REVIEW ARTICLE

Pathophysiology

doi: 10.25005/2074-0581-2023-25-3-370-379
LABORATORY BIOMARKERS FOR BRAIN DAMAGE IN DIABETES MELLITUS

Yu.V. Bykov1,2, A.A. Muravyova1

1Department of Anesthesiology and Intensive Care with a Course of Additional Professional Education, Stavropol State Medical University, Stavropol, Russian Federation
2Children's City Clinical Hospital named after G.K. Philippskiy, Stavropol, Russian Federation

Objective: This review outlines the literature data on the main laboratory biomarkers of brain damage in diabetes mellitus (DM) type I and II. Neurospecific proteins: S-100 protein, neurospecific enolase, glial fibrillar acidic protein, myelin basic protein, and brain-derived neurotrophic factor (BDNF) are considered specific markers of cerebral dysfunction in DM. Emphasis is placed on pro-inflammatory cytokines (IL-1, IL-6, tumor necrosis factor-α, C-reactive protein), as blood biomarkers, the increase of which indicates brain damage in DM type I and II. High concentrations of adipokines, inflammatory mediators of adipose tissue, are a reliable laboratory sign of brain damage in this endocrinopathy. Advanced glycation end products (AGEs), as pathogenic metabolites of oxidative stress (OS), detected in blood in high concentration, can act as indicators of cognitive deficit in DM. Increased concentration of autoantibodies to some neuroreceptors (dopamine, glutamate) may serve as specific laboratory biomarkers of brain damage in DM type I. Further searches of new laboratory biomarkers of brain dysfunction are needed in order to improve the diagnosis of cerebral insufficiency in DM

Keywords: Diabetes mellitus, biomarkers, brain damage, neurospecific proteins, adipokines.

Download file:


References
  1. Zhao X, Han Q, Lv Y, Sun L, Gang X, Wang G. Biomarkers for cognitive decline in patients with diabetes mellitus: Evidence from clinical studies. Oncotarget. 2018;9(7):7710-26. https://doi.org/10.18632/oncotarget.23284
  2. Rozanska O, Uruska A, Zozulinska-Ziolkiewicz D. Brain-derived neurotrophic factor and diabetes. Int J Mol Sci. 2020;21(3):841. https://doi.org/10.3390/ ijms21030841
  3. Bykov YuV. Oksidativnyy stress i diabeticheskaya entsefalopatiya: patofiziologicheskie mekhanizmy [Oxidative stress and diabetic encephalopathy: pathophysiological mechanisms]. Sovremennye problemy nauki i obrazovaniya. 2022;6-2:39. https://doi.org/10.17513/spno.32314
  4. Geijselaers SLC, Sep SJS, Stehouwer CDA, Biessels GJ. Glucose regulation, cognition, and brain MRI in type 2 diabetes: A systematic review. Lancet Diabetes & Endocrinology. 2015;3:75-89. https://doi.org/10.1016/S2213-8587(14)70148- 2
  5. Willette AA, Bendlin BB, Starks EJ, Birdsill AC, Johnson SC, Christian BT, et al. Association of insulin resistance with cerebral glucose uptake in late middle-aged adults at risk for Alzheimer disease. JAMA Neurology. 2015;72:1013- 20. https://doi.org/10.1001/jamaneurol.2015.0613
  6. Moran C, Beare R, Phan TG, Bruce DG, Callisaya ML, Srikanth V. Type 2 diabetes mellitus and biomarkers of neurodegeneration. Neurology. 2015;85:1123-30. https://doi.org/10.1212/WNL.0000000000001982
  7. Biessels GJ, Nobili F, Teunissen CE, Simó R, Scheltens P. Understanding multifactorial brain changes in type 2 diabetes: A biomarker perspective. Lancet Neurol. 2020;19(8):699-710. https://doi.org/10.1016/S1474-4422(20)30139-3
  8. Markelova EV, Zenina AA, Kadyrov RV. Neyropeptidy kak markyory povrezhdeniya golovnogo mozga [Neuropeptides as markers of brain damage]. Sovremennye problemy nauki i obrazovaniya. 2018;5:206.
  9. Fasshauer M, Blüher M. Adipokines in health and disease. Trends Pharmacol Sci. 2015;36(7):461-70. https://doi.org/ 10.1016/j.tips.2015.04.014
  10. Menzel A, Samouda H, Dohet F, Loap S, Ellulu MS, Bohn T. Common and novel markers for measuring inflammation and oxidative stress ex vivo in research and clinical practice – which to use regarding disease outcomes? Antioxidants (Basel). 2021;10(3):414. https://doi.org/ 10.3390/antiox10030414
  11. Arnason S, Molewijk K, Henningsson AJ, Tjernberg I, Skogman BH. Brain damage markers neuron-specific enolase (NSE) and S100B in serum in children with Lyme neuroborreliosis-detection and evaluation as prognostic biomarkers for clinical outcome. Eur J Clin Microbiol Infect Dis. 2022;41(7):1051-7. https://doi. org/ 10.1007/s10096-022-04460-1
  12. Ryan CM, van Duinkerken E, Rosano C. Neurocognitive consequences of diabetes. Am Psychol. 2016;71(7):563-76. https://doi.org/10.1037/a0040455
  13. Sergi D, Renaud J, Simola N, Martinoli MG. Diabetes, a contemporary risk for Parkinson’s disease: Epidemiological and cellular evidences. Front Aging Neurosci. 2019;11:302. https://doi.org/10.3389/fnagi.2019.00302
  14. Wootton-Gorges SL, Buonocore MH, Kuppermann N, Marcin JP, Barnes PD, Neely EK, et al. Cerebral proton magnetic resonance spectroscopy in children with diabetic ketoacidosis. Am J Neuroradiol. 2007;28:895-9.
  15. Poittevin M, Bonnin P, Pimpie C, Rivière L, Sebrié C, Dohan A, et al. Diabetic microangiopathy: Impact of impaired cerebral vasoreactivity and delayed angiogenesis after permanent middle cerebral artery occlusion on stroke damage and cerebral repair in mice. Diabetes. 2015;64(3):999-1010. https://doi. org/10.2337/db14-0759
  16. Wang DQ, Wang L, Wei MM, Xia XS, Tian XL, Cui XH, et al. Relationship between type 2 diabetes and white matter hyperintensity: A systematic review. Front Endocrinol (Lausanne). 2020;11:595962. https://doi.org/10.3389/fendo.2020.595962
