Login Register Cart 0
Generic placeholder image

Current Diabetes Reviews

Editor-in-Chief

ISSN (Print): 1573-3998
ISSN (Online): 1875-6417

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Diabetes Mellitus and SARS-CoV-2 Infection: Pathophysiologic Mechanisms and Implications in Management

Author(s): Natalia G. Vallianou*, Angelos Evangelopoulos, Dimitris Kounatidis, Theodora Stratigou, Gerasimos Socrates Christodoulatos, Irene Karampela and Maria Dalamaga

Volume 17, Issue 6, 2021

Published on: 01 January, 2021

Article ID: e123120189797 Pages: 11

DOI: 10.2174/1573399817666210101110253

Price: $65

Abstract

Introduction: Currently, diabetes mellitus (DM), as well as coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are major public health issues worldwide.

Background: It has been suggested that patients with DM are more vulnerable to SARS-CoV-2 infection and suffer from more severe forms of the disease.

Methods: A literature search was performed using PubMed, Scopus, and Google search engines.

Results: Angiotensin-converting enzyme-2 (ACE2) is the major receptor of SARS-CoV-2 in the human host. The differential expression of ACE2 in the lungs of patients with DM makes them more susceptible to COVID-19. Additionally, acute or chronic hyperglycemia renders individuals in an immune-suppressive state, with impaired innate and adaptive immunity function, also contributing to the severity of COVID-19 infection among patients with DM. Other factors contributing to a more severe course of COVID-19 include the coexistence of obesity in T2DM, the endothelial inflammation induced by the SARS-CoV-2 infection, which aggravates the endothelial dysfunction observed in both T1DM and T2DM, and the hypercoagulability presented in COVID-19 infection that increases the thrombotic tendency in DM.

Conclusion: This review summarizes the pathophysiologic mechanisms underlying the coexistence of both pandemics as well as the current recommendations and future perspectives regarding the optimal treatment of inpatients and outpatients with DM in the era of SARS-CoV-2 infection. Notably, the currently recommended drugs for the treatment of severe COVID-19, dexamethasone and remdesivir, may cause hyperglycemia, an adverse effect that physicians should bear in mind when caring for patients with DM and COVID-19.

Keywords: Diabetes mellitus, COVID-19, pandemic, pathogenesis, SARS-CoV-2, treatment.

