Abstract
Currently, when the world is fighting against the rapidly spreading pandemic of COVID-19, the silent epidemic of diabetes should not be set aside. In comparison, while COVID- 19 led to about 6 million deaths in 2021, diabetes caused 6.7 million deaths in the same year. Diabetes mellitus is a serious risk factor for worse outcomes in COVID-19 patients. Moreover, it seems that there is a bidirectional relationship between pre-existing diabetes pandemic and the rapidly spreading COVID-19 pandemic.
In this article, we summarize mechanisms by which SARS-CoV-2 infects the host cell and discuss the bidirectional relationship between diabetes and COVID-19. We also focus on clinical variables in which diabetic patients differ from non-diabetic patients and which could have promising predictive value for the course and outcome of diabetic COVID-19 patients’ therapy management.
Keywords: COVID-19, diabetes, angiotensin converting enzyme 2, immunity, inflammation
[1]
Lai CC, Ko WC, Lee PI, Jean SS, Hsueh PR. Extra-respiratory manifestations of COVID-19. Int J Antimicrob Agents 2020; 56(2): 106024.
[http://dx.doi.org/10.1016/j.ijantimicag.2020.106024] [PMID: 32450197]
[http://dx.doi.org/10.1016/j.ijantimicag.2020.106024] [PMID: 32450197]
[2]
Puelles VG, Lütgehetmann M, Lindenmeyer MT, et al. Multiorgan and renal tropism of SARS-CoV-2. N Engl J Med 2020; 383(6): 590-2.
[http://dx.doi.org/10.1056/NEJMc2011400] [PMID: 32402155]
[http://dx.doi.org/10.1056/NEJMc2011400] [PMID: 32402155]
[3]
Song E, Zhang C, Israelow B, et al. Neuroinvasion of SARS-CoV-2 in human and mouse brain. bioRxiv 2020.
[http://dx.doi.org/10.1101/2020.06.25.169946]
[http://dx.doi.org/10.1101/2020.06.25.169946]
[4]
Xiao F, Tang M, Zheng X, Liu Y, Li X, Shan H. Evidence for gastrointestinal infection of SARS-CoV-2. Gastroenterology 2020; 158(6): 1831-3.
[http://dx.doi.org/10.1053/j.gastro.2020.02.055]
[http://dx.doi.org/10.1053/j.gastro.2020.02.055]
[5]
Chan JFW, Kok KH, Zhu Z, et al. Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan. Emerg Microbes Infect 2020; 9(1): 221-36.
[http://dx.doi.org/10.1080/22221751.2020.1719902] [PMID: 31987001]
[http://dx.doi.org/10.1080/22221751.2020.1719902] [PMID: 31987001]
[6]
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]
[http://dx.doi.org/10.1016/j.cell.2020.02.052] [PMID: 32142651]
[7]
Huang Y, Yang C, Xu X, Xu W, Liu S. Structural and functional properties of SARS-CoV-2 spike protein: Potential antivirus drug development for COVID-19. Acta Pharmacol Sin 2020; 41(9): 1141-9.
[http://dx.doi.org/10.1038/s41401-020-0485-4] [PMID: 32747721]
[http://dx.doi.org/10.1038/s41401-020-0485-4] [PMID: 32747721]
[8]
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]
[http://dx.doi.org/10.1038/s41586-020-2179-y] [PMID: 32225175]
[9]
Batlle D, Jose Soler M, Ye M. ACE2 and diabetes: ACE of ACEs? Diabetes 2010; 59(12): 2994-6.
[http://dx.doi.org/10.2337/db10-1205] [PMID: 21115782]
[http://dx.doi.org/10.2337/db10-1205] [PMID: 21115782]
[10]
Patel VB, Parajuli N, Oudit GY. Role of Angiotensin-Converting Enzyme 2 (ACE2) in diabetic cardiovascular complications. Clin Sci (Lond) 2014; 126(7): 471-82.