  17. Newby D, Garfield V. Understanding the inter-relationships of type 2 diabetes and hypertension with brain and cognitive health: A UK Biobank study. Diabetes Obes Metab. 2022;24(5):938-47. https://doi.org/10.1111/dom.14658
  18. Skripchenko NV, Shirokova AS. Neyrospetsificheskaya enolaza i belok S100 – biomarkyory povrezhdeniya golovnogo mozga. Sostoyanie voprosa i klinicheskoe primenenie [Neurospecific enolase and protein S100 are biomarkers of brain damage. The state of the issue and clinical application]. Neyrokhirurgiya i nevrologiya detskogo vozrasta. 2016;4:16-25.
  19. Samoylova YuG, Novosyolova MV, Kostyunina AK, Zhukova NG, Tonkikh OS. Prediktory razvitiya entsefalopatii u patsientov s sakharnym diabetom [Predictors of encephalopathy development in patients with diabetes mellitus]. Problemy endokrinologii. 2013;5:67-71. https://doi.org/10.14341/probl201359567-71
  20. Bykov YuV, Uglova TA. Autoantitela k belku S-100V kak prediktor tyazhesti techeniya sakharnogo diabeta 1 tipa u detey [Autoantibodies to protein S100 B as a predictor of the severity of type 1 diabetes mellitus in children]. Meditsinskiy vestnik Severnogo Kavkaza. 2022;1:31-3. https://doi.org/10.14300/ mnnc.2022.17009
  21. Lotosh HG, Savel'eva EK, Selishcheva AA, Savel'ev SV. Autoantibodies to neuron-specific proteins S100, GFAP, MBP and NGF in the serum of rats with streptozotocin-induced diabetes. Bull Exp Biol Med. 2013;155(1):48-51. https://doi. org/10.1007/s10517-013-2077-5
  22. McIntyre EA, Abraha HD, Perros P, Sherwood RA. Serum S-100beta protein is a potential biochemical marker for cerebral oedema complicating severe diabetic ketoacidosis. Diabet Med. 2000;17:807-9. https://doi.org/10.1046/j.1464- 5491.2000.00370.x
  23. Yarets YuI, Malkov AB. Neyrospetsificheskie belki krovi v diagnostike doklinicheskikh form diabeticheskoy distal'noy polineyropatii [Neurospecific blood proteins in the diagnosis of preclinical forms of diabetic distal polyneuropathy]. Problemy zdorov'ya i ekologii. 2018;2:60-6.
  24. Hafner A, Glavan G, Obermajer N, Živin M, Schliebs R, Kos J. Neuroprotective role of γ-enolase in microglia in a mouse model of Alzheimer’s disease is regulated by cathepsin X. Aging Cell. 2013;12(4):604-14. https://doi.org/ 10.1111/ acel.12093
  25. Yu ZW, Liu R, Li X, Wang Y, Fu YH, Li HY, et al. High serum neuron-specific enolase level is associated with mild cognitive impairment in patients with diabetic retinopathy. Diabetes Metab Syndr Obes. 2020;13:1359-65. https://doi. org/10.2147/DMSO.S249126
  26. Hamed S, Metwalley KA, Farghaly HS, Sherief T. Serum levels of neuron-specific enolase in children with diabetic ketoacidosis. J Child Neurol. 2017;32(5):475- 81. https://doi.org/10.1177/0883073816686718
  27. Gonzalez-Quevedo A, González-García S, Hernández-Díaz Z, Concepción OF, Sotolongo LQ, Peña-Sánchez M, et al. Serum neuron specific enolase could predict subclinical brain damage and the subsequent occurrence of brain related vascular events during follow up in essential hypertension. J Neurol Sci. 2016;363:158-63. https://doi.org/10.1016/j.jns.2016.02.052
  28. Pang Z, Kushiyama A, Sun J, Kikuchi T, Yamazaki H, Iwamoto Y, et al. Glial fibrillary acidic protein (GFAP) is a novel biomarker for the prediction of autoimmune diabetes. FASEB J. 2017;31(9):4053-63. https://doi.org/10.1096/ fj.201700110R
  29. Baydas G, Nedzvetskii VS, Tuzcu M, Yasar A, Kirichenko SV. Increase of glial fibrillary acidic protein and S-100B in hippocampus and cortex of diabetic rats: Effects of vitamin E. Eur J Pharmacol. 2003;462(1-3):67-71. https://doi. org/10.1016/s0014-2999(03)01294-9