[1]
IDF Diabetes Atlas. (8th ed). 2017.
[2]
Zhu N, Zhang D, Wang W, et al. China novel coronavirus investigating and research team. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020; 382(8): 727-33.
[http://dx.doi.org/10.1056/NEJMoa2001017] [PMID: 31978945]
[3]
Del Rio C, Malani PN. COVID-19-New insights on a rapidly changing epidemic. JAMA 2020; 323(14): 1339-40.
[http://dx.doi.org/10.1001/jama.2020.3072] [PMID: 32108857]
[4]
Coronavirus Disease 2019 (COVID-2019) Management in hospitalized adults www.uptodate.com2019.
[5]
WHO Coronavirus COVID-19 Dashboard Report 2020.
[6]
Huang I, Lim MA, Pranata R. Diabetes mellitus is associated with increased mortality and severity of disease in COVID-19 pneumonia - A systematic review, meta-analysis, and meta-regression. Diabetes Metab Syndr 2020; 14(4): 395-403.
[http://dx.doi.org/10.1016/j.dsx.2020.04.018] [PMID: 32334395]
[7]
Kumar A, Arora A, Sharma P, et al. Is diabetes mellitus associated with mortality and severity of COVID-19? A meta-analysis. Diabetes Metab Syndr 2020; 14(4): 535-45.
[http://dx.doi.org/10.1016/j.dsx.2020.04.044] [PMID: 32408118]
[8]
Pearson-Stuttard J, Blundell S, Harris T, Cook DG, Critchley J. Diabetes and infection: assessing the association with glycaemic control in population-based studies. Lancet Diabetes Endocrinol 2016; 4(2): 148-58.
[http://dx.doi.org/10.1016/S2213-8587(15)00379-4] [PMID: 26656292]
[9]
Knapp S. Diabetes and infection: is there a link?-A mini-review. Gerontology 2013; 59(2): 99-104.
[http://dx.doi.org/10.1159/000345107] [PMID: 23182884]
[10]
Allard R, Leclerc P, Tremblay C, Tannenbaum TN. Diabetes and the severity of pandemic influenza A (H1N1) infection. Diabetes Care 2010; 33(7): 1491-3.
[http://dx.doi.org/10.2337/dc09-2215] [PMID: 20587722]
[11]
Jain S, Kamimoto L, Bramley AM, et al. 2009 Pandemic Influenza A (H1N1) Virus Hospitalizations Investigation Team. Hospitalized patients with 2009 H1N1 influenza in the United States, April-June 2009. N Engl J Med 2009; 361(20): 1935-44.
[http://dx.doi.org/10.1056/NEJMoa0906695] [PMID: 19815859]
[12]
Wilking H, Buda S, von der Lippe E, et al. Mortality of 2009 pandemic influenza A(H1N1) in Germany. Euro Surveill 2010; 15(49): 49.
[http://dx.doi.org/10.2807/ese.15.49.19741-en] [PMID: 21163179]
[13]
Wang W, Chen H, Li Q, et al. Fasting plasma glucose is an independent predictor for severity of H1N1 pneumonia. BMC Infect Dis 2011; 11: 104.
[http://dx.doi.org/10.1186/1471-2334-11-104] [PMID: 21510870]
[14]
Yang JK, Feng Y, Yuan MY, et al. Plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with SARS. Diabet Med 2006; 23(6): 623-8.
[http://dx.doi.org/10.1111/j.1464-5491.2006.01861.x] [PMID: 16759303]
[15]
Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet 2020.doi.org/10.1016/S0140-
[16]
Remuzzi A, Remuzzi G. COVID-19 and Italy: what next? The Lancet 2020.doi.org/10.1016/S0140-6736(20)30627-9
[17]
Marzona I, Avanzini F, Tettamanti M, et al. Prevalence and management of diabetes in immigrants resident in the Lombardy Region: the importance of ethnicity and duration of stay. Acta Diabetol 2018; 55(4): 355-62.
[http://dx.doi.org/10.1007/s00592-018-1102-6] [PMID: 29357034]
[18]
Li G, Fan Y, Lai Y, et al. Coronavirus infections and immune responses. J Med Virol 2020; 92(4): 424-32.
[http://dx.doi.org/10.1002/jmv.25685] [PMID: 31981224]
[19]
Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; 181(2): 271-280.e8.
[http://dx.doi.org/10.1016/j.cell.2020.02.052] [PMID: 32142651]
[20]
Raj VS, Mou H, Smits SL, et al. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature 2013; 495(7440): 251-4.
[http://dx.doi.org/10.1038/nature12005] [PMID: 23486063]
[21]
Shang J, Ye G, Shi K, et al. Structural basis of receptor recognition by SARS-CoV-2. Nature 2020; 581(7807): 221-4.
[http://dx.doi.org/10.1038/s41586-020-2179-y] [PMID: 32225175]
[22]
AlGhatrif M, Cingolani O, Lakatta EG. The dilemma of coronavirus disease 2019, aging, and cardiovascular disease: insights from cardiovascular aging science. JAMA Cardiol 2020; 5(7): 747-8.
