BRAIN METABOLITES ANALYSIS IN PATIENTS WITH TYPE 2 DIABETES AND COGNITIVE IMPAIREMENT

DOI: https://doi.org/10.29296/24999490-2019-04-04

M.V. Matveeva(1), Y.G. Samoilova(1), N.G. Zhukova(1), D.A. Kudlay(2) 1-Siberian State Medical University, Moscow Road, 2, Tomsk, 634050, Russian Federation; 2-State Research Center «Institute of Immunology» of the Federal Medical-Biological Agency, Kashirskoye sh., 24, Moscow, 115522, Russian Federation E-mail: matveeva.mariia@yandex.ru

Introduction. Type 2 diabetes mellitus (DM) is a metabolic disease characterized by prolonged hyperglycemia, which can cause various complications. Some studies have reported on the relationship between changes in cerebral metabolism and glucose levels. The aim of the study. Assessment of the content of brain metabolites in patients with type 2 diabetes. Methods. The study was an observational, one-stage, one-time, selective. Objects – patients with type 2 diabetes aged 45–65 years. All subjects were sampled to determine fasting plasma glucose, glycated hemoglobin (HbA1c), and tau protein. To assess the variability of glycemia was assessed using continuous monitoring for 14 days. Neuropsychological testing was performed using the Montreal cognitive dysfunction scale (MoCA test). Neurochemical changes in the brain were studied using proton spectroscopy (1HMRS) and the analysis of the following metabolites: N-acetylaspartate (NAA), choline (Cho), creatine (Cr), creatine phosphate (Cr2). The main indicators that were determined during this study were fasting glucose levels, HbA1c, glycemic variability coefficients, tau protein levels, MoCA test results, and the content of brain metabolites in the hippocampus. Results. As a result, 48 patients with type 2 diabetes were examined. The level of tau protein in serum was increased in the presence of cognitive disorders and amounted to 44,6 pg/ml, its increase is associated with age, high HbA1c (r=0,211, p=0,034; r=0,342, p=0,006). An increase in glycemia variability coefficients is recorded. Patients with type 2 diabetes have cognitive impairment, the MoCA test was 20 points on average. There is an increase in NAA and Cho of the hippocampal region. It has been found that elevated NAA levels are found in patients with high tau protein content, and high HbA1c levels, glycemia lability index and average glucose value in patients with type 2 diabetes with a reduced Cr level in the hippocampus region. Conclusion. Type 2 diabetes occurs with cognitive impairment, changes in brain metabolism and increased tau protein. The model for predicting cognitive impairment according to 1HMRS in patients with type 2 diabetes is 79%.
Keywords: 
type 2 diabetes mellitus, cognitive impairment, proton spectroscopy, metabolites, glycemic variability