  30. Ayala-Guerrero L, García-delaTorre P, Sánchez-García S, Guzmán-Ramos K. Serum levels of glial fibrillary acidic protein association with cognitive impairment and type 2 diabetes. Arch Med Res. 2022;53(5):501-7. https://doi. org/10.1016/j.arcmed.2022.06.001
  31. Galiano MR, Andrieux A, Deloulme JC, Bosc C, Schweitzer A, Job D, et al. Myelin basic protein functions as a microtubule stabilizing protein in differentiated oligodendrocytes. J Neurosci Res. 2006;84(3):534-41. https://doi.org/10.1002/ jnr.20960
  32. Pesaresi M, Giatti S, Calabrese D, Maschi O, Caruso D, Melcangi RC. Dihydroprogesterone increases the gene expression of myelin basic protein in spinal cord of diabetic rats. J Mol Neurosci. 2010;42(2):135-9. https://doi.org/10.1007/ s12031-010-9344-y
  33. Nam SM, Kwon HJ, Kim W, Kim JW, Hahn KR, Jung HY, et al. Changes of myelin basic protein in the hippocampus of an animal model of type 2 diabetes. Lab Anim Res. 2018;34(4):176-84. https://doi.org/10.5625/lar.2018.34.4.176
  34. Samoylova YuG, Novosyolova MV, Zhukova NG., Tonkikh OS. Analiz roli neyrospetsificheskikh belkov v diagnostike kognitivnoy disfunktsii u patsientov s sakharnym diabetom [Analysis of the role of neurospecific proteins in the diagnosis of cognitive dysfunction in patients with diabetes mellitus]. Sakharnyy diabet. 2014;2:83-90. https://doi.org/10.14341/DM2014283-90
  35. Ehtewish H, Arredouani A, El-Agnaf O. Diagnostic, Prognostic, and mechanistic biomarkers of diabetes mellitus-associated cognitive decline. Int J Mol Sci. 2022;23(11):6144. https://doi.org/10.3390/ijms23116144
  36. Zhen YF, Zhang J, Liu XY, Fang H, Tian LB, Zhou DH, et al. Low BDNF is associated with cognitive deficits in patients with type 2 diabetes. Psychopharmacology. 2012;227:93-100. https://doi.org/10.1007/s00213-012-2942-3
  37. Murillo Ortiz B, Ramirez Emiliano J, Ramos-Rodriguez E, Martinez-Garza S, Macias-Cervantes H, Solorio-Meza S, et al. Brain-derived neurotrophic factor plasma levels and premature cognitive impairment/dementia in type 2 diabetes. World J Diabetes. 2016;7:615-20. https://doi.org/10.4239/wjd.v7.i20.615
  38. Passaro A, Nora ED, Morieri ML, Soavi C, Sanz JM, Zurlo A, et al. Brain-derived neurotrophic factor plasma levels: Relationship with dementia and diabetes in the elderly population. Journals Gerontol. Ser. A. 2014;70:294-302. https://doi. org/10.1093/gerona/glu028
  39. Zilliox LA, Chadrasekaran K, Kwan JY, Russell JW. Diabetes and cognitive impairment. Curr Diab Rep. 2016;16:87. https://doi.org/10.1007/s11892-016- 0775-x
  40. Gaspar JM, Babtista FI, Macedo MP, Ambrósio AF. Inside the diabetic brain: Role of different players involved in cognitive decline. ACS Chem Neurosci. 2016;7:131-42. https://doi.org/10.1021/acschemneuro.5b00240
  41. Marioni RE, Strachan MW, Reynolds RM, Lowe GD, Mitchell RJ, Fowkes FGR, et al. Association between raised inflammatory markers and cognitive decline in elderly people with type 2 diabetes: The Edinburgh Type 2 Diabetes Study. Diabetes. 2010;59:710-3. https://doi.org/10.2337/db09-1163
  42. Gorska-Ciebiada M, Saryusz-Wolska M, Borkowska A, Ciebiada M, Loba J. Serum levels of inflammatory markers in depressed elderly patients with diabetes and mild cognitive impairment. PLoS ONE. 2015;10:e0120433. https://doi. org/10.1371/journal.pone.0120433
  43. Liu Y, Liu F, Grundke-Iqbal I, Iqbal K, Gong CX. Deficient brain insulin signalling pathway in Alzheimer’s disease and diabetes. J Pathol. 2011;225:54-62. https://doi.org/10.1002/path.2912
  44. Arnoldussen IA, Kiliaan AJ, Gustafson DR. Obesity and dementia: Adipokines interact with the brain. Eur Neuropsychopharmacol. 2014;24:1982-99. https:// doi.org/10.1016/j.euroneuro.2014.03.002
