Oxidative Stress and Diabetes Mellitus: Unravelling the Intricate Connection: A Comprehensive Review

Nadeem Rais *

Department of Pharmacy, Bhagwant University, Ajmer, Rajasthan 305004, India.

Akash Ved

Faculty of Pharmacy, Dr. A.P.J. Abdul Kalam Technical University, Lucknow, Uttar Pradesh 226031, India.

Rizwan Ahmad

Department of Pharmacy, Vivek College of Technical Education, Bijnor, Uttar Pradesh 246701, India.

Aashna Parveen

Faculty of Applied Science, Bhagwant Global University, Kotdwar, Uttarakhand 246149, India.

*Author to whom correspondence should be addressed.


Background: Diabetes mellitus (DM) is often associated with oxidative stress (OS), which is defined as an imbalance between the body's antioxidant defense systems and the generation of reactive oxygen species (ROS). OS serves as a crucial factor in the intricate relationship between DM and cellular dysfunction, influencing the generation of ROS and subsequent DM complications such as retinopathy, cardiomyopathy, neuropathy, nephropathy, encephalopathy, and peripheral arteriopathy.

Objective: This comprehensive review aims to elucidate the complex interplay between OS and DM, providing a thorough understanding of the underlying mechanisms and highlighting emerging therapeutic interventions for the management of OS-related complications in DM. It also explores novel antioxidant-based therapies aiming at specific OS markers and developing personalized interventions, which represents a promising avenue for enhancing treatment efficacy in DM.

Method: The search was conducted on scientific databases and web portals such as PubMed, ScienceDirect, Web of Science, Embase, Google Scholar, EBSCO, DOAJ, etc.

Conclusion: In conclusion, OS and DM are related through a dynamic and intricate interaction involving genetic, molecular, and environmental variables. Interdisciplinary approaches hold the potential to uncover novel biomarkers for early detection, prognosis, and oriented therapeutic interventions, thereby revolutionizing the clinical management of DM-related complications. With research continuing to advance and customized treatments being more widely incorporated into clinical practice, there is hope that the impact of OS-related DM complications will be significantly mitigated in the future. Despite notable progress, certain unexplored facets necessitate deeper investigations into the precise mechanisms through which OS exacerbates the progression of DM.

Keywords: Oxidative stress, diabetes mellitus, reactive oxygen species, insulin resistance, diabetic complications

How to Cite

Rais , N., Ved , A., Ahmad , R. and Parveen , A. (2024) “Oxidative Stress and Diabetes Mellitus: Unravelling the Intricate Connection: A Comprehensive Review”, Journal of Pharmaceutical Research International, 36(1), pp. 13–30. doi: 10.9734/jpri/2024/v36i17493.


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Azzi A. Oxidative stress: What is it? Can it be measured? Where is it located? Can it be good or bad? Can it be prevented? Can It be cured? Antioxidants. 2022;11:1431. DOI: 10.3390/antiox11081431

Sharifi-Rad M, Anil Kumar NV, Zucca P, et al. Lifestyle, oxidative stress, and antioxidants: Back and forth in the pathophysiology of chronic diseases. Front Physiol. 2020;11:694. DOI: 10.3389/fphys.2020.00694

González P, Lozano P, Ros G, et al. Hyperglycemia and oxidative stress: An Integral, updated and critical overview of their metabolic interconnections. Int J Mol Sci. 2023;24:9352. DOI: 10.3390/ijms24119352

Bhatti JS, Sehrawat A, Mishra J, et al. Oxidative stress in the pathophysiology of type 2 diabetes and related complications: Current therapeutics strategies and future perspectives. Free Radic Biol Med. 2022; 184:114–34. DOI: 10.1016/j.freeradbiomed.2022.03.019

Masenga SK, Kabwe LS, Chakulya M, et al. Mechanisms of oxidative stress in metabolic syndrome. Int J Mol Sci. 2023;24:7898. DOI: 10.3390/ijms24097898

Caturano A, D’Angelo M, Mormone A, et al. Oxidative stress in type 2 diabetes: Impacts from pathogenesis to lifestyle modifications. Curr Issues Mol Biol. 2023;45:6651–66. DOI: 10.3390/cimb45080420

Ly LD, Xu S, Choi S-K, et al. Oxidative stress and calcium dysregulation by palmitate in type 2 diabetes. Exp Mol Med. 2017;49:e291–e291. DOI: 10.1038/emm.2016.157

Rehman K, Akash MSH. Mechanism of generation of oxidative stress and pathophysiology of type 2 diabetes mellitus: How Are they interlinked? J Cell Biochem. 2017;118:3577–85. DOI: 10.1002/jcb.26097

Chianese R, Pierantoni R. Mitochondrial Reactive Oxygen Species (ROS) production alters sperm quality. Antioxidants. 2021;10:92. DOI: 10.3390/antiox10010092

Twarda-Clapa A, Olczak A, Białkowska AM, et al. Advanced Glycation End-Products (AGEs): Formation, chemistry, classification, receptors, and diseases related to AGEs. Cells. 2022;11: 1312. DOI: 10.3390/cells11081312

Njeim R, Alkhansa S, Fornoni A. Unraveling the crosstalk between lipids and NADPH oxidases in diabetic kidney disease. Pharmaceutics. 2023;15: 1360. DOI: 10.3390/pharmaceutics15051360

Aldosari DI, Malik A, Alhomida AS, et al. Implications of Diabetes-induced altered metabolites on retinal neurodegeneration. Front Neurosci. 2022;16. DOI: 10.3389/fnins.2022.938029 DOI: 10.3389/fnins.2022.938029

Black HS. A synopsis of the associations of oxidative stress, ROS, and antioxidants with diabetes mellitus. Antioxidants. 2022;11:2003. DOI: 10.3390/antiox11102003

Abdal Dayem A, Hossain M, Lee S, et al. The role of reactive oxygen species (ROS) in the biological activities of metallic nanoparticles. Int J Mol Sci. 2017;18:120. DOI: 10.3390/ijms18010120

Kang Q, Yang C. Oxidative stress and diabetic retinopathy: Molecular mechanisms, pathogenetic role and therapeutic implications. Redox Biol. 2020; 37:101799. DOI: 10.1016/j.redox.2020.101799

Asmat U, Abad K, Ismail K. Diabetes mellitus and oxidative stress—A concise review. Saudi Pharm J. 2016;24:547–53. DOI: 10.1016/j.jsps.2015.03.013

Su L-J, Zhang J-H, Gomez H, et al. Reactive oxygen species-induced lipid peroxidation in apoptosis, autophagy, and ferroptosis. Oxid Med Cell Longev. 2019;2019:1–13. DOI: 10.1155/2019/5080843

Andrés CMC, Pérez de la Impact of Lastra JM, Andrés Juan C, et al. reactive species on amino acids—biological relevance in proteins and induced pathologies. Int J Mol Sci. 2022;23:14049. DOI: 10.3390/ijms232214049

Juan CA, Pérez de la Lastra JM, Plou FJ, et al. The chemistry of reactive oxygen species (ros) revisited: Outlining their role in biological macromolecules (DNA, Lipids and Proteins) and Induced Pathologies. Int J Mol Sci. 2021;22:4642. DOI: 10.3390/ijms22094642

Rowe LA, Degtyareva N, Doetsch PW. DNA damage-induced reactive oxygen species (ROS) stress response in Saccharomyces cerevisiae. Free Radic Biol Med. 2008;45:1167–77. DOI: 10.1016/j.freeradbiomed.2008.07.018

Kowalczyk P, Sulejczak D, Kleczkowska P, et al. Mitochondrial Oxidative Stress—A causative factor and therapeutic target in many diseases. Int J Mol Sci. 2021;22: 13384. DOI: 10.3390/ijms222413384

Amen OM, Sarker SD, Ghildyal R, et al. Endoplasmic reticulum stress activates unfolded protein response signaling and mediates inflammation, obesity, and cardiac dysfunction: Therapeutic and molecular approach. Front Pharmacol. 2019;10:977. DOI: 10.3389/fphar.2019.00977

Checa J, Aran JM. Reactive Oxygen species: Drivers of physiological and pathological processes. J Inflamm Res. 2020;13:1057–73. DOI: 10.2147/JIR.S275595

Miller MA, Zachary JF. Mechanisms and morphology of cellular injury, adaptation, and death. Pathologic Basis of Veterinary Disease. Elsevier. 2017:2-43.e19. Available:https://doi.org/10.1016/B978-0-323-35775-3.00001-1 DOI: 10.1016/B978-0-323-35775-3.00001-1

Goycheva P, Petkova-Parlapanska K, Georgieva E, et al. Biomarkers of oxidative stress in diabetes mellitus with diabetic nephropathy complications. Int J Mol Sci. 2023;24:13541. DOI: 10.3390/ijms241713541

Fujii J, Homma T, Osaki T. Superoxide radicals in the execution of cell death. Antioxidants. 2022;11:501. DOI: 10.3390/antiox11030501

Wang Y, Branicky R, Noë A, et al. Superoxide dismutases: Dual roles in controlling ROS damage and regulating ROS signaling. J Cell Biol. 2018;217: 1915–28. DOI: 10.1083/jcb.201708007

Zhao Z. Iron and oxidizing species in oxidative stress and Alzheimer’s disease. AGING Med. 2019;2:82–7. DOI: 10.1002/agm2.12074

Forstermann U, Sessa WC. Nitric oxide synthases: Regulation and function. Eur Heart J. 2012;33:829–37. DOI: 10.1093/eurheartj/ehr304

Andrés CMC, Pérez de la Lastra JM, Andrés Juan C, et al. Superoxide anion chemistry—Its role at the core of the innate immunity. Int J Mol Sci. 2023;24:1841. DOI: 10.3390/ijms24031841

Tarafdar A, Pula G. The role of NADPH Oxidases and oxidative stress in neurodegenerative disorders. Int J Mol Sci. 2018;19:3824. DOI: 10.3390/ijms19123824

Tenopoulou M, Doulias P-T. Endothelial nitric oxide synthase-derived nitric oxide in the regulation of metabolism. F1000Research. 2020;9:1190. DOI: 10.12688/f1000research.19998.1

Król M, Kepinska M. Human nitric oxide synthase—Its functions, polymorphisms, and inhibitors in the context of inflammation, diabetes and cardiovascular diseases. Int J Mol Sci. 2020;22:56. DOI: 10.3390/ijms22010056

Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial Reactive Oxygen Species (ROS) and ROS-Induced ROS Release. Physiol Rev. 2014;94:909–50. DOI: 10.1152/physrev.00026.2013

Mittal M, Siddiqui MR, Tran K, et al. Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal. 2014;20:1126–67. DOI: 10.1089/ars.2012.5149

Ayala A, Muñoz MF, Argüelles S. Lipid Peroxidation: Production, metabolism, and signaling mechanisms of malondialdehyde and 4-Hydroxy-2-Nonenal. Oxid Med Cell Longev. 2014;2014:1–31. DOI: 10.1155/2014/360438

Cherian D, Peter T, Narayanan A, et al. Malondialdehyde as a marker of oxidative stress in periodontitis patients. J Pharm Bioallied Sci. 2019;11:297. DOI: 10.4103/JPBS.JPBS_17_19

Li Y, Zhao T, Li J, et al. Oxidative Stress and 4-hydroxy-2-nonenal (4-HNE): Implications in the pathogenesis and treatment of aging-related diseases. J Immunol Res. 2022;2022:1–12. DOI: 10.1155/2022/2233906

Milne GL, Yin H, Hardy KD, et al. Isoprostane generation and function. Chem Rev. 2011;111:5973–96. DOI: 10.1021/cr200160h

Chang X, Wang Y, Zheng B, et al. The Role of acrolein in neurodegenerative diseases and its protective strategy. Foods. 2022;11:3203. DOI: 10.3390/foods11203203

Barrera G. Oxidative stress and lipid peroxidation products in cancer progression and therapy. ISRN Oncol. 2012;2012:1–21. DOI: 10.5402/2012/137289

De Freitas FA, Levy D, Zarrouk A, et al. Impact of oxysterols on cell death, proliferation, and differentiation induction: current status. Cells. 2021;10:2301. DOI: 10.3390/cells10092301

Nandi A, Yan L-J, Jana CK, et al. Role of catalase in oxidative stress- and age-associated degenerative diseases. Oxid Med Cell Longev. 2019;2019:1–19. DOI: 10.1155/2019/9613090

Lubos E, Loscalzo J, Handy DE. Glutathione peroxidase-1 in health and disease: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal. 2011;15:1957–97. DOI: 10.1089/ars.2010.3586

Lee S, Kim SM, Lee RT. Thioredoxin and thioredoxin target proteins: from molecular mechanisms to functional significance. Antioxid Redox Signal. 2013;18:1165–207. DOI: 10.1089/ars.2011.4322

Puentes-Pardo JD, Moreno-SanJuan S, Carazo Á, et al. Heme oxygenase-1 in gastrointestinal tract health and disease. Antioxidants. 2020;9:1214. DOI: 10.3390/antiox9121214

Karpenko IL, Valuev-Elliston VT, Ivanova ON, et al. Peroxiredoxins—The underrated actors during virus-induced oxidative stress. Antioxidants. 2021;10:977. DOI: 10.3390/antiox10060977.

Silva Rosa SC, Nayak N, Caymo AM, et al. Mechanisms of muscle insulin resistance and the cross‐talk with liver and adipose tissue. Physiol Rep. 2020;8:e14607. DOI: 10.14814/phy2.14607

Boucher J, Kleinridders A, Kahn CR. Insulin Receptor Signaling in Normal and Insulin-Resistant States. Cold Spring Harb Perspect Biol. 2014;6:a009191–a009191. DOI: 10.1101/cshperspect.a009191.

Petersen MC, Shulman GI. Mechanisms of insulin action and insulin resistance. Physiol Rev. 2018;98:2133–223. DOI: 10.1152/physrev.00063.2017

White MF. The insulin signalling system and the IRS proteins. Diabetologia. 1997;40:S2–17. DOI: 10.1007/s001250051387

White MF, Kahn CR. Insulin action at a molecular level – 100 years of progress. Mol Metab. 2021;52:101304. DOI: 10.1016/j.molmet.2021.101304

Chadt A, Al-Hasani H. Glucose transporters in adipose tissue, liver, and skeletal muscle in metabolic health and disease. Pflügers Arch - Eur J Physiol. 2020;472:1273–98. DOI: 10.1007/s00424-020-02417-x

Fazakerley DJ, Krycer JR, Kearney AL, et al. Muscle and adipose tissue insulin resistance: malady without mechanism? J Lipid Res. 2019;60:1720–32. DOI: 10.1194/jlr.R087510

Tangvarasittichai S. Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus. World J Diabetes. 2015;6:456. DOI: 10.4239/wjd.v6.i3.456

Rains JL, Jain SK. Oxidative stress, insulin signaling, and diabetes. Free Radic Biol Med. 2011;50:567–75. DOI: 10.1016/j.freeradbiomed.2010.12.006

Park SS, Seo Y-K. Excess accumulation of lipid impairs insulin sensitivity in skeletal muscle. Int J Mol Sci. 2020;21:1949. DOI: 10.3390/ijms21061949

Cao SS, Kaufman RJ. Endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease. Antioxid Redox Signal. 2014;21:396–413. DOI: 10.1089/ars.2014.5851

Oyenihi AB, Ayeleso AO, Mukwevho E, et al. Antioxidant strategies in the management of diabetic neuropathy. Biomed Res Int. 2015;2015:1–15. DOI: 10.1155/2015/515042

Kayama Y, Raaz U, Jagger A, et al. Diabetic cardiovascular disease induced by oxidative stress. Int J Mol Sci. 2015;16:25234–63. DOI: 10.3390/ijms161025234

Petrie JR, Guzik TJ, Touyz RM. Diabetes, hypertension, and cardiovascular disease: clinical insights and vascular mechanisms. Can J Cardiol. 2018;34:575–84. DOI: 10.1016/j.cjca.2017.12.005

Sytze van Dam P. Oxidative stress and diabetic neuropathy: pathophysiological mechanisms and treatment perspectives. Diabetes Metab Res Rev. 2002;18:176–84. DOI: 10.1002/dmrr.287.

Pang L, Lian X, Liu H, et al. Understanding diabetic neuropathy: Focus on oxidative stress. Oxid Med Cell Longev. 2020;2020: 1–13. DOI: 10.1155/2020/9524635

Jha JC, Banal C, Chow BSM, et al. Diabetes and kidney disease: role of oxidative stress. Antioxid Redox Signal. 2016;25:657–84. DOI: 10.1089/ars.2016.6664

Darenskaya M, Kolesnikov S, Semenova N, et al. Diabetic nephropathy: Significance of determining oxidative stress and opportunities for antioxidant therapies. Int J Mol Sci. 2023;24:12378. DOI: 10.3390/ijms241512378

Kowluru RA, Chan P-S. Oxidative stress and diabetic retinopathy. Exp Diabetes Res. 2007;2007:1–12. DOI: 10.1155/2007/43603

Zhou J, Chen B. Retinal cell damage in diabetic retinopathy. Cells. 2023;12:1342. DOI: 10.3390/cells12091342.

Jelinek M, Jurajda M, Duris K. Oxidative Stress in the Brain: Basic concepts and treatment strategies in stroke. Antioxidants. 2021;10:1886. DOI: 10.3390/antiox10121886

Muriach M, Flores-Bellver M, Romero FJ, et al. Diabetes and the brain: Oxidative stress, inflammation, and autophagy. Oxid Med Cell Longev. 2014;2014:1–9. DOI: 10.1155/2014/102158

Signorelli SS, Scuto S, Marino E, et al. oxidative stress in peripheral arterial disease (pad) mechanism and biomarkers. Antioxidants. 2019;8:367. DOI: 10.3390/antiox8090367

Soyoye DO, Abiodun OO, Ikem RT, et al. Diabetes and peripheral artery disease: A review. World J Diabetes. 2021;12:827–38. DOI: 10.4239/wjd.v12.i6.827

Korczowska-Łącka I, Słowikowski B, Piekut T, et al. Disorders of endogenous and exogenous antioxidants in neurological diseases. Antioxidants. 2023;12:1811. DOI: 10.3390/antiox12101811

Averill-Bates DA. The antioxidant glutathione. Vitam Horm. 2023;121:109–41. DOI: 10.1016/bs.vh.2022.09.002

Hasan AA, Kalinina E, Tatarskiy V, et al. The Thioredoxin system of mammalian cells and its modulators. Biomedicines. 2022;10:1757. DOI: 10.3390/biomedicines10071757

ORINO K, LEHMAN L, TSUJI Y, et al. Ferritin and the response to oxidative stress. Biochem J. 2001;357:241. DOI: 10.1042/0264-6021:3570241

Ryter SW. Significance of heme and heme degradation in the pathogenesis of acute lung and inflammatory disorders. Int J Mol Sci. 2021;22:5509. DOI: 10.3390/ijms22115509

Kushiyama A, Nakatsu Y, Matsunaga Y, et al. Role of uric acid metabolism-related inflammation in the pathogenesis of metabolic syndrome components such as atherosclerosis and nonalcoholic steatohepatitis. Mediators Inflamm. 2016: 1–15. DOI: 10.1155/2016/8603164

Ponnampalam EN, Kiani A, Santhiravel S, et al. The importance of dietary antioxidants on oxidative stress, meat and milk production, and their preservative aspects in farm animals: antioxidant action, animal health, and product quality—invited review. Animals. 2022;12:3279. DOI: 10.3390/ani12233279

Susa F, Pisano R. Advances in ascorbic acid (Vitamin C) manufacturing: Green extraction techniques from natural sources. Processes. 2023;11:3167. DOI: 10.3390/pr11113167

Michalak M, Pierzak M, Kręcisz B, et al. Bioactive compounds for skin health: A review. Nutrients. 2021;13:203. DOI: 10.3390/nu13010203

Elvira-Torales LI, García-Alonso J, Periago-Castón MJ. Nutritional importance of carotenoids and their effect on liver health: A review. Antioxidants. 2019;8:229. DOI: 10.3390/antiox8070229

Tinggi U. Selenium: its role as antioxidant in human health. Environ Health Prev Med. 2008;13:102–8. DOI: 10.1007/s12199-007-0019-4

Khan J, Deb PK, Priya S, et al. Dietary flavonoids: Cardioprotective potential with antioxidant effects and their pharmacokinetic, toxicological and therapeutic concerns. Molecules. 2021;26:4021. DOI: 10.3390/molecules26134021