Список литературы: 
  1. Biessels G.J., Kappelle A.C., Bravenboer B. et al. Cerebral function in diabetes mellitus.Diabetologia. 1994; 37 (7): 6.
  2. Strachan M.W., Price J.F., Frier B.M. Diabetes, cognitive impairment, and dementia. BMJ. 2008; 336 (7634): 6.
  3. Mukesh G. Gohel, Evaluation of glycemic control in patients with type 2 diabetes mellitus with and without microvascular complications International. Journal of Pharma and Bio Sciences. 2013; 4 (4): 794–802.
  4. Ross B., Bluml S. Magnetic resonance spectroscopy of the human brain. Anat Rec. 2001; 265 (2): 54–84.
  5. Самойлова Ю.Г., Ротканк М.А., Жукова Н.Г., Матвеева М.В., Толмачев И.В., Тонких О.С., Кудлай Д.А. Применение магнитно-резонансных методов исследования головного мозга у пациентов с сахарным диабетом 1-го типа и когнитивной дисфункцией. Неврологический журнал. 2018; 23 (2): 86–92. [Samoylova Ju.G., Rotkank M.A., Zhukova N.G., Matveeva M.V., Tolmachev I.V., Tonkih O.S., Kudlay D.A. Application of magnetic resonance methods of brain research in patients with type 1 diabetes mellitus and cognitive dysfunction. Nevrologicheskiy zhurnal. 2018; 23 (2): 86–92 (in Russian)]
  6. Самойлова Ю.Г., Ротканк М.А., Жукова Н.Г., Матвеева М.В., Толмачев И.В., Кудлай Д.А. Вариабельность гликемии у пациентов с сахарным диабетом 1-го типа: связь с когнитивной дисфункцией и данными магнитно-резонансных методов исследования. Проблемы Эндокринологии. 2018. 64 (5): 286-291. [Samoylova Ju.G., Rotkank M.A., Zhukova N.G., Matveeva M.V., Tolmachev I.V., Kudlay D.A. Variability of glycaemia in patients with diabetes mellitus of the 1st type: relationship with cognitive dysfunction and data magnetic resonance methods of research. Problemy Jendokrinologii. 2018; 64 (5): 286–91 (in Russian)]
  7. Williams SR. In vivo proton spectroscopy: experimental aspects and potential. In: Rudin M, editor. NMR basic principles and progress. Berlin: Springer, 1992; 55–71.
  8. Sahin I., Alkan A., Keskin L. et al. Evaluation of in vivo cerebral metabolism on proton magnetic resonance spectroscopy in patients with impaired glucose tolerance and type 2 diabetes mellitus. J. Diabetes Complications. 2008; 22 (4): 254–60.
  9. Kreis R., Ross B.D. Cerebral metabolic disturbances in patients with subacute and chronic diabetes mellitus: detection with proton MR spectroscopy. Radiology. 1992; 184 (1): 123–30.
  10. Modi S., Bhattacharya M., Sekhri T. et al. Assessment of the metabolic profile in Type 2 diabetes mellitus and hypothyroidism through proton MR spectroscopy.Magn Reson Imaging. 2008; 26 (3): 420–5.
  11. Иванов Р., Секарева Г., Кравцова О., Кудлай Д., Лукьянов С., Тихонова И., Демин А., Максумова Л., Никитина И., Обухов А., Зайцев Д., Сте-панов А., Носырева М., Самсонов М. Правила проведения исследова-ний биоаналоговых лекарственных средств (биоаналогов). Фармако-кинетика и фармакодинамика. 2014; 1: 21–36.
  12. [Ivanov R., Sekaryova G., Kravcova O., Kudlay D., Luk’yanov S., Tihonova I., Dyomin A., Maksumova L., Nikitina I., Obuhov A., Zaycev D., Stepanov A., Nosyreva M., Samsonov M. Rules for conducting research on biosimilar drugs (biosimilars). Farmakokinetika i farmakodinamika. 2014; 1: 21–36 (in Russian)]
  13. Biessels G.J., Deary I.J., Ryan C.M. Cognition and diabetes: a lifespan perspective. Lancet Neurol. 2008; 7 (2): 184–90.
  14. Xiao-Ying Yuan. Mild cognitive impairment in type 2 diabetes mellitus and related risk factors: a review. Published Online: 2017-07-12. DOI: https://doi.org/10.1515/revneuro-2017-0016»-2017-0016
  15. Rdzak G.M., Abdelghany O. Does insulin therapy for type 1 diabetes mellitus protect against Alzheimer’s disease? Pharmacotherapy. 2014; 34 (12): 1317–23. doi: https://doi.org/10.1002/phar.1494. Epub 2014 Oct 3.
  16. Clodfelder-Miller B.J., Zmijewska A.A., Johnson G.V., Jope R.S. Tau is hyperphosphorylated at multiple sites in mouse brain in vivo after streptozotocin-induced insulin deficiency. Diabetes. 2006; 55 (12): 3320–5.
  17. Zhou Y., Zhao Y., Xie H. et al. Alteration in amyloid β42, phosphorylated tau protein, interleukin 6, and acetylcholine during diabetes-accelerated memory dysfunction in diabetic rats: correlation of amyloid β42 with changes in glucose metabolism. Behav Brain Funct. 2015; 11: 24. doi: https://doi.org/10.1186/s12993-015-0069-5.
  18. Sinha S., Ekka M., Sharma U. et al. Assessment of changes in brain metabolites in Indian patients with type-2 diabetes mellitus using proton magnetic resonance spectroscopy. BMC Res. 2014; 7: 1–7. https://doi.org/10.1186/1756-0500-7-41.
  19. Sahin I., Alkan A., Keskin L. et al. Evaluation of in vivo cerebral metabolism on proton magnetic resonance spectroscopy in patients with impaired glucose tolerance and type 2 diabetes mellitus. J. Diabetes Complications. 2008; 22 (4): 254–60.
  20. Rae C.D. A guide to the metabolic pathways and function of metabolites observed in human brain 1H magnetic resonance spectra. Neurochem Res. 2014; 39 (1): 1–36.
  21. Gujar S.K., Maheshwari S., Björkman-Burtscher I., Sundgren P.C. Magnetic resonance spectroscopy. J. Neuroophthalmol. 2005; 25 (3): 217–26.
  22. Ross B., Bluml S. Magnetic resonance spectroscopy of the human brain. Anat Rec. 2001; 265 (2): 54–84.
  23. Wang Y., Xu X.Y., Feng C.H. et al. Patients with type 2 diabetes exhibit cognitive impairment with changes of metabolite concentration in the left hippocampus. Metab. Brain Dis. 2015; 30:м 1027–34. https://doi.org/10.1007/s11011-015-9670-4