[http://dx.doi.org/10.1042/CS20130344] [PMID: 24329564]
[http://dx.doi.org/10.1042/CS20130344] [PMID: 24329564]
[11]
Sarkar S, Das D, Borsingh Wann S, Kalita J, Manna P. Is diabetes mellitus a wrongdoer to COVID-19 severity? Diabetes Res Clin Pract 2021; 178: 108936.
[http://dx.doi.org/10.1016/j.diabres.2021.108936] [PMID: 34217771]
[http://dx.doi.org/10.1016/j.diabres.2021.108936] [PMID: 34217771]
[12]
International Diabetes Federation. IDF Diabetes Atlas. (10th ed.), Brussels, Belgium: International Diabetes Federation 2021.
[13]
Sun H, Saeedi P, Karuranga S, et al. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract 2022; 183: 109119.
[http://dx.doi.org/10.1016/j.diabres.2021.109119] [PMID: 34879977]
[http://dx.doi.org/10.1016/j.diabres.2021.109119] [PMID: 34879977]
[14]
American Diabetes Association Professional Practice. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes—2022. Diabetes Care 2022; 45 (Suppl. 1): S17-38.
[http://dx.doi.org/10.2337/dc22-S002] [PMID: 34964875]
[http://dx.doi.org/10.2337/dc22-S002] [PMID: 34964875]
[15]
Alves C, Casqueiro J, Casqueiro J. Infections in patients with diabetes mellitus: A review of pathogenesis. Indian J Endocrinol Metab 2012; 16(7) (Suppl. 1): 27.
[http://dx.doi.org/10.4103/2230-8210.94253] [PMID: 22701840]
[http://dx.doi.org/10.4103/2230-8210.94253] [PMID: 22701840]
[16]
Carey IM, Critchley JA, DeWilde S, Harris T, Hosking FJ, Cook DG. Risk of infection in type 1 and type 2 diabetes compared with the general population: A matched cohort study. Diabetes Care 2018; 41(3): 513-21.
[http://dx.doi.org/10.2337/dc17-2131] [PMID: 29330152]
[http://dx.doi.org/10.2337/dc17-2131] [PMID: 29330152]
[17]
Critchley JA, Carey IM, Harris T, DeWilde S, Hosking FJ, Cook DG. Glycemic control and risk of infections among people with type 1 or type 2 diabetes in a large primary care cohort study. Diabetes Care 2018; 41(10): 2127-35.
[http://dx.doi.org/10.2337/dc18-0287] [PMID: 30104296]
[http://dx.doi.org/10.2337/dc18-0287] [PMID: 30104296]
[18]
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]
[http://dx.doi.org/10.1111/j.1464-5491.2006.01861.x] [PMID: 16759303]
[19]
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.
[http://dx.doi.org/10.1007/s00592-009-0109-4] [PMID: 19333547]
[http://dx.doi.org/10.1007/s00592-009-0109-4] [PMID: 19333547]
[20]
Ceriello A. Hyperglycemia and COVID-19: What was known and what is really new? Diabetes Res Clin Pract 2020; 167: 108383.
[http://dx.doi.org/10.1016/j.diabres.2020.108383] [PMID: 32853690]
[http://dx.doi.org/10.1016/j.diabres.2020.108383] [PMID: 32853690]
[21]
Lim S, Bae JH, Kwon HS, Nauck MA. COVID-19 and diabetes mellitus: From pathophysiology to clinical management. Nat Rev Endocrinol 2021; 17(1): 11-30.
[http://dx.doi.org/10.1038/s41574-020-00435-4] [PMID: 33188364]
[http://dx.doi.org/10.1038/s41574-020-00435-4] [PMID: 33188364]
[22]
Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 2011; 11(2): 98-107.
[http://dx.doi.org/10.1038/nri2925] [PMID: 21233852]
[http://dx.doi.org/10.1038/nri2925] [PMID: 21233852]
[23]
Donath MY, Schumann DM, Faulenbach M, Ellingsgaard H, Perren A, Ehses JA. Islet inflammation in type 2 diabetes: From metabolic stress to therapy. Diabetes Care 2008; 31 (Suppl. 2): S161-4.
