Ukr.Biochem.J. 2019; Volume 91, Issue 5, Sep-Oct, pp. 46-54


The effect of quercetin on oxidative stress markers and mitochondrial permeability transition in the heart of rats with type 2 diabetes

N. I. Gorbenko1, O. Yu. Borikov2, O. V. Ivanova1, E. V. Taran1,
Т. S. Litvinova1, T. V. Kiprych1, A. S. Shalamai3

1V. Danilevsky Institute of Endocrine Pathology Problems, National Academy of Medical Sciences of Ukraine, Kharkiv;
2V. N. Karazin Kharkiv National University, Ukraine;
3PJSC SIC “Borshchahivskiy Chemical-Pharmaceutical Plant”, Kyiv, Ukraine;

Received: 24 June 2019; Accepted: 13 August 2019

Increasing evidence suggests that oxidative stress and induction of mitochondrial permeability transition in cardiomyocytes are linked to tissue damage and the development of diabetic cardiovascular complications. The aim of this study was to assess the effects of quercetin (Q) on oxidative stress and mitochondrial permeability transition in the heart of rats with type 2 diabetes mellitus (DM). Type 2 DM was induced in 12-week-old male Wistar rats by intraperitoneal injections of 25 mg/kg streptozotocin twice per week followed by a high-fat diet during four weeks. The rats were divided into three groups: control intact group (C, n = 8), untreated diabetic group (Diabetes, n = 8) and diabetic rats treated with Q (50 mg/kg/day per os for 8 weeks) after diabetes induction (Diabetes+Q, n = 8). Administration of Q increased insulin sensitivity and normali­zed the functional state of cardiac mitochondria due to increased aconitase and succinate dehydrogenase activities in rats with type 2 DM. Q also ameliorated oxidative stress, decreasing the level of advanced oxidation protein products and increasing the activity of thioredoxin-reductase in heart mitochondria of diabetic rats. In addition, Ca2+-induced opening of the mitochondrial permeability transition pore was significantly inhibited in diabetic rats treated with Q in comparison with the untreated diabetic group. These data demonstrate that Q can protect against oxidative stress, mitochondrial permeability transition induction and mitochondrial dysfunction in cardiomyocytes of diabetic rats. We suggest that the use of Q may contribute to the amelioration of cardiovascular risk in type 2 DM.

Keywords: , , , ,


  1. IDF Diabetes Atlas / International Diabetes Federation. 8th ed. Brussels, Belgium, 2017. 145 p.
  2. Tate M, Grieve DJ, Ritchie RH. Are targeted therapies for diabetic cardiomyopathy on the horizon? Clin Sci (Lond). 2017 May 1;131(10):897-915. PubMed, CrossRef
  3. Fisher-Wellman KH, Neufer PD. Linking mitochondrial bioenergetics to insulin resistance via redox biology. Trends Endocrinol Metab. 2012 Mar;23(3):142-53.  PubMed, PubMedCentral, CrossRef
  4. Kayama Y, Raaz U, Jagger 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 Oct 23;16(10):25234-63. PubMed, PubMedCentral, CrossRef
  5. Zhou T, Prather ER, Garrison DE, Zuo L. Interplay between ROS and Antioxidants during Ischemia-Reperfusion Injuries in Cardiac and Skeletal Muscle. Int J Mol Sci. 2018 Jan 31;19(2). pii: E417. PubMed, PubMed, CrossRef
  6. Bai T, Wang F, Zheng Y, Liang Q, Wang Y, Kong J, Cai L. Myocardial redox status, mitophagy and cardioprotection: a potential way to amend diabetic heart? Clin Sci (Lond). 2016 Sep 1;130(17):1511-21. PubMed, CrossRef
  7. Brown DI, Griendling KK. Regulation of signal transduction by reactive oxygen species in the cardiovascular system. Circ Res. 2015 Jan 30;116(3):531-49. PubMed, PubMedCentral, CrossRef
  8. Takimoto E, Kass DA. Role of oxidative stress in cardiac hypertrophy and remodeling. Hypertension. 2007 Feb;49(2):241-8. PubMed, CrossRef, PubMedCentral
  9. Lin S, Yang J, Wu G, Liu M, Luan X, Lv Q, Zhao H, Hu J. Preventive effect of taurine on experimental type II diabetic nephropathy. J Biomed Sci. 2010 Aug 24;17(Suppl 1):S46.  PubMed, PubMedCentral, CrossRef
  10. Bowe JE, Franklin ZJ, Hauge-Evans AC, King AJ, Persaud SJ, Jones PM. Metabolic phenotyping guidelines: assessing glucose homeostasis in rodent models. J Endocrinol. 2014 Sep;222(3):G13-25. PubMed, CrossRef
  11. Di Lisa F, Menabò R, Barbato R, Siliprandi N. Contrasting effects of propionate and propionyl-L-carnitine on energy-linked processes in ischemic hearts. Am J Physiol. 1994 Aug;267(2 Pt 2):H455-61. PubMed, CrossRef
  12. Talbot DA, Brand MD. Uncoupling protein 3 protects aconitase against inactivation in isolated skeletal muscle mitochondria. Biochim Biophys Acta. 2005 Sep 5;1709(2):150-6. PubMed, CrossRef
  13. Anastacio MM, Kanter EM, Keith AD, Schuessler RB, Nichols CG, Lawton JS. Inhibition of Succinate Dehydrogenase by Diazoxide Is Independent of the ATP-Sensitive Potassium Channel Subunit Sulfonylurea Type 1 Receptor. J Am Coll Surg. 2013 Jun;216(6):1144-9. PubMed, PubMedCentral, CrossRef
  14. Arnér ES, Zhong L, Holmgren A. Preparation and assay of mammalian thioredoxin and thioredoxin reductase. Methods Enzymol. 1999;300:226-39. PubMed
  15. Taylor EL, Armstrong KR, Perrett D, Hattersley AT, Winyard PG. Optimization of an advanced oxidation protein products assay: its application to studies of oxidative stress in diabetes mellitus. Oxid Med Cell Longev. 2015; 2015:496271.  CrossRef
  16. Lowry O, Rosenbrought NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265-75. PubMed
  17. Di Lisa F, Menabò R, Canton M, Barile M, Bernardi P. Opening of the mitochondrial permeability transition pore causes depletion of mitochondrial and cytosolic NAD+ and is a causative event in the death of myocytes in postischemic reperfusion of the heart. J Biol Chem. 2001 Jan 26;276(4):2571-5. PubMed, CrossRef
  18. Shi GJ, Li Y, Cao QH, Wu HX, Tang XY, Gao XH, Yu JQ, Chen Z, Yang Y. In vitro and in vivo evidence that quercetin protects against diabetes and its complications: A systematic review of the literature. Biomed Pharmacother. 2019 Jan;109:1085-1099. PubMed, CrossRef
  19. Gasparrini M, Giampieri F, Alvarez Suarez J M, Mazzoni L, Y Forbes Hernandez T, Quiles JL, Bullon P, Battino M. AMPK as a New Attractive Therapeutic Target for Disease Prevention: The Role of Dietary Compounds AMPK and Disease Prevention. Curr Drug Targets. 2016;17(8):865-89. PubMed, CrossRef
  20. Piwowar A, Knapik-Kordecka M, Warwas M. AOPP and its relations with selected markers of oxidative/antioxidative system in type 2 diabetes mellitus. Diabetes Res Clin Pract. 2007 Aug;77(2):188-92. PubMed, CrossRef
