Ukr.Biochem.J. 2023; Volume 95, Issue 2, Mar-Apr, pp. 48-57

doi: https://doi.org/10.15407/ubj95.02.048

Oxydative stress in type 2 diabetic patients: involvement of HIF-1 alpha AND mTOR genes expression

Y. A. Saenko1, O. O. Gonchar2*, I. M. Mankovska2,
T. I. Drevytska2, L. V. Bratus2, B. M. Mankovsky1,3

1SI “The Scientific and Practical Medical Center of Pediatric Cardiology and Cardiac Surgery
of the Ministry of Health of Ukraine”, Clinic for Adults, Kyiv;
2Department of Hypoxia, Bogomoletz Institute of Physiology,
National Academy of Sciences of Ukraine, Kyiv;
3Shupyk National Healthcare University of Ukraine, Kyiv;
*e-mail:olga.gonchar@i.ua

Received: 22 March 2023; Revised: 25 May 2023;
Accepted: 05 June 2023; Available on-line:  20 June 2023

Biochemical and genetic mechanisms of oxidative stress (OS) developing in the blood of patients with type 2 Diabetes mellitus (T2DM) were studied. Twenty patients with T2DM and 10 healthy persons participated in this study. Lipid peroxidation, the content of protein carbonyls and H2O2 production were measured in blood plasma and erythrocytes as OS biomarkers. Activity of SOD, catalase, and GPx as well as reduced glutathionе (GSH) level in plasma and erythrocytes were estimated. The gene expression of key regulators of oxygen and metabolic homeostasis (HIF-1α and mTOR) in leukocytes were studied. It was found a significant rise in TBARS and protein carbonyls content in plasma as well as H2O2 production in erythrocytes from patients with T2DM compared to control. The diabetic patients also demonstrated an increase in the SOD and catalase activity in plasma and significantly lower GSH content and GPx activity in erythrocytes compared to the healthy participants. The established marked inhibition of mTOR gene expression and the tendency to an increase in HIF-1α gene expression in leukocytes of patients with T2DM may serve as a protective mechanism which counteracts OS developing and oxidative cell damage.

Keywords: , , ,


References:

