 diabetes. Vestnik problem biologii i meditsiny. 2014;1-4 (113):156-160 (in Ukr.).

9. Parakhonsky A.P. neuroimmune endocrine interactions to the regulation of homeostasis. Modern high technologies. 2007;8:45-47 (in Russ.).

10. Parakhonsky A.P., Tsyganok S.S. Basic principles of correction of dysregulatory pathology. Advances in current natural sciences. 2003;12:60-61 (in Russ.).

11. Prokhorenko T.S., Saprina T.V., Lazarenko F.E., Ryazantseva N.V., Vorozhtsova I.N., Novitsky V.V. System of tumor necrosis factor α in the pathogenesis of autoimmune diabetes mellitus. Bulletin of Siberian Medicine. 2011;10(1):64-69 (in Russ.).

12. Ryzhkov P.A., Ryzhkova N.S., Konovalova R.V. Genetics of type I diabetes. Zhivye biokosnye sist. 2013;4:14 (in Russ.). URL: http://jbks.ru/archive/issue-4/article-14

13. Tatarkin A.A., tatarkina N.D., Andryukov B.G. Neuroimmunoendocrine interactions in the system of intercellular functional multilevel regulation of homeostasis. Health. Medical ecology. Science. 2010;3(43):13-17 (in Russ.).

14. Farkhutdinov I.M., Farkhutdinova L.M. Geoecological aspects of type 2 diabetes mellitus. Bulletin of the Academy of Sciences. 2016;21(3-83):31 (in Russ.).

15. Shapovalyants O.S., Nikonova T.V. Diagnostic and prognostic value of autoantibodies for diabetes mellitus. a novel T1D autoimmunity target - zinc transporter 8 (ZNT8). Sakharnyy diabet. 2011;2:18-21 (in Russ.).

16. Shpakov A.O. Functional activity of the brain insulin signaling sys tem in norm and in type 2 diabetes mellitus. Russian journal of physiology. 2015;101(10):1103-1127 (in Russ.).

17. Shpakov A.O., Derkach K.V. Melanocortin signaling system of the hypothalamus and its functional state in the conditions of type 2 diabetes mellitus and metabolic syndrome. Russian journal of physiology. 2016;102(1):18-40 (in Russ.).

18. Shpakov A.O., Derkach K.V. The brain peptidergic signaling systems in diabetes mellitus. Cell and tissue biology. 2013;7(3):212-220. DOI: 10.1134/S1990519X13030115

19. Shpakov A.O., Derkach K.V., Sukhov I.B. Dopamine signaling system of the brain in type 2 diabetes and metabolic syndrome. Tsitologiya. 2016;58(3):167-177 (in Russ.).

20. Afrisham R., Paknejad M., Soliemanifar O., Sadegh-Nejadi S., Meshkani R., Ashtary-Larky D. The Influence of Psychological Stress on the Initiation and Progression of Diabetes and Cancer. Int J Endocrinol Metab. 2019;17(2):e67400. DOI: 10.5812/ijem.67400

21. Akmaev I.G. Neuroimmunoendocrine interactions: their role in dysregulatory pathologies. Patol Fiziol Eksp Ter. 2001;(4):3-10

22. Anders A.F.S. Encephalopathies: the emerging diabetic complications. Acta Diabetol. 2010;47(4):279-293. DOI: 10.1007/s00592-010-0218-0

23. Andersen M.K., Hansen T. Genetic Aspects of Latent Autoimmune Diabetes in Adults: A Mini-Review. Curr Diabetes Rev. 2019;15(3):194-198. DOI: 10.2174/1573399814666180730123226

24. Aslan I.R., Ranadive S.A., Valle I., Kollipara S., Noble J.A., Vaisse C. The melanocortin system and insulin resistance in humans: insights from a patient with complete POMC deficiency and type 1 diabetes mellitus. Int J Obes (Lond). 2014;38(1):148-51. DOI: 10.1038/ijo.2013.53

25. Assar M.E., Angulo J., Rodríguez-Mañas L. Diabetes and ageing-induced vascular inflammation. J Physiol. 2016;594(8):2125-2146. DOI: 10.1113/JP270841

26. Bakshi D., Kaur G., Singh D., Sahota J., Thakur A., Grover S. Estimation of Plasma Levels of Tumor Necrosis Factor-a, Interleukin-4 and 6 in Patients with Chronic Periodontitis and Type II Diabetes Mellitus. J Contemp Dent Pract. 2018;19(2):166-169. DOI: 10.5005/jp-journals-10024-2231