  21. 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 Oct 30;92:313-22.  PubMed, CrossRef
  22.  Zhang H, Xiong Z, Wang J, Zhang S, Lei L, Yang L, Zhang Z. Glucagon-like peptide-1 protects cardiomyocytes from advanced oxidation protein product-induced apoptosis via the PI3K/Akt/Bad signaling pathway. Mol Med Rep. 2016 Feb;13(2):1593-601.  PubMed, PubMedCentralCrossRef
  23. Conrad M, Jakupoglu C, Moreno SG, Lippl S, Banjac A, Schneider M, Beck H, Hatzopoulos AK, Just U, Sinowatz F, Schmahl W, Chien KR, Wurst W, Bornkamm GW, Brielmeier M. Essential role for mitochondrial thioredoxin reductase in hematopoiesis, heart development, and heart function. Mol Cell Biol. 2004 Nov;24(21):9414-23. PubMed, PubMedCentral, CrossRef
  24. Yoshioka J. Thioredoxin Reductase 2 (Txnrd2) Regulates Mitochondrial Integrity in the Progression of Age-Related Heart Failure. J Am Heart Assoc. 2015 Jul 21; 4(7). pii: e002278. PubMed, PubMedCentral, CrossRef
  25. Martins AR, Nachbar RT, Gorjao R, Vinolo MA, Festuccia WT, Lambertucci RH, Cury-Boaventura MF, Silveira LR, Curi R, Hirabara SM. Mechanisms underlying skeletal muscle insulin resistance induced by fatty acids: importance of the mitochondrial function. Lipids Health Dis. 2012 Feb 23;11:30. PubMed, PubMedCentral, CrossRef
  26. Stanley WC, Recchia FA. Lipotoxicity and the development of heart failure: moving from mouse to man. Cell Metab. 2010 Dec 1;12(6):555-6. PubMed, PubMedCentral, CrossRef
  27. Fernandez-Marcos PJ, Auwerx J. Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis.  Am J Clin Nutr. 2011 Apr;93(4):884S-90. PubMed, PubMedCentral, CrossRef
  28. Ventura-Clapier R, Garnier A, Veksler V. Transcriptional control of mitochondrial biogenesis: the central role of PGC-1alpha. Cardiovasc Res. 2008 Jul 15;79(2):208-17. PubMed, CrossRef
  29. Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science. 2009 Aug 14;325(5942):834-40. PubMed, CrossRef
  30. Iyer A, Fairlie DP, Brown L. Lysine acetylation in obesity, diabetes and metabolic disease. Immunol Cell Biol. 2012 Jan;90(1):39-46.  PubMed, CrossRef
  31. Shi L, Zhang T, Zhou Y, Zeng X, Ran L, Zhang Q, Zhu J, Mi M. Dihydromyricetin improves skeletal muscle insulin sensitivity by inducing autophagy via the AMPK-PGC-1α-Sirt3 signaling pathway. Endocrine. 2015 Nov;50(2):378-89.  PubMed, CrossRef
  32. Riojas-Hernández A, Bernal-Ramírez J, Rodríguez-Mier D, Morales-Marroquín FE, Domínguez-Barragán EM, Borja-Villa C, Rivera-Álvarez I, García-Rivas G, Altamirano J, García N. Enhanced oxidative stress sensitizes the mitochondrial permeability transition pore to opening in heart from Zucker Fa/fa rats with type 2 diabetes. Life Sci. 2015;141(15):32-43. PubMed, CrossRef
  33. Halestrap AP, McStay GP, Clarke SJ. The permeability transition pore complex: another view. Biochimie. 2002 Feb-Mar;84(2-3):153-66. PubMed, CrossRef
  34. De Marchi U, Biasutto L, Garbisa S, Toninello A, Zoratti M. Quercetin can act either as an inhibitor or an inducer of the mitochondrial permeability transition pore: A demonstration of the ambivalent redox character of polyphenols. Biochim Biophys Acta. 2009 Dec;1787(12):1425-32. PubMed, CrossRef
  35. de Oliveira MR, Nabavi SM, Braidy N, Setzer WN, Ahmed T, Nabavi SF. Quercetin and the mitochondria: A mechanistic view. Biotechnol Adv. 2016 Sep-Oct;34(5):532-549. PubMed, CrossRef
  36. Shahbaz AU, Kamalov G, Zhao W, Zhao T, Johnson PL, Sun Y, Bhattacharya SK, Ahokas RA, Gerling IC, Weber KT. Mitochondria-targeted cardioprotection in aldosteronism. J Cardiovasc Pharmacol. 2011 Jan;57(1):37-43.  PubMed, PubMedCentral, CrossRef
  37. Costa LG, Garrick JM, Roquè PJ, Pellacani C. Mechanisms of Neuroprotection by Quercetin: Counteracting Oxidative Stress and More.  Oxid Med Cell Longev. 2016;2016:2986796.  PubMed, PubMedCentral, CrossRef
  38. Biasutto L, Szabo’ I, Zoratti M. Mitochondrial effects of plant-made compounds. Antioxid Redox Signal. 2011 Dec 15;15(12):3039-59. PubMed, CrossRef

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