[http://dx.doi.org/10.1001/jamacardio.2020.1329] [PMID: 32242886]
[23]
Kiely DG, Cargill RI, Wheeldon NM, Coutie WJ, Lipworth BJ. Haemodynamic and endocrine effects of type 1 angiotensin II receptor blockade in patients with hypoxaemic cor pulmonale. Cardiovasc Res 1997; 33(1): 201-8.
[http://dx.doi.org/10.1016/S0008-6363(96)00180-0] [PMID: 9059545]
[24]
Imai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature 2005; 436(7047): 112-6.
[http://dx.doi.org/10.1038/nature03712] [PMID: 16001071]
[25]
Tikellis C, Johnston CI, Forbes JM, et al. Characterization of renal angiotensin-converting enzyme 2 in diabetic nephropathy. Hypertension 2003; 41(3): 392-7.
[http://dx.doi.org/10.1161/01.HYP.0000060689.38912.CB] [PMID: 12623933]
[26]
Mizuiri S, Hemmi H, Arita M, et al. Expression of ACE and ACE2 in individuals with diabetic kidney disease and healthy controls. Am J Kidney Dis 2008; 51(4): 613-23.
[http://dx.doi.org/10.1053/j.ajkd.2007.11.022] [PMID: 18371537]
[27]
Roca-Ho H, Riera M, Palau V, Pascual J, Soler MJ. Characterization of ACE and ACE2 expression within different organs of the NOD mouse. Int J Mol Sci 2017; 18(3): 18.
[http://dx.doi.org/10.3390/ijms18030563] [PMID: 28273875]
[28]
Rao S, Lau A, So HC. Exploring diseases/traits and blood proteins causally related to expression of ACE2, the putative receptor of 2019-nCov: a Mendelian Randomization analysis. Diabetes Care 2020; 43(7): 1416-26.
[http://dx.doi.org/10.2337/dc20-0643] [PMID: 32430459]
[29]
Delamaire M, Maugendre D, Moreno M, Le Goff MC, Allannic H, Genetet B. Impaired leucocyte functions in diabetic patients. Diabet Med 1997; 14(1): 29-34.
[http://dx.doi.org/10.1002/(SICI)1096-9136(199701)14:1<29::AID-DIA300>3.0.CO;2-V] [PMID: 9017350]
[30]
Kim JH, Park K, Lee SB, et al. Relationship between natural killer cell activity and glucose control in patients with type 2 diabetes and prediabetes. J Diabetes Investig 2019; 10(5): 1223-8.
[http://dx.doi.org/10.1111/jdi.13002] [PMID: 30618112]
[31]
Lumeng CN, DelProposto JB, Westcott DJ, Saltiel AR. Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes 2008; 57(12): 3239-46.
[http://dx.doi.org/10.2337/db08-0872] [PMID: 18829989]
[32]
Tsigalou C, Vallianou N, Dalamaga M. Autoantibody production in obesity: Is there evidence for a link between obesity and autoimmunity? Curr Obes Rep 2020; 9(3): 245-54.
[http://dx.doi.org/10.1007/s13679-020-00397-8] [PMID: 32632847]
[33]
Espinoza-Jiménez A, Peón AN, Terrazas LI. Alternatively activated macrophages in types 1 and 2 diabetes. Mediators Inflamm 2012; 2012
[http://dx.doi.org/10.1155/2012/815953] [PMID: 23326021]
[34]
Huang J, Xiao Y, Zheng P, et al. Distinct neutrophil counts and functions in newly diagnosed type 1 diabetes, latent autoimmune diabetes in adults, and type 2 diabetes. Diabetes Metab Res Rev 2019; 35(1)
[http://dx.doi.org/10.1002/dmrr.3064] [PMID: 30123986]
[35]
Harsunen MH, Puff R, D’Orlando O, et al. Reduced blood leukocyte and neutrophil numbers in the pathogenesis of type 1 diabetes. Horm Metab Res 2013; 45(6): 467-70.
[http://dx.doi.org/10.1055/s-0032-1331226] [PMID: 23322517]
[36]
Valle A, Giamporcaro GM, Scavini M, et al. Reduction of circulating neutrophils precedes and accompanies type 1 diabetes. Diabetes 2013; 62(6): 2072-7.
[http://dx.doi.org/10.2337/db12-1345] [PMID: 23349491]
[37]
Cao X. COVID-19: immunopathology and its implications for therapy. Nat Rev Immunol 2020; 20(5): 269-70.
[http://dx.doi.org/10.1038/s41577-020-0308-3] [PMID: 32273594]
[38]
Hussain A, Bhowmik B, do Vale Moreira NC. COVID-19 and diabetes: Knowledge in progress. Diabetes Res Clin Pract 2020; 162
[http://dx.doi.org/10.1016/j.diabres.2020.108142] [PMID: 32278764]
[39]
Bouayad A. Innate immune evasion by SARS-CoV-2: Comparison with SARS-CoV. Rev Med Virol 2020.
[http://dx.doi.org/10.1002/rmv.2135] [PMID: 32734714]
[40]
Inácio DP, Amado T, Silva-Santos B, Gomes AQ. Control of T cell effector functions by miRNAs. Cancer Lett 2018; 427: 63-73.
[http://dx.doi.org/10.1016/j.canlet.2018.04.011] [PMID: 29679611]
[41]
Stentz FB, Kitabchi AE. Activated T lymphocytes in Type 2 diabetes: implications from in vitro studies. Curr Drug Targets 2003; 4(6): 493-503.
[http://dx.doi.org/10.2174/1389450033490966] [PMID: 12866664]
[42]
Nicholas DA, Proctor EA, Agrawal M, et al. Fatty acid metabolites combine with reduced beta oxidation to activate Th17 inflammation in human type 2 diabetes. Cell Metab 2019; 30(3): 447-461.e5.
[http://dx.doi.org/10.1016/j.cmet.2019.07.004] [PMID: 31378464]
[43]
Garidou L, Pomié C, Klopp P, et al. The gut microbiota regulates intestinal CD4 T cells expressing RORgammat and controls metabolic disease. Cell Metab 2015; 22(1): 100-12.
[http://dx.doi.org/10.1016/j.cmet.2015.06.001] [PMID: 26154056]
[44]
Nishimura S, Manabe I, Nagasaki M, et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 2009; 15(8): 914-20.
[http://dx.doi.org/10.1038/nm.1964] [PMID: 19633658]
[45]
Jagannathan-Bogdan M, McDonnell ME, Shin H, et al. Elevated proinflammatory cytokine production by a skewed T cell compartment requires monocytes and promotes inflammation in type 2 diabetes J Immunol 2011; 186(2): 1162-7.
[46]
Sireesh D, Dhamodharan U, Ezhilarasi K, Vijay V, Ramkumar KM. Association of NF-E2 related factor 2 (Nrf2) and inflammatory cytokines in recent onset type 2 diabetes mellitus. Sci Rep 2018; 8(1): 5126.
[http://dx.doi.org/10.1038/s41598-018-22913-6] [PMID: 29572460]
[47]
Cortez-Espinosa N, Cortés-Garcia JD, Martínez-Leija E, et al. CD39 expression on Treg and Th17 cells is associated with metabolic factors in patients with type 2 diabetes. Hum Immunol 2015; 76(9): 622-30.
[http://dx.doi.org/10.1016/j.humimm.2015.09.007] [PMID: 26386144]
[48]
Xufré C, Costa M, Roura-Mir C, et al. Low frequency of GITR+ T cells in ex vivo and in vitro expanded Treg cells from type 1 diabetic patients. Int Immunol 2013; 25(10): 563-74.
[http://dx.doi.org/10.1093/intimm/dxt020] [PMID: 23929911]
[49]
Muniyappa R, Gubbi S. COVID-19 pandemic, coronaviruses, and diabetes mellitus. Am J Physiol Endocrinol Metab 2020; 318(5): E736-41.
[http://dx.doi.org/10.1152/ajpendo.00124.2020] [PMID: 32228322]
[50]
Altmann DM, Boyton RJ. SARS-CoV-2 T cell immunity: Specificity, function, durability, and role in protection. Sci Immunol 2020; 5(49)
[http://dx.doi.org/10.1126/sciimmunol.abd6160] [PMID: 32680954]
[51]
Ceriello A, Stoian AP, Rizzo M. COVID-19 and diabetes management: What should be considered? Diabetes Res Clin Pract 2020; 163
[http://dx.doi.org/10.1016/j.diabres.2020.108151] [PMID: 32305399]
[52]
Klonoff DC, Umpierrez GE. Letter to the Editor: COVID-19 in patients with diabetes: Risk factors that increase morbidity. Metabolism 2020; 108
[http://dx.doi.org/10.1016/j.metabol.2020.154224] [PMID: 32275971]
[53]
Riddle MC, Buse JB, Franks PW, et al. COVID-19 in people with diabetes: urgently needed lessons from early reports. Diabetes Care 2020; 43(7): 1378-81.
[http://dx.doi.org/10.2337/dci20-0024] [PMID: 32409505]
[54]
Bornstein SR, Rubino F, Khunti K, et al. Practical recommendations for the management of diabetes in patients with COVID-19. Lancet Diabetes Endocrinol 2020; 8(6): 546-50.
[http://dx.doi.org/10.1016/S2213-8587(20)30152-2] [PMID: 32334646]
[55]
Lönnrot M, Lynch KF, Elding Larsson H, et al. TEDDY Study Group. Respiratory infections are temporally associated with initiation of type 1 diabetes autoimmunity: the TEDDY study. Diabetologia 2017; 60(10): 1931-40.
[http://dx.doi.org/10.1007/s00125-017-4365-5] [PMID: 28770319]
[56]
Yang J, Hu J, Zhu C. Obesity aggravates COVID-19: A systematic review and meta-analysis. J Med Virol 2020.
[http://dx.doi.org/10.1002/jmv.26237] [PMID: 32603481]
[57]
Belanger MJ, Hill MA, Angelidi AM, Dalamaga M, Sowers JR, Mantzoros CS. Covid-19 and disparities in nutrition and obesity. N Engl J Med 2020; 383(11): e69.
[http://dx.doi.org/10.1056/NEJMp2021264] [PMID: 32668105]
[58]
Wang T, Du Z, Zhu F, et al. Comorbidities and multi-organ injuries in the treatment of COVID-19. Lancet 2020; 395(10228): e52.