[http://dx.doi.org/10.2337/dc08-s243] [PMID: 18227479]
[http://dx.doi.org/10.2337/dc08-s243] [PMID: 18227479]
[24]
Masters SL, Dunne A, Subramanian SL, et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nat Immunol 2010; 11(10): 897-904.
[http://dx.doi.org/10.1038/ni.1935] [PMID: 20835230]
[http://dx.doi.org/10.1038/ni.1935] [PMID: 20835230]
[25]
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.
[http://dx.doi.org/10.1038/s41577-020-0311-8] [PMID: 32346093]
[http://dx.doi.org/10.1038/s41577-020-0311-8] [PMID: 32346093]
[26]
Akarsu C, Karabulut M, Aydin H, et al. Association between acute pancreatitis and COVID-19: Could pancreatitis be the missing piece of the puzzle about increased mortality rates? J Invest Surg 2022; 35(1): 119-25.
[http://dx.doi.org/10.1080/08941939.2020.1833263] [PMID: 33138658]
[http://dx.doi.org/10.1080/08941939.2020.1833263] [PMID: 33138658]
[27]
Liu F, Long X, Zhang B, Zhang W, Chen X, Zhang Z. ACE2 expression in pancreas may cause pancreatic damage after SARS-CoV-2 infection. Clin Gastroenterol Hepatol 2020; 18(9): 2128-2130.e2.
[http://dx.doi.org/10.1016/j.cgh.2020.04.040] [PMID: 32334082]
[http://dx.doi.org/10.1016/j.cgh.2020.04.040] [PMID: 32334082]
[28]
Xue T. Blood glucose levels in elderly subjects with type 2 diabetes during COVID-19 outbreak: A retrospective study in a single center. medRxiv 2020.
[29]
Unsworth R, Wallace S, Oliver NS, et al. New-onset type 1 diabetes in children during COVID-19: Multicenter regional findings in the U.K. Diabetes Care 2020; 43(11): e170-1.
[http://dx.doi.org/10.2337/dc20-1551] [PMID: 32816997]
[http://dx.doi.org/10.2337/dc20-1551] [PMID: 32816997]
[30]
Alexandre MI, Henriques AR, Cavaco D, et al. New-onset type 1 diabetes in children and COVID-19. Acta Med Port 2021.
[http://dx.doi.org/10.20344/amp.16412]
[http://dx.doi.org/10.20344/amp.16412]
[31]
Salmi H, Heinonen S, Hästbacka J, et al. New-onset type 1 diabetes in Finnish children during the COVID-19 pandemic. Arch Dis Child 2022; 107(2): 180-5.
[http://dx.doi.org/10.1136/archdischild-2020-321220] [PMID: 34045208]
[http://dx.doi.org/10.1136/archdischild-2020-321220] [PMID: 34045208]
[32]
Goldman N, Fink D, Cai J, Lee YN, Davies Z. High prevalence of COVID-19-associated diabetic ketoacidosis in UK secondary care. Diabetes Res Clin Pract 2020; 166: 108291.
[http://dx.doi.org/10.1016/j.diabres.2020.108291] [PMID: 32615280]
[http://dx.doi.org/10.1016/j.diabres.2020.108291] [PMID: 32615280]
[33]
Li J, Wang X, Chen J, Zuo X, Zhang H, Deng A. COVID -19 infection may cause ketosis and ketoacidosis. Diabetes Obes Metab 2020; 22(10): 1935-41.
[http://dx.doi.org/10.1111/dom.14057] [PMID: 32314455]
[http://dx.doi.org/10.1111/dom.14057] [PMID: 32314455]
[34]
Pugliese G, Vitale M, Resi V, Orsi E. Is diabetes mellitus a risk factor for COronaVIrus Disease 19 (COVID-19)? Acta Diabetol 2020; 57(11): 1275-85.
[http://dx.doi.org/10.1007/s00592-020-01586-6] [PMID: 32865671]
[http://dx.doi.org/10.1007/s00592-020-01586-6] [PMID: 32865671]
[35]
Shi Q, Zhang X, Jiang F, et al. Clinical characteristics and risk factors for mortality of COVID-19 patients with diabetes in Wuhan, China: A two-center, retrospective study. Diabetes Care 2020; 43(7): 1382-91.