27. Berchtold L.A., Prause M., Stоrling J., Mandrup-Poulsen T. Cytokines and pancreatic β-cell apoptosis. Adv Clin Chem. 2016;75:99-158. DOI: 10.1016/bs.acc.2016.02.001

28. Calderon B., Unanue E.R. Antigen presentation events in autoimmune diabetes. Curr Opin Immunol. 2012;24(1):119-128. DOI: 10.1016/j.coi.2011.11.005

29. Chiloiro S., De Marinis L. Diabetes insipidus is an unfavorable prognostic factor for response to glucocorticoids in patients with autoimmune hypophysitis. Eur J Endocrinol. 2018;178(2):L1. DOI: 10.1530/EJE-17-0910

30. Cuschieri S. The genetic side of type 2 diabetes - A review. Diabetes Metab Syndr. 2019;13(4):2503-2506. DOI: 10.1016/j.dsx.2019.07.012

31. Donath M.Y., Dinarello C.A., Mandrup-Poulsen T. Targeting innate immune mediators in type 1 and type 2 diabetes. Nat Rev Immunol. 2019;19(12):734-746. DOI: 10.1038/s41577-019-0213-9

32. Feldman E.L., Callaghan B.C., Pop-Busui R., Zochodne D.W., Wright D.E., Bennett D.L., Bril V., Russell J.W., et al. Diabetic neuropathy. Nat Rev Dis Primers. 2019;13;5(1):42. DOI: 10.1038/s41572-019-0097-9

33. Fève B., Bastard J.P. The role of interleukins in insulin resistance and type 2 diabetes mellitus. Nat Rev Endocrinol. 2009;5(6):305-311. DOI: 10.1038/nrendo.2009.62

34. Fiory F., Perruolo G., Cimmino I., Cabaro S., Pignalosa F.C., Miele C., Beguinot F., Formisano P., et al. The Relevance of Insulin Action in the Dopaminergic System. Front Neurosci. 2019;13:868. DOI: 10.3389/fnins.2019.00868

35. Frisbee J.C. Obesity, insulin resistance, and microvascular adaptation. Microcirculation. 2017;24(2). DOI: 10.1111/micc.12346

36. Girardet C., Butler A.A. Neural melanocortin receptors in obesity and related metabolic disorders. Biochim Biophys Acta. 2014;1842(3):482-494. DOI: 10.1016/j.bbadis.2013.05.004

37. Goligorsky M.S. Vascular endothelium in diabetes. Am J Physiol Renal Physiol. 2017;312(2):F266-F275. DOI: 10.1152/ajprenal.00473.2016

38. Hardt P.D, Ewald N. Exocrine pancreatic insufficiency in diabetes mellitus: a complication of diabetic neuropathy or a different type of diabetes? Exp Diabetes Res. 2011;2011:761950. DOI: 10.1155/2011/761950

39. Herder C., Carstensen M., Ouwens D.M. Anti-inflammatory cytokines and risk of type 2 diabetes. Diabetes Obes Metab. 2013;15 Suppl 3:39-50. DOI: 10.1111/dom.12155

40. Howson J.M., Walker N.M., Clayton D., Todd J.A. Confirmation of HLA class II independent type 1 diabetes associations in the major histocompatibility complex including HLA-B and HLA-A. Diabetes Obes Metab. 2009;11 Suppl 1(Suppl 1):31-45. DOI: 10.1111/j.1463-1326.2008.01001.x

41. Kakleas K., Soldatou A., Karachaliou F., Karavanaki K. Associated autoimmune diseases in children and adolescents with type 1 diabetes mellitus (T1DM). Autoimmun Rev. 2015;14(9):781-797. DOI: 10.1016/j.autrev.2015.05.002

42. Karayannis G., Giamouzis G., Cokkinos D., Skoularigis J., Triposkiadis F. Diabetic cardiovascular autonomic neuropathy: clinical implications. Expert Rev Cardiovasc Ther. 2012;10(6):747-765. DOI: 10.1586/erc.12.53

43. Kibel A., Selthofer-Relatic K., Drenjancevic I., Bacun T., Bosnjak I., Kibel D., Gros M. Coronary microvascular dysfunction in diabetes mellitus. J Int Med Res. 2017;45(6):1901-1929. DOI: 10.1177/0300060516675504

44. King G.L. The role of inflammatory cytokines in diabetes and its complications. J Periodontol. 2008;79(8 Suppl):1527-1534. DOI: 10.1902/jop.2008.080246