  45. Davis C, Mudd J, Hawkins M. Neuroprotective effects of leptin in the context of obesity and metabolic disorders. Neurobiol Dis. 2014;72:61-71. https://doi. org/10.1016/j.nbd.2014.04.012
  46. Labad J, Price JF, Strachan MW, Deary IJ, Seckl JR, Sattar N, et al. Serum leptin and cognitive function in people with type 2 diabetes. Neurobiol Aging. 2012;33:2938-41.e2. https://doi.org/10.1016/j.neurobiolaging.2012.02.026
  47. Garcia-Casares N, Garcia-Arnes JA, Rioja J, Ariza MJ, Gutierrez A, Alfaro F, et al. Alzheimer’s like brain changes correlate with low adiponectin plasma levels in type 2 diabetic patients. J Diabetes Complications. 2016;30:281-6. https://doi. org/ 10.1016/j.jdiacomp.2015.12.001
  48. Evans JL, Goldfine ID, Maddux BA, Grodsky GM. Oxidative stress and stress-activated signaling pathways: A unifying hypothesis of type 2 diabetes. Endocrinol Rev. 2002;23:599-622. https://doi.org/10.1210/er.2001-0039
  49. Yang Y, Hu SH, Zhang JH, Zhang MX. Alzheimer-like hyperphosphorylation of tau in brains of rats with obesity and type 2 diabetes. Prog Biochem Biophys. 2006;33:458-64
  50. Spauwen PJJ, Van Eupen MGA, Köhler S, Stehouwer CDA, Verhey FRJ, Van Der Kallen CJH, et al. Associations of advanced glycation end-products with cognitive functions in individuals with and without type 2 diabetes: The Maastricht Study. J Clin Endocrinol Metab. 2015;100:951-60. https://doi.org/10.1210/ jc.2014-2754
  51. Wang P, Huang R, Lu S, Xia W, Cai R, Sun H, Wang S. RAGE and AGEs in mild cognitive impairment of diabetic patients: A cross-sectional study. PLoS ONE. 2016;11:e0145521. https://doi.org/10.1371/journal.pone.0145521
  52. Robinson R, Krishnakumar A, Paulose CS. Enhanced dopamine D1 and D2 receptor gene expression in the hippocampus of hypoglycaemic and diabetic rats. Cell Mol Neurobiol. 2009;29(3):365-72. https://doi.org/10.1007/s10571- 008-9328-4
  53. Qaddumi WN, Jose PA. The role of the renal dopaminergic system and oxidative stress in the pathogenesis of hypertension. Biomedicines. 2021;9(2):139. https://doi.org/10.3390/biomedicines9020139
  54. Bykov YuV, Baturin VA. Opredelenie urovney autoantitel k neyroretseptoram u detey bol'nykh sakharnym diabetom 1-go tipa [Determination of levels of autoantibodies to neuroreceptors in children with type 1 diabetes mellitus]. Patologicheskaya fiziologiya i eksperimental'naya terapiya. 2022;66(4):61-6. https://doi.org/10.25557/0031-2991.2022.04.61-66

Author information:


Bykov Yuriy Vitalievich,
Candidate of Medical Sciences, Assistant of the Department of Anesthesiology and Intensive Care with a Course of Additional Professional Education, Stavropol State Medical University; Anesthesiologist, Children's City Clinical Hospital named after G.K. Philippskiy
ORCID ID: 0000-0003-4705-3823
E-mail: yubykov@gmail.com

Muravyova Alla Anatolievna,
Candidate of Medical Sciences, Assistant of the Department of Anesthesiology and Intensive Care with a Course of Additional Professional Education, Stavropol State Medical University
ORCID ID: 0000-0002-4460-870X
Е-mail: muravyeva81@mail.ru

Information about support in the form of grants, equipment, medications

The authors did not receive financial support from manufacturers of medicines and medical equipment

Conflicts of interest: No conflict

Address for correspondence:


Bykov Yuriy Vitalievich
Candidate of Medical Sciences, Assistant of the Department of Anesthesiology and Intensive Care with a Course of Additional Professional Education, Stavropol State Medical University

355031, Russian Federation, Stavropol, Mira str., 310

Теl.: +7 (962) 4430492

E-mail: yubykov@gmail.com

Materials on the topic: