Diabetes mellitus augments the complications of patients with COVID-19: a review

Parthiba Pramanik, Purushottam Pramanik


Corona virus disease 2019 (COVID-19) is current pandemic infection caused by RNA virus named severe acute respiratory syndrome coronavirus-2 (SARS Cov-2). The lungs are the organs most affected by COVID-19 and people were died due to severe acute respiratory s syndrome, pneumonia and multi-organs failure. Fatality rate was more, those who suffer in chronic diseases including diabetes mellitus (DM). As COVID-19 pandemic is accelerating , it is important to understand the molecular mechanism through which DM increases the severity related to COVID-19 to able to design more appropriate therapy. The aims of this study was to identify mechanisms through re-analysis of publicly available data by which DM increases susceptibility for COVID-19 infection and/or increase complication for SARS-Cov-2 infection. SARS Cov-2 accesses host cells via membrane bound enzyme, angiotensin converting enzyme-2 (ACE2). This leads to imbalance of vasoprotective and vasodeletorious arms of renin angiotensin system (RAS) with over activity of vasodeletorious arms. Such imbalance of RAS induces alveolar damage, flooding the alveoli and difficulty in breathing. DM augmented the chance of pulmonary infection by impairment of innate immunity and down regulation of ACE2. Hence, diabetic patients of COVID-19 die from multi-organ failure, shock, heart failure, arrhythmias and renal failure along with severe acute respiratory syndrome. Thus it is concluded that DM augments the complications from COVID-19 by enhancing development of RAS imbalance. From view point of public health it is suggested to keep the lung healthy, maintain blood glucose level properly, and intake foods rich in antioxidant and anti-inflammatory agents to prevent and ameliorate the acute effect of COVID-19 in diabetic patients.


Angiotensin converting enzyme, Antioxidant, COVID-19, Diabetes mellitus, Renin angiotensin system

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Centers for disease control and prevention (CDC). How to protect yourself and others. Accessed 8th April 2020.

WHO Director General’s opening remarks at the media briefing on COVID-19. Available at: media-briefing-on-covid-19--11 March-2020. Accessed 11 March 2020.

Corona virus Update (Live):1,001,069 Cases and 51378 Deaths from COVID-19 Virus Outbreak-Worldometer. Available at: https;//www.worldometers.nfo/coronavirus Accessed 2nd April 2020.

Coronavirus COVID-19Global cases by the Center of Systems Science and Engineering (CSSE) at Johns Hopkins University. Available at: https;//;ArcGis. Johns Hopkins CSSE.

Hui DS, Azhar EE, Madani TA, Ntoumi F, Kock R, Dar O, et al. The continuing epidemic threat of novel coronaviruses to global health-the latest novel coronavirus outbreak in Wuhang, China. Inter J Infect Dis. 2020 Jan 14;91:264-6.

Patel AB, Verma A. COVID-19 and angiotensin converting enzyme inhibitors and angiotensin receptor blockers. JAMA. 2020 May 12;323(18):1769-70

Castillo JJ, Mull N, Reagan JL, Nemr S, Mitri J. Increased incidence of non-Hodgkin lymphoma, leukemia, and myeloma in patients with diabetes mellitus type 2: a meta-analysis of observational studies. Blood, J Am Soc Hematol. 2012 May 24;119(21):4845-50.

King H, Aubert RE, Herman WH. Global burden of diabetes, 1995-2025: prevalence, numerical estimates and projections. Diabetes Care. 1998; 21(9):1414-31.

Guariguata L, Whiting D, Weil C, Unwin N. The International Diabetes Federation diabetes atlas methodology for estimating global and national prevalence of diabetes in adults. Diabetes Res Clini Pract. 2011 Dec 1;94(3):322-32.

Achuth KS, Mangala S, Pradeep C, Mini J, Subrahmanyam G. Risk of Type 2 diabetes mellitus in adolescents in a medical college in Bangalore, India. Inter J Scientific Study. 2015 Jul 1;3(4):86-9.

Park S, Rich J, Hanses F, Lee JC. Defects of innate immunity predispose c57BL/6J/Leprdb mice to infection by Staphylococcus aureus. Infect Immun. 2009;77:1008-14.

Zozulinska D, Wierusz-Wysocka B. Type-2 diabetes mellitus as inflammatory disease. Diabetes Res Clin. 2006;74:s12-s16.

Klein OL, Krishnan JA, Glick S, Smith LJ. Systemic review of the association between lung function and type-2 diabetes mellitus. Diabetic Med. 2010;27:977-87.

Tegegne BS, Habtewold TD, Mengesha MM, Burgerhof JGM. Association between diabetes mellitus and multi-drug-resistant tuberculosis: a protocol for systemic review and mete-analysis. Syst Rev. 2017;6:44.

Yang J, Tan Y, Zhao F, Ma Z, Wang Y, Zheng S, Epstein PN, Yu J, Yin X, Zheng Y, Li X. Angiotensin II plays a critical role in diabetic pulmonary fibrosis most likely via activation of NADPH oxidase-mediated nitrosative damage. Am J Physiology-Endocrinol Metab. 2011 Jul;301(1):E132-44.

Casqueiro J, Casqueiro J, Alves S. Infections in patients with diabetes mellitus: a review of pathogenesis. Ind. J. Endocrinol. Metab. 2012;16:S27-36.

Yang X, Yu Y, Xu J, Shu H, Liu H, Wu Y, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020 Feb 24.

Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708-20.

Richman DD, Whitley RJ, Hayden FG, editors. Clinical virology. 4th edition. John Wiley & Sons; 2016.

Ksiazek TG, Erdman D, Goldsmith CS, Zaki SR, Peret T, Emery S, Tong S, Urbani C, Comer JA, Lim W, Rollin PE. A novel coronavirus associated with severe acute respiratory syndrome. N Engl J Med. 2003 May 15;348(20):1953-66.

Drosten C, Günther S, Preiser W, Van Der Werf S, Brodt HR, Becker S, et al. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med. 2003 May 15;348(20):1967-76.

de Groot RJ, Baker SC, Baric RS, Brown CS, Drosten C, Enjuanes L, et al. Commentary: Middle East respiratory syndrome coronavirus (MERS-CoV): announcement of the Coronavirus Study Group. J Virol. 2013 Jul 15;87(14):7790-2.

Zaki AM, Van Boheemen S, Bestebroer TM, Osterhaus AD, Fouchier RA. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med. 2012;367(19):1814-20.

To KK, Tsang OT, Yip CC, Chan KH, Wu TC, Chan JM, et al. Consistent detection of 2019 novel coronavirus in saliva. Clini Infect Dis. 2020 Feb 12.

Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005 Jul;436(7047):112-6.

Xudong X, Junzhu C, Xingxiang W, Furong Z, Yanrong L. Age-and gender-related difference of ACE2 expression in rat lung. Life Sci. 2006 Apr 4;78(19):2166-71.

Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury. Nature Med. 2005 Aug;11(8):875-9.

Rey-Parra GJ, Vadivel A, Coltan L, Hall A, Eaton F, Schuster M, et al. Angiotensin converting enzyme 2 abrogates bleomycin-induced lung injury. J Molecular Med. 2012 Jun 1;90(6):637-47.

Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus. J Virol. 2020 Mar 17;94(7).

Vaduganathan M, Vardeny O, Michel T, McMurray JJ, Pfeffer MA, Solomon SD. Renin–angiotensin–aldosterone system inhibitors in patients with Covid-19. N Engl J Med. 2020;382(17):1653-9.

Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, et al. A novel angiotensin-converting enzyme–related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circulation Res. 2000 Sep 1;87(5):e1-9.

Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ. A human homolog of angiotensin-converting enzyme cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem. 2000 Oct 27;275(43):33238-43.

Rice GI, Thomas DA, Grant PJ, Turner AJ, Hooper NM. Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. Biochem J. 2004 Oct 1;383(1):45-51.

Ferrario CM, Jessup J, Gallagher PE. Effects of renin angiotensin system blockade on renal Ang-(1-7) forming enzymes and receptors. Kidney Int. 2005;68:2189-96.