[http://dx.doi.org/10.1016/S0140-6736(20)30558-4] [PMID: 32171074]
[59]
Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endotheliitis in COVID-19 Lancet 2020; 395(10234): 1417-8.
[60]
Hayden MR. Endothelial activation and dysfunction in metabolic syndrome, type 2 diabetes and coronavirus disease 2019. J Int Med Res 2020; 48(7)
[http://dx.doi.org/10.1177/0300060520939746] [PMID: 32722979]
[61]
Sobczak AIS, Stewart AJ. Coagulatory defects in type 1 and type 2 diabetes. Int J Mol Sci 2019; 20(24): 6345.
[http://dx.doi.org/10.3390/ijms20246345] [PMID: 31888259]
[62]
Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood 2020; 135(23): 2033-40.
[http://dx.doi.org/10.1182/blood.2020006000] [PMID: 32339221]
[63]
Sharma S, Ray A, Sadasivam B. Metformin in COVID-19: A possible role beyond diabetes. Diabetes Res Clin Pract 2020; 164
[http://dx.doi.org/10.1016/j.diabres.2020.108183] [PMID: 32360697]
[64]
Bilanges B, Posor Y, Vanhaesebroeck B. PI3K isoforms in cell signalling and vesicle trafficking. Nat Rev Mol Cell Biol 2019; 20(9): 515-34.
[http://dx.doi.org/10.1038/s41580-019-0129-z] [PMID: 31110302]
[65]
Kindrachuk J, Ork B, Hart BJ, et al. Antiviral potential of ERK/MAPK and PI3K/AKT/mTOR signaling modulation for Middle East respiratory syndrome coronavirus infection as identified by temporal kinome analysis. Antimicrob Agents Chemother 2015; 59(2): 1088-99.
[http://dx.doi.org/10.1128/AAC.03659-14] [PMID: 25487801]
[66]
Iacobellis G. COVID-19 and diabetes: Can DPP4 inhibition play a role? Diabetes Res Clin Pract 2020; 162
[http://dx.doi.org/10.1016/j.diabres.2020.108125] [PMID: 32224164]
[67]
Li K, Wohlford-Lenane CL, Channappanavar R, et al. Mouse-adapted MERS coronavirus causes lethal lung disease in human DPP4 knockin mice. Proc Natl Acad Sci USA 2017; 114(15): E3119-28.
[http://dx.doi.org/10.1073/pnas.1619109114] [PMID: 28348219]
[68]
Fan C, Wu X, Liu Q, et al. A Human DPP4-Knockin Mouse’s Susceptibility to Infection by Authentic and Pseudotyped MERS- CoV. Viruses 2018; 10(9): 10-9.
[http://dx.doi.org/10.3390/v10090448] [PMID: 30142928]
[69]
Conarello SL, Li Z, Ronan J, et al. Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance. Proc Natl Acad Sci USA 2003; 100(11): 6825-30.
[http://dx.doi.org/10.1073/pnas.0631828100] [PMID: 12748388]
[70]
Yang W, Cai X, Han X, Ji L. DPP-4 inhibitors and risk of infections: a meta-analysis of randomized controlled trials. Diabetes Metab Res Rev 2016; 32(4): 391-404.
[http://dx.doi.org/10.1002/dmrr.2723] [PMID: 26417956]
[71]
Iacobellis G. Local and systemic effects of the multifaceted epicardial adipose tissue depot. Nat Rev Endocrinol 2015; 11(6): 363-71.
[http://dx.doi.org/10.1038/nrendo.2015.58] [PMID: 25850659]
[72]
RECOVERY collaborative group. Dexamethasone in hospitalized patients with Vovid-19-preliminary report. N Engl J Med 2020.
[http://dx.doi.org/10.1056/NEJMoa2021436]
[73]
Beigel JH, Tomashek KM, Dodd LE, et al. ACTT-1 study group members. Remdesivir for the treatment of Covid-19 - final report. N Engl J Med 2020.
[http://dx.doi.org/10.1056/NEJMoa2007764] [PMID: 32445440]
[74]
Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2020; 395(10236): 1569-78.
[http://dx.doi.org/10.1016/S0140-6736(20)31022-9] [PMID: 32423584]
[75]
Chakravarti HN, Nag A. Efficacy and safety of hydroxychloroquine as add-on therapy in uncontrolled type 2 diabetes patients who were using two oral antidiabetic drugs. J Endocrinol Invest 2020; 1-12.
[http://dx.doi.org/10.1007/s40618-020-01330-5] [PMID: 32594451]
[76]
Stoian AP, Catrinoiu D, Rizzo M, Ceriello A. Hydroxychloroquine, COVID-19 and diabetes. Why it is a different story. Diabetes Metab Res Rev 2020.
[http://dx.doi.org/10.1002/dmrr.3379] [PMID: 32592507]
[77]
Cai Q, Yang M, Liu D, et al. Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study. Engineering (Beijing) 2020.
[http://dx.doi.org/10.1016/j.eng.2020.03.007] [PMID: 32346491]

Rights & Permissions Print Cite
Article Metrics
69
1
© 2024 Bentham Science Publishers | Privacy Policy