Review Article

Effect of COVID-19 Infection on the Immune System and Risk of Developing Diabetes Complications: A Review


Coronavirus disease (COVID-19) is caused by SARS-COV2 and represents the causative agent of a potentially fatal disease that is of great global public health concern. The pandemic outbreak of COVID-19 is rapidly spreading all over the world. This review aims to provide a relationship between the alteration of immune system during  COVID-19 infection and the risk of developing diabetes complications. The risk of COVID-19 infection in patients is due not only to the severity of the viral infection but also to the host's immune response. The risk of infection is one of the main complications of diabetics, as it has been suggested that diabetes inhibits the immune response which contributes to infection and progression to symptoms. also, The evidence of generation of oxygen free radicals and oxidative stress is a key process in the onset of diabetes mellitus which participate in the development of the systemic inflammatory response syndrome. In addition, chronic hyperglycemia during COVID-19 infection may increase the release of inflammatory cytokines, a high ability to bind to the virus ACE2 glycosylated, worsen the ketoacidosis and vascular complications that may explain the severity of the SARS-CoV-2 infection in diabetic patients.

1. Singhal T. A Review of Coronavirus Disease-2019 (COVID-19). Indian J Pediatr 2020;87(4):281-6.
2. Raoult D, Zumla A, Locatelli F, Ippolito G, Kroemer G. Coronavirus infections: Epidemiological, clinical and immunological features and hypotheses. Cell Stress 2020;4(4):66-75.
3. DC COVID-19 response team. preliminary estimates of the prevalence of selected underlying health conditions among patients with Coronavirus Disease 2019 - United States, February 12-March 28, 2020. MMWR Morb Mortal Wkly Rep 2020;69(13):382-6.
4. Derouiche S, Kechrid Z. Influence of calcium supplements on zinc status, carbohydrate metabolism and the liver activity of detoxifying glutathione enzymatic system in alloxan induced diabetic rats J Exp Biol Agr Sci 2013;1(6):424-9.
5. Hulme KD, Gallo LA, Short KR. Influenza Virus and Glycemic Variability in Diabetes: A Killer Combination? Front Microbiol 2017;8:861.
6. Wu Y, Ding Y, Tanaka Y, Zhang W. Risk factors contributing to type 2 diabetes and recent advances in the treatment and prevention. Int J Med Sci 2014;11(11):1185-200.
7. Asmat U, Abad K, Ismail K. Diabetes mellitus and oxidative stress-A concise review. Saudi Pharm J 2016;24(5):547-53.
8. Derouiche S, DoudiDalal, Atia N. Study of Oxidative Stress during Pregnancy. Global Journal of Pharmacy & Pharmaceutical Science 2018;4(5):GJPPS.MS.ID.555646.
9. Parast VM, Paknahad Z. Antioxidant Status and Risk of Gestational Diabetes Mellitus: a Case-Control Study. Clin Nutr Res 2017;6(2):81-8.
10. Vlassara H, Uribarri J. Advanced glycation end products (AGE) and diabetes: cause, effect, or both? Curr Diab Rep. 2014; 14(1):453.
11. Tu YF, Chien CS, Yarmishyn AA, et al. A Review of SARS-CoV-2 and the Ongoing Clinical Trials. Int J Mol Sci 2020;21(7):2657.
12. Tay MZ, Poh CM, Rénia L, MacAry PA, Ng LFP. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol. 2020;20(6):363-74.
13. Nikolich-Zugich J, Knox KS, Rios CT, Natt B, Bhattacharya D, Fain MJ. SARS-CoV-2 and COVID-19 in older adults: what we may expect regarding pathogenesis, immune responses, and outcomes. GeroScience 2020;42(2):505-14.
14. Yi Y, Lagniton PNP, Ye S, Li E, Xu RH. COVID-19: what has been learned and to be learned about the novel coronavirus disease. Int J Biol Sci 2020;16(10):1753-66.
15. Li H, Liu SM, Yu XH, Tang SL, Tang CK. Coronavirus disease 2019 (COVID-19): current status and future perspectives. Int J Antimicrob Agents 2020;29:105951.
16. Cheng VC, Lau SK, Woo PC, Yuen KY. Severe acute respiratory syndrome coronavirus as an agent of emerging and reemerging infection. Clin Microbiol Rev 2007;20(4):660-94.
17. Cristiani L, Mancino E, Matera L, et al. Will children reveal their secret? The coronavirus dilemma. Eur Respir J 2020;55(4):2000749.
18. Maggi E, Canonica G W, Moretta L. COVID-19: Unanswered questions on immune response and pathogenesis. J Allergy Clin Immunol 2020;146(1):18–22
19. Favalli EG, Ingegnoli F, De Lucia O, Cincinelli G, Cimaz R, Caporali R. COVID-19 infection and rheumatoid arthritis: Faraway, so close!. Autoimmun Rev 2020;19(5):102523.
20. Astuti I, Ysrafil. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): An overview of viral structure and host response. Diabetes Metab Syndr. 2020;14(4):407-12.
21. Newton AH, Cardani A, Braciale TJ. The host immune response in respiratory virus infection: balancing virus clearance and immunopathology. Semin Immunopathol 2016;38(4):471-82.
22. Zheng M, Gao Y, Wang G, et al. Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cell Mol Immunol 2020;17(5):533-5.
23. Mandó P, Rizzo M, Roberti MP, et al. High neutrophil to lymphocyte ratio and decreased CD69+NK cells represent a phenotype of high risk in early-stage breast cancer patients. Onco Targets Ther 2018;11:2901-10.
24. Derouiche S, Kaouther A, Manel D. Changes in metabolism of Zinc and carbohydrate and testis oxidative stress of diabetic rats fed zinc-over dose diet. International Journal of Biological & Medical Research 2017;8(3):6041-6045.
25. Stunault MI, Bories G, Guinamard RR, Ivanov S. Metabolism Plays a Key Role during Macrophage Activation. Mediators Inflamm 2018;2018:2426138.
26. Kawahito S, Kitahata H, Oshita S. Problems associated with glucose toxicity: role of hyperglycemia-induced oxidative stress. World J Gastroenterol 2009;15(33):4137-42.
27. Toniolo A, Cassani G, Puggioni A, et al. The diabetes pandemic and associated infections: suggestions for clinical microbiology. Rev Med Microbiol 2019;30(1):1-17.
28. Lucier J, Weinstock RS. Diabetes Mellitus Type 1. [Updated 2020 Jul 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from:
29. Di Paolo NC, Shayakhmetov DM. Interleukin 1α and the inflammatory process. Nat Immunol 2016;17(8):906-13.
30. vashkiv LB. IFNγ: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy. Nat Rev Immunol 2018;18(9):545-58.
31. Zhou T, Hu Z, Yang S, Sun L, Yu Z, Wang G. Role of Adaptive and Innate Immunity in Type 2 Diabetes Mellitus. J Diabetes Res 2018:8;2018:7457269.
32. Singh VP, Bali A, Singh N, Jaggi AS. Advanced glycation end products and diabetic complications. Korean J Physiol Pharmacol 2014;18(1):1-14.
33. Vozarova B1, Weyer C, Lindsay RS, Pratley RE, Bogardus C, Tataranni PA. High white blood cell count is associated with a worsening of insulin sensitivity and predicts the development of type 2 diabetes. Diabetes 2002;51(2):455-61.
34. Dosch M, Gerber J, Jebbawi F, Beldi G. Mechanisms of ATP Release by Inflammatory Cells. Int J Mol Sci 2018;19(4):1222.
35. Teng TS, Ji AL, Ji XY, Li YZ. Neutrophils and Immunity: From Bactericidal Action to Being Conquered. J Immunol Res 2017;2017:9671604.
36. Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation. Cell 2014;157(1):121-41.
37. Kaouachi A, Derouiche S. Phytochemical analysis, DPPH antioxidant activity and Acute toxicity of bark aqueous extracts of Pinus halepensis. Research Journal of Chemical and Environmental Sciences 2018;6(3):86-91.
38. Derouiche S, Rezzag-mohcen OS, Serouti A. Triazinone herbicide metribuzin induced acute liver injury: A study of animal model. Journal of Acute Disease 2018;7(4):152-157.
39. Ceriello A, Testa R. Antioxidant anti-inflammatory treatment in type 2 diabetes. Diabetes Care 2009;32 (Suppl 2):S232-S236.
40. Closa D, Folch-Puy E. Oxygen Free Radicals and the Systemic Inflammatory Response IUBMB Life 2004;56(4): 185-191.
41. Aprioku JS. Pharmacology of free radicals and the impact of reactive oxygen species on the testis. J Reprod Infertil 2013;14(4):158-72.
42. Atoussi N, Guediri S, Derouiche S. Changes in Haematological, Biochemical and Serum Electrolytes Markers in Women Breast Cancer Patients. Scholars Journal of Research in Agriculture and Biology 2018;3(2):173-177.
43. Lega S, Naviglio S, Volpi S, Tommasini A. Recent Insight into SARS-CoV2 Immunopathology and Rationale for Potential Treatment and Preventive Strategies in COVID-19. Vaccines 2020;14;8(2):224.
44. Gupta R, Hussain A, Misra A. Diabetes and COVID-19: evidence, current status and unanswered research questions. Eur J Clin Nutr 2020;74(6):864-70.
45. Verdecchia P, Cavallini C, Spanevello A, Angeli F. The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur J Intern Med 2020;76:14-20.
46. Arendse LB, Danser AHJ, Poglitsch M, et al. Novel Therapeutic Approaches Targeting the Renin-Angiotensin System and Associated Peptides in Hypertension and Heart Failure. Pharmacol Rev 2019;71(4):539-70.
47. Brufsky A. Hyperglycemia, hydroxychloroquine, and the COVID-19 pandemic. J Med Virol 2020;92(7):770-5.
48. Ceriello A. Hyperglycemia and the worse prognosis of COVID-19. Why a fast blood glucose control should be mandatory. Diabetes Res Clin Pract 2020;163:108186.
49. Robson B. COVID-19 Coronavirus spike protein analysis for synthetic vaccines, a peptidomimetic antagonist, and therapeutic drugs, and analysis of a proposed achilles’ heel conserved region to minimize probability of escape mutations and drug resistance. Comput Biol Med 2020;121:103749.
50. Cure E, Cumhur Cure M. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may be harmful in patients with diabetes during COVID-19 pandemic. Diabetes Metab Syndr 2020;14(4):349-50.
51. Li SR, Tang ZJ, Li ZH, Liu X. Searching therapeutic strategy of new coronavirus pneumonia from angiotensin-converting enzyme 2: the target of COVID-19 and SARS-CoV. Eur J Clin Microbiol Infect Dis 2020;39(6):1021–6.
52. South AM, Tomlinson L, Edmonston D, Hiremath S, Sparks MA. Controversies of renin-angiotensin system inhibition during the COVID-19 pandemic. Nat Rev Nephrol 2020;16(6):305-7.
53. Mourad JJ, Levy BI. Interaction between RAAS inhibitors and ACE2 in the context of COVID-19. Nat Rev Cardiol 2020;17(5):313.
54. Belouzard S, Millet JK, Licitra BN, Whittaker GR. Mechanisms of coronavirus cell entry mediated by the viral spike protein. Viruses 2012;4(6):1011-33.
55. Yang JK, Lin SS, Ji XJ, Guo LM. Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes. Acta Diabetol 2010;47(3):193-9.
56. Kanikarla-Marie P, Jain SK. Hyperketonemia and ketosis increase the risk of complications in type 1 diabetes. Free Radic Biol Med 2016; 95:268-77.
57. Imai Y, Kuba K, Penninger JM. The renin-angiotensin system in acute respiratory distress syndrome. Drug Discov Today Dis Mech 2006; 3(2):225-9.
58. Kardalas E, Paschou SA, Anagnostis P, Muscogiuri G, Siasos G, Vryonidou A. Hypokalemia: a clinical update. Endocr Connect 2018;7(4):R135-R146.
59. Imai Y, Kuba K, Penninger JM. Angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Cell Mol Life Sci 2007;64(15):2006-12.
60. Bernardi S, Michelli A, Zuolo G, Candido R, Fabris B. Update on RAAS Modulation for the Treatment of Diabetic Cardiovascular Disease. J Diabetes Res 2016;2016:8917578.
61. Ribeiro-Oliveira A Jr, Nogueira AI, Pereira RM, Boas WW, Dos Santos RA, Simões e Silva AC. The renin-angiotensin system and diabetes: an update. Vasc Health Risk Manag 2008;4(4):787-803.
62. Cade WT. Diabetes-related microvascular and macrovascular diseases in the physical therapy setting. Phys Ther 2008; 88(11):1322-35.
63. Bakunina N, Pariante CM, Zunszain PA. Immune mechanisms linked to depression via oxidative stress and neuroprogression. Immunology 2015;144(3):365-73.
64. Gheblawi M, Wang K, Viveiros A, et al. Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System. Circ Res 2020;;126(10):1456-74.
65. Ghosal S, Sinha B, Majumder M, Misra A. Estimation of effects of nationwide lockdown for containing coronavirus infection on worsening of glycosylated haemoglobin and increase in diabetes-related complications: A simulation model using multivariate regression analysis. Diabetes Metab Syndr 2020;14(4):319-23.
66. Choudhary R, Kapoor MS, Singh A, Bodakhe SH. Therapeutic targets of renin-angiotensin system in ocular disorders. J Curr Ophthalmol 2016;29(1):7-16.
67. Mohamed A, Alawna M. Role of increasing the aerobic capacity on improving the function of immune and respiratory systems in patients with coronavirus (COVID-19): A review. Diabetes Metab Syndr 2020;14(4):489-96.
68. Felsenstein S, Herbert JA, McNamara PS, Hedrich CM. COVID-19: Immunology and treatment options. Clin Immunol. 2020;215:108448.
69. Spiezia L, Boscolo A, Poletto F, et al. COVID-19-Related Severe Hypercoagulability in Patients Admitted to Intensive Care Unit for Acute Respiratory Failure. Thromb Haemost 2020;120(6):998-1000.
IssueVol 8, No 3 (Summer 2020) QRcode
SectionReview Article(s)
COVID-19 Diabetes Mellitus Immune System Oxidative Stress

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Derouiche S, Cheradid T, Abdelmalek D, Achi I. Effect of COVID-19 Infection on the Immune System and Risk of Developing Diabetes Complications: A Review. J Pharm Care. 8(3):133-139.