  1. Piconi L, Quagliaro L, Ceriello A. Oxidative stress in diabetes. Clin Chem Lab Med. 2003;41(9):1144-1149. PubMed, CrossRef
  2. Moussa SA. Oxidative stress in diabetes mellitus. Romanian J Biophys. 2008;18(3):225-236.
  3. Sivitz WI, Yorek MA. Mitochondrial dysfunction in diabetes: from molecular mechanisms to functional significance and therapeutic opportunities. Antioxid Redox Signal. 2010;12(4):537-577. PubMed, PubMedCentral, CrossRef
  4. Kayama Y, Raaz U, Jagger A, Matti A, Adam M, Schellinger IN, Sakamoto M, Suzuki H, Toyama K, Spin JM, Tsao PS. Diabetic Cardiovascular Disease Induced by Oxidative Stress. Int J Mol Sci. 2015;16(10):25234-25263. PubMed, PubMedCentral, CrossRef
  5. Yasuda-Yamahara M, Kume S, Maegawa H. Roles of mTOR in Diabetic Kidney Disease. Antioxidants (Basel). 2021;10(2):321. PubMed, PubMedCentral, CrossRef
  6. Catrina SB, Zheng X. Hypoxia and hypoxia-inducible factors in diabetes and its complications. Diabetologia. 2021;64(4):709-716. PubMed, PubMedCentral, CrossRef
  7. Bandeira SM, Guedes GS, da Fonseca LJ, Pires AS, Gelain DP , Moreira JC, Rabelo LA, Vasconcelos SM, Goulart MO. Characterization of blood oxidative stress in type 2 diabetes mellitus patients: increase in lipid peroxidation and SOD activity. Oxid Med Cell Longev. 2012;2012:819310. PubMed, PubMedCentral, CrossRef
  8. Padalkar RK, Shinde AV, Patil SM. Lipid profile, serum malondialdehyde, superoxide dismutase in chronic kidney diseases and type 2 diabetes mellitus. Biomed Res. 2012;23(2):207-210.
  9. Mendoza-Núñez VM, García-Martínez BI, Rosado-Pérez J, Rosado-Pérez J, Santiago-Osorio E, Pedraza-Chaverri J, Hernández-Abad VJ. The Effect of 600 mg Alpha-lipoic Acid Supplementation on Oxidative Stress, Inflammation, and RAGE in Older Adults with Type 2 Diabetes Mellitus. Oxid Med Cell Longev. 2019;2019:3276958. PubMed, PubMedCentral, CrossRef
  10. Tavares AM, Silva JH, Bensusan OCh, Ferreira ACF, de Lima Matos LP, de Araujo E Souza KL, de Carvalho Cardoso-Weide L, Taboada GF. Altered superoxide dismutase-1 activity and intercellular adhesion molecule 1 (ICAM-1) levels in patients with type 2 diabetes mellitus. PLoS One. 2019;14(5):e0216256. PubMed, PubMedCentral, CrossRef
  11. Nakhjavani M, Esteghamati A, Nowroozi S, Asgarani F, Rashidi A, Khalilzadeh O. Type 2 diabetes mellitus duration: an independent predictor of serum malondialdehyde levels. Singapore Med J. 2010;51(7):582-585. PubMed
  12. Kolesnichenko T, Bardimova E, Sergeeva M, Sergeeva N, Verlan N, Belouova I. Glutathione antioxidant system in patients with diabetes mellitus. J Clin Lipidol. 2008;2(5):S124-S125. CrossRef
  13. Mendez MM, Folgado J, Tormo C, Artero A, Ascaso M, Martinez-Hervás S, Chaves FJ, Ascaso JF, Real JT. Altered glutathione system is associated with the presence of distal symmetric peripheral polyneuropathy in type 2 diabetic subjects. J Diabetes Complications. 2015;29(7):923-927. PubMed, CrossRef
  14.  Gunton JE. Hypoxia-inducible factors and diabetes. J Clin Invest. 2020;130(10):5063-5073. PubMed, PubMedCentral, CrossRef
  15. López-Cano C, Gutiérrez-Carrasquilla L, Barbé F, Sánchez E, Hernández M, Martí R, Ceperuelo-Mallafre V, Dalmases M, Fernández-Veledo S, Vendrell J, Hernández C, Simó R, Lecube A. Effect of Type 2 Diabetes Mellitus on the Hypoxia-Inducible Factor 1-Alpha Expression. Is There a Relationship with the Clock Genes? J Clin Med. 2020;9(8):2632. PubMed, PubMedCentral, CrossRef
  16. Persson P, Palm F. Hypoxia-inducible factor activation in diabetic kidney disease. Curr Opin Nephrol Hypertens. 2017;26(5):345-350.
    PubMed, CrossRef
  17. 17. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274-293. PubMed, PubMedCentral, CrossRef
  18. Mao Z, Zhang W. Role of mTOR in Glucose and Lipid Metabolism. Int J Mol Sci. 2018;19(7):2043. PubMed, PubMedCentral, CrossRef
  19. Maiese K. Novel nervous and multi-system regenerative therapeutic strategies for diabetes mellitus with mTOR. Neural Regen Res. 2016;11(3):372-385. PubMed, PubMedCentral, CrossRef
  20. Buege JA, Aust SD. Microsomal lipid peroxidation. Methods Enzymol. 1978;52:302-310. PubMed, CrossRef
  21. Levine RL, Garland D, Oliver CN, Amici A, Climent I, Lenz AG, Ahn BW, Shaltiel S, Stadtman ER. Determination of carbonyl content in oxidatively modified proteins. Methods Enzymol. 1990;186:464-478. PubMed, CrossRef
  22. Wolff SP. Ferrous ion oxidation in presence of ferric ion indicator xylenol orange for measurement of hydroperoxides. Methods Enzymol. 1994; 233: 182-189. CrossRef
  23. Misra HP, Fridovich I. The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem. 1972;247(10):3170-3175. PubMed, CrossRef
  24. Aebi H. Catalase. In: Methods of Enzymatic Analysis, Ed: Bergmeyer, H.U. Weinheim and Academic Press. 1983:227-282.
  25. Flohé L, Günzler WA. Assays of glutathione peroxidase. Methods Enzymol. 1984;105:114-121. PubMed, CrossRef
  26. Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem. 1968;25(1):192-205. PubMed, CrossRef
  27. Beal MF. Oxidatively modified proteins in aging and disease. Free Radic Biol Med. 2002;32(9):797-803. PubMed, CrossRef
  28. Naskalski JW, Bartosz G. Oxidative modifications of protein structures. Adv Clin Chem. 2000;35:161-253. PubMed, CrossRef
  29. Stadtman ER, Levine RL. Free radical-mediated oxidation of free amino acids and amino acid residues in proteins. Amino Acids. 2003;25(3-4):207-218. PubMed, CrossRef
  30. Pandey KB, Mishra N, Rizvi SI. Protein oxidation biomarkers in plasma of type 2 diabetic patients. Clin Biochem. 2010;43(4-5):508-511. PubMed, CrossRef
  31. Gradinaru D, Borsa C, Ionescu C, Margina D. Advanced oxidative and glycoxidative protein damage markers in the elderly with type 2 diabetes. J Proteomics. 2013;92:313-322. PubMed, CrossRef
  32. Soliman GZA. Blood lipid peroxidation (superoxide dismutase, malondialdehyde, glutathione) levels in Egyptian type 2 diabetic patients. Singapore Med J. 2008;49(2):129-136. PubMed
  33. Niedowicz DM, Daleke DL. The role of oxidative stress in diabetic complications. Cell Biochem Biophys. 2005;43(2):289-330.PubMed, CrossRef
  34. Padalkar RK, Shinde AV, Patil SM. Lipid profile, serum malondialdehyde,superoxide dismutase in chronic kidney diseases and type 2 diabetes mellitus. Biomed Res. 2012;23:207-210.
  35. Kumawat M, Pahwa MB, Gahlaut VS, Singh N. Status of antioxidant enzymes and lipid peroxidation in type 2 diabetes mellitus with micro vascular complications. Open Endocrinol J. 2009;3(1):12-15. CrossRef
  36. Al-Nimer MS, Al-Ani FS, Ali FS. Role of nitrosative and oxidative stress in neuropathy in patients with type 2 diabetes mellitus. J Neurosci Rural Pract. 2012;3(1):41-44. PubMed, PubMedCentral, CrossRef
  37. Mezzetti A, Cipollone P, Cuccurullo F. Oxidative stress and cardiovascular complications in diabetes: isoprostanes as new markers on an old paradigm. Cardiovasc Res. 2000;47(3):475-488. PubMed, CrossRef
  38. Koyasu S, Kobayashi M, Goto Y, Hiraoka M, Harada H. Regulatory mechanisms of hypoxia-inducible factor 1 activity: Two decades of knowledge. Cancer Sci. 2018;109(3):560-571. PubMed, PubMedCentral, CrossRef
  39. Zhang H, Basch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, Gonzalez, Semenza GL. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem. 2008;283(16):10892-10903. PubMed, PubMedCentral, CrossRef
  40. Weidemann A, Johnson RS. Biology of HIF-1alpha. Cell Death Differ. 2008;15(4):621-627. PubMed, CrossRef
  41. Botusan IR, Sunkari VG, Savu O, Catrina AI, Grünler J, Lindberg S, Pereira T, Ylä-Herttuala S, Poellinger L, Brismar K, Catrina SB. Stabilization of HIF-1alpha is critical to improve wound healing in diabetic mice. Proc Natl Acad Sci USA. 2008;105(49):19426-19431. PubMed, PubMedCentral, CrossRef
  42. Liu Y, Palanivel R, Rai E, Park M, Gabor TV, Scheid MP, Xu A, Sweeney G. Adiponectin stimulates autophagy and reduces oxidative stress to enhance insulin sensitivity during high-fat diet feeding in mice. Diabetes. 2015;64(1):36-48. PubMed, CrossRef
  43. Yu T, Li L, Chen T, Liu Z, Liu H, Li Z. Erythropoietin attenuates advanced glycation endproducts-induced toxicity of Schwann cells in vitro. Neurochem Res. 2015;40(4):698-712. PubMed, CrossRef
  44. Sanghera KP, Mathalone N, Baigi R, Panov E, Wang D, Zhao X, Hsu H, Wang H, Tropepe V, Ward M, Boyd SR. The PI3K/Akt/mTOR pathway mediates retinal progenitor cell survival under hypoxic and superoxide stress. Mol Cell Neurosci. 2011;47(2):145-153. PubMed, CrossRef
  45. Ryou MG, Choudhury GR, Li W, Winters A, Yuan F, Lui R, Yang SH. Methylene blue-induced neuronal protective mechanism against hypoxia-reoxygenation stress. Neuroscience. 2015;301:193-203. PubMed, PubMedCentral, CrossRef
  46. Wang L, Di L, Noguchi CT. AMPK is involved in mediation of erythropoietin influence on metabolic activity and reactive oxygen species production in white adipocytes. Int J Biochem Cell Biol. 2014;54:1-9. PubMed, PubMedCentral, CrossRef

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License.