Rudrapal M, Khairnar SJ, Khan J, et al. Dietary polyphenols and their role in oxidative stress-induced human diseases: Insights into protective effects, antioxidant potentials and mechanism(s) of action. Front Pharmacol. 2022;13: 806470. DOI: 10.3389/fphar.2022.806470

Imran M, Ghorat F, Ul-Haq I, et al. Lycopene as a Natural antioxidant used to prevent human health disorders. Antioxidants. 2020;9:706. DOI: 10.3390/antiox9080706

Pallotti F, Bergamini C, Lamperti C, et al. The roles of coenzyme q in disease: Direct and indirect involvement in cellular functions. Int J Mol Sci. 2021;23:128. DOI: 10.3390/ijms23010128

Souyoul SA, Saussy KP, Lupo MP. Nutraceuticals: A review. Dermatol Ther (Heidelb). 2018;8:5–16. DOI: 10.1007/s13555-018-0221-x

Gonçalves AC, Nunes AR, Falcão A, et al. Dietary effects of anthocyanins in human health: A comprehensive review. Pharmaceuticals. 2021;14:690. DOI: 10.3390/ph14070690

Janciauskiene S. The beneficial effects of antioxidants in health and diseases. Chronic Obstr Pulm Dis J COPD Found. 2020;7:182–202. DOI: 10.15326/jcopdf.7.3.2019.0152

Bouayed J, Bohn T. Exogenous antioxidants—double-edged swords in cellular redox state: health beneficial effects at physiologic doses versus deleterious effects at high doses. Oxid Med Cell Longev. 2010;3:228–37. DOI: 10.4161/oxim.3.4.12858

Meulmeester FL, Luo J, Martens LG, et al. Antioxidant supplementation in oxidative stress-related diseases: What have we learned from studies on alpha-tocopherol? Antioxidants. 2022;11:2322. DOI: 10.3390/antiox11122322

Ghodeshwar GK, Dube A, Khobragade D. Impact of lifestyle modifications on cardiovascular health: A narrative review. Cureus. 2023;15:e42616. DOI: 10.7759/cureus.42616

Leonidis A, Korozi M, Sykianaki E, et al. Improving stress management and sleep hygiene in intelligent homes. Sensors. 2021;21:2398. DOI: 10.3390/s21072398

Tyuryaeva I, Lyublinskaya O. Expected and unexpected effects of pharmacological antioxidants. Int J Mol Sci. 2023;24:9303. DOI: 10.3390/ijms24119303

Vassalle C, Maltinti M, Sabatino L. Targeting oxidative stress for disease prevention and therapy: Where do we stand, and where do we go from here. Molecules. 2020;25:2653. DOI: 10.3390/molecules25112653

Curpan AS, Luca A-C, Ciobica A. Potential novel therapies for neurodevelopmental diseases targeting oxidative stress. Oxid Med Cell Longev. 2021;2021:1–13. DOI: 10.1155/2021/6640206

Forman HJ, Zhang H. Targeting oxidative stress in disease: Promise and limitations of antioxidant therapy. Nat Rev Drug Discov. 2021;20: 689–709. DOI: 10.1038/s41573-021-00233-1

Scheen AJ. Precision medicine: The future in diabetes care? Diabetes Res Clin Pract. 2016;117:12–21. DOI: 10.1016/j.diabres.2016.04.033

Williams DM, Jones H, Stephens JW. Personalized Type 2 Diabetes Management: An Update on Recent Advances and Recommendations. Diabetes, Metab Syndr Obes Targets Ther. 2022;15:281–95. DOI: 10.2147/DMSO.S331654.

Darenskaya MA, Kolesnikova LI, Kolesnikov SI. Oxidative stress: Pathogenetic role in diabetes mellitus and its complications and therapeutic approaches to correction. Bull Exp Biol Med. 2021;171:179–89. DOI: 10.1007/s10517-021-05191-7

Van den Brink WJ, van den Broek TJ, Palmisano S, et al. Digital biomarkers for personalized nutrition: Predicting meal moments and interstitial glucose with non-invasive, wearable technologies. Nutrients. 2022; 14:4465. DOI: 10.3390/nu14214465