45. Langenberg C., Lotta L.A. Genomic insights into the causes of type 2 diabetes. Lancet. 2018;391(10138):2463-2474. DOI: 10.1016/S0140-6736(18)31132-2

46. Laugesen E., Оstergaard J.A., Leslie R.D, Danish Diabetes Academy Workshop and Workshop Speakers. Latent autoimmune diabetes of the adult: current knowledge and uncertainty. Diabet Med. 2015; l-32(7):843-852. DOI: 10.1111/dme.12700

47. Lindner J.R. Cause or Effect? Microvascular Dysfunction in Insulin-Resistant States. Circ Cardiovasc Imaging. 2018;11(4):e007725 DOI: 10.1161/CIRCIMAGING.118.007725

48. Maiese K. New Insights for Oxidative Stress and Diabetes Mellitus. Oxid Med Cell Longev. 2015;2015:875961. DOI: 10.1155/2015/875961

49. Mandrup-Poulsen T., Pickersgill L., Donath M.Y. Blockade of interleukin 1 in type 1 diabetes mellitus. Nat Rev Endocrinol. 2010;6(3):158-166. DOI: 10.1038/nrendo.2009.271

50. Meek T.H., Matsen M.E., Damian V., Cubelo A., Chua S.C. Jr., Morton G.J. Role of melanocortin signaling in neuroendocrine and metabolic actions of leptin in male rats with uncontrolled diabetes. Endocrinology. 2014;155(11):4157-4167. DOI: 10.1210/en.2014-1169

51. Mizisin A.P. Mechanisms of diabetic neuropathy: Schwann cells. Handb Clin Neurol. 2014;126:401-428. DOI: 10.1016/B978-0-444-53480-4.00029-1

52. Nederstigt C., Uitbeijerse B.S., Janssen L.G.M., Corssmit E.P.M., de Koning E.J.P., Dekkers O.M. Associated auto-immune disease in type 1 diabetes patients: a systematic review and meta-analysis. Eur J Endocrinol. 2019;180(2):135-144. DOI: 10.1530/EJE-18-0515

53. Nokoff N., Rewers M. Pathogenesis of type 1 diabetes: lessons from natural history studies of high-risk individuals. Ann N Y Acad Sci. 2013;1281(1):1-15. DOI: 10.1111/nyas.12021

54. Sadosky A., Schaefer C., Mann R., Bergstrom F., Baik R., Parsons B., Nalamachu S., Nieshoff E., et al. Burden of illness associated with painful diabetic peripheral neuropathy among adults seeking treatment in the UC: results of retrospective charts review and cross-sectional survey. Diabetes Metab Syndr Obes. 2013;6:79-92. DOI: 10.2147/DMSO.S37415

55. Saxena M., Srivastava N., Banerjee M. Cytokine Gene Variants as Predictors of Type 2 Diabetes Mellitus. Curr Diabetes Rev. 2018;14(3):307-319. DOI: 10.2174/1573399813666170112145429

56. Strain W.D., Paldánius P.M. Diabetes, cardiovascular disease and the microcirculation. Cardiovasc Diabetol. 2018;17(1):57. DOI: 10.1186/s12933-018-0703-2

57. Valdes A.M., Erlich H.A., Noble J.A. Human leukocyte antigen class I B and C loci contribute to type 1 diabetes (T1D) susceptibility and age at T1D onset. Hum Immunol. 2005;66:301-313. DOI: 10.1016/j.humimm.2004.12.001

58. Vinik A.I., Nevoret M.L., Casellini C., Parson H. Diabetic neuropathy. Endocrinol Metab Clin North Am. 2013;42(4):747-787. DOI: 10.1016/j.ecl.2013.06.001

59. Volmer-Thole M., Lobmann R. Neuropathy and Diabetic Foot Syndrome. Int J Mol Sci. 2016;10;17(6):917. DOI: 10.3390/ijms17060917

60. Xiao J., Li J., Cai L., Chakrabarti S., Li X. Cytokines and diabetes research. J Diabetes Res. 2014;2014:920613. DOI: 10.1155/2014/920613

61. Zakin E., Abrams R., Simpson D.M. Diabetic Neuropathy. Semin Neurol. 2019;39(5):560-569. DOI: 10.1055/s-0039-1688978

62. Ziegler D., Papanas N., Vinik A.I., Shaw J.E. Epidemiology of polyneuropathy in diabetes and prediabetes. Handb Clin Neurol. 2014;126:3-22. DOI: 10.1016/B978-0-444-53480-4.00001-1