Chappell MC. Emerging evidence for a functional angiotensin converying enzyme-2-angiotensin-(1-7)-Mas receptor axis: more than regulation of blood pressure? Hypertension. 2007;50:596-9.

Santos RAS, Ferreira AJ. Angiotensin-(1-7) and the renin-angiotensin system. Curr Opin Nephrol Hypertense. 2007;16:122-8.

Touyz RM, Schiffrin EL. Signal transduction mechanisms mediating the physiological and pathophysiological actions of angiotensin-II in vascular smooth muscle cells. Pharmacol Rev. 2000; 52:639-72.

Hunyadi L, Catt KJ. Pleiotropic AT1 receptor signaling pathway mediating physiological and pathogenic action of angiotensin-II. Mol Endocrinal. 2006;20:953-70.

Plante GE, Chakir M, Ettauil K, Lehoux S, Sirois P. Consequences of alteration in capillary permeability. Can J Physiol Pharmacol. 1996;74:824-33.

Ware LB, Matthay MA. The acute respiratory distress syndrome. New Eng J Med. 2000;342:1334-49.

Liu Y, Yang Y, Zhang C. Clinical and biochemical indexes from 2019-nCov infected patients linked to viral loads and lung injury. Sci China Life Sci. 2020;63:364-74.

Sodhi CP, Wohlford-Lenane C, Yamaguchi Y. Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg9 bradykinin/BKBIR axis and facilitate LPS-induced neutrophil infiltration. Am J Physiol Lung Cell Mol Physiol. 2018;314:L17-31.

Zou Z, Yan Y, Shu Y. Angiotensin converting enzyme-2 protect from lethal avian influenza: A H5N1 infection. Nat Commun. 2014;5:3594.

Gu H, Xin Z, Li T. Angiotensin converting enzyme-2 inhibits lung injury induced by respiratory syncytial virus. Sci Rep. 2016;6:19840.

Yang W, Huang W, Su S. Association study of angiotensin converting enzyme 2 gene polymorphism with coronary heart disease and myocardial infraction in Chinese Han population. Clin Sci (London). 2007;111:333-340.

Money C, Kaplan S, Kim MJ. The coronavirus killing far more men than women. The Washington Post. 2020.

Coronavirus disease-2019. Available at: Accessed 14 April 2020.

Bornstein SR, Dalan R, Hopkins D, Mingrone G, Boehm BO. Endocrine and metabolic link to coronavirus infection. Nature Reviews Endocrinol. 2020 Jun;16(6):297-8.

Graves DT, Kayal RA. Diabetes complication and dysregulated innate immunity. Front Biosci. 2008;13:1257.

Mooney JP, Galloway LJ, Riley EM. Malaria, anemia and invasive bacterial disease: a neutrophil problem? J Leukocyte Biol. 2019;105:645-55.

Gheblawi M, Wang K, Viveiros A, Nguyen Q, Zhong JC, Turner AJ, et al. Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2. Circulation Res. 2020 May 8;126(10):1456-74.

Lindholm LH, Ibsen H, Dalhoff B. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention for endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet. 2020;359:1004-10.

Simoes E, Silva AC, Silveria KD, Ferreira AJ, Teixeira MM. ACE2 angiotensin-(1-7) and Mas receptor axis in inflammation and fibrosis. Br J Pharmacol. 2013;169:477-92.

Benter IF, Yousif MH, Dhaunsi GS. Angiotensin-(1-7) prevents activation of NADPH oxidase and renal vascular dysfunction in diabetic hypertensive rats. Am J Nephrol. 2008;28:25-33.

Jarajapu YPR, Bhatwadekar AD, Cabellero S, Hazra S, Shenoy V, Activation of the ACE2/ Angiotensin (1-7)/ Mas receptor axis enhances the reparative function of dysfunctional diabetes endothelial progenitors. Diabetes. 2013;62(4):1258-69.

Forstermann U, Sesser WC. Nitric oxide synthases: regulation and function. Eur Heart J. 2012;33:829-37.

Forstermann U, Munzel T. Endothelial nitric oxide synthase in vascular disease from marvel to menace. Circulation. 2006;113:1708-14.

Surks JW, Marlette MA. Guanylate cyclase and the NO/cGMP signaling pathway. Biochimica et Biophysica Acta. 1999;1411:334-50.

IgnarroLJ, Buga GM, Wei LH. Role of the arginine-nitric oxide pathway in the regulation of vascular smooth muscle cell proliferation. Proceedings Nat Acad Sci United States of America. 2001;98(7):4202-8.

Fukai T, Siegfried MR, Ushio-Fukai M, Cheng Y, Kojda G, Harrison DG. Regulation of the vascular extracellular superoxide dismutase by nitric oxide and exercise training. J Clini Investigation. 2000 Jun 1;105(11):1631-9.

Aicher A, Zeiher AM, Dimmeler S. Mobilizing endothelial progenitor cells. Hypertension. 2005;45:321-5.

Urao N, Okigaki M, Yamada H, Aadachi Y, Matsuno K, Matsui A, et al. Erythropoietin-mobilized endothelial progenitors enhance reendothelialization via Akt-endothelial nitric oxide synthase activation and prevent neointimal hyperplasia. Circulation Res. 2006 Jun 9;98(11):1405-13.

Chen F, Castranova V, Shi X, Demers LM. New insights into the role of nuclear factor-κB, a ubiquitous transcription factor in the initiation of diseases. Clinical Chem. 1999 Jan 1;45(1):7-17.

Guzik TJ, Mussa S, Gastaldi D, Sadowski J, Ratnatunga C, Pillai R, et al. Mechanisms of increased vascular superoxide production in human diabetes mellitus: role of NAD (P) H oxidase and endothelial nitric oxide synthase. Circulation. 2002 Apr 9;105(14):1656-62.

Repine JD, Elkins ND, Fini M. Insulin decreases lung inflammation and acute lung injuryin rats. J Inves Med. 2006.

Zemans RL, Colgan SP, Downey GP. Transepithelial migration of neutrophils: mechanisms and implications for acute lung injury. Am J Res Cell Mol Biol. 2009;40:519-35.

Dushianthan A, Grocott MPW, Postle AD, Cusack R. Acute respiratory distress syndrome and acute lung injury. Postgrad. Med. 2011;87:611-22.

Wang L, Zhou X, Yin Y, Mai Y, Wang D, Zhang X. Hyperglycemia induces neutrophil extracellular traps formation through an NADPH oxidase-dependent pathway in diabetic retinopathy. Front Immunol. 2019 Jan 8;9:3076.

Soto M, Gaffney KJ, Rodgers KE. Improving the innate immune response in diabetes by modifying the renin angiotensin system. Frontiers Immunology. Published 10th December, 2019.

Shah BR, Hux JE. Quantifying the risk of infectious diseases for people with diabetes mellitus. Diabetes Care. 2003;26:510-3.

Yang JK, Feng Y, Yuan MY. Plasma glucose level and diabetes are independent predictors for mortality and morbidity in patients with SERS. Diab Med. 2006;23:623-8.

Kulcsar KA, Coleman CM, Beck SE, Frieman MB. Comorbid diabetes results in immune dysregulation and enhanced disease severity following MERS-CoV infection. JCI insight. 2019 Oct 17;4(20).

Ribeiro-Oliveria A, Impliziere AN, Maria-Pereira R. The renin-angiotensin system and diabetes. Vascular Health and Risk Management. 2008;4(4):787-803.

Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China. Jama. 2020 Mar 17;323(11):1061-9.

Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506.

Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020 Feb 15;395(10223):507-13.

Roca-Ho H, Riera M, Palau V, Pascual J, Soler MJ. Characterization of ACE and ACE2 expression within different organs of the NOD mouse. International J Molecular Sciences. 2017 Mar;18(3):563.

Wang T, Du Z, Zhu F, Cao Z, An Y, Gao Y, Jiang B. Comorbidities and multi-organ injuries in the treatment of COVID-19. Lancet. 2020 Mar 21;395(10228):e52.