[http://dx.doi.org/10.2337/dc20-0598] [PMID: 32409504]
[http://dx.doi.org/10.2337/dc20-0598] [PMID: 32409504]
[36]
Scheen AJ, Marre M, Thivolet C. Prognostic factors in patients with diabetes hospitalized for COVID-19: Findings from the CORONADO study and other recent reports. Diabetes Metab 2020; 46(4): 265-71.
[http://dx.doi.org/10.1016/j.diabet.2020.05.008] [PMID: 32447101]
[http://dx.doi.org/10.1016/j.diabet.2020.05.008] [PMID: 32447101]
[37]
Alvarado-Vasquez N. Could a family history of type 2 diabetes be a risk factor to the endothelial damage in the patient with COVID-19? Med Hypotheses 2021; 146: 110378.
[http://dx.doi.org/10.1016/j.mehy.2020.110378] [PMID: 33189452]
[http://dx.doi.org/10.1016/j.mehy.2020.110378] [PMID: 33189452]
[38]
Wang X, Liu Z, Li J, et al. Impacts of type 2 diabetes on disease severity, therapeutic effect, and mortality of patients with COVID-19. J Clin Endocrinol Metab 2020; 105(12): dgaa535.
[http://dx.doi.org/10.1210/clinem/dgaa535] [PMID: 32979271]
[http://dx.doi.org/10.1210/clinem/dgaa535] [PMID: 32979271]
[39]
Li G, Deng Q, Feng J, Li F, Xiong N, He Q. Clinical characteristics of diabetic patients with COVID-19. J Diabetes Res 2020; 2020: 1652403.
[http://dx.doi.org/10.1155/2020/1652403] [PMID: 32851093]
[http://dx.doi.org/10.1155/2020/1652403] [PMID: 32851093]
[40]
Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China. JAMA 2020; 323(11): 1061-9.
[http://dx.doi.org/10.1001/jama.2020.1585] [PMID: 32031570]
[http://dx.doi.org/10.1001/jama.2020.1585] [PMID: 32031570]
[41]
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. Lancet 2020; 395(10229): 1054-62.
[http://dx.doi.org/10.1016/S0140-6736(20)30566-3] [PMID: 32171076]
[http://dx.doi.org/10.1016/S0140-6736(20)30566-3] [PMID: 32171076]
[42]
Khan MUF, Ali BR, Mohammed HQ, et al. Serum level estimation of some biomarkers in diabetic and non-diabetic COVID-19 infected patients. Appl Nanosci 2022; 1-8.
[http://dx.doi.org/10.1007/s13204-021-02167-x] [PMID: 35136705]
[http://dx.doi.org/10.1007/s13204-021-02167-x] [PMID: 35136705]
[43]
Varikasuvu SR, Varshney S, Dutt N. Markers of coagulation dysfunction and inflammation in diabetic and non-diabetic COVID-19. J Thromb Thrombolysis 2021; 51(4): 941-6.
[http://dx.doi.org/10.1007/s11239-020-02270-w] [PMID: 32889620]
[http://dx.doi.org/10.1007/s11239-020-02270-w] [PMID: 32889620]
[44]
Li Y, Zhao K, Wei H, et al. Dynamic relationship between D-dimer and COVID-19 severity. Br J Haematol 2020; 190(1): e24-7.
[http://dx.doi.org/10.1111/bjh.16797] [PMID: 32420615]
[http://dx.doi.org/10.1111/bjh.16797] [PMID: 32420615]
[45]
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.
[http://dx.doi.org/10.1055/s-0040-1710018] [PMID: 32316063]
[http://dx.doi.org/10.1055/s-0040-1710018] [PMID: 32316063]
[46]
Yan Y, Yang Y, Wang F, et al. Clinical characteristics and outcomes of patients with severe covid-19 with diabetes. BMJ Open Diabetes Res Care 2020; 8(1): e001343.
[http://dx.doi.org/10.1136/bmjdrc-2020-001343] [PMID: 32345579]
[http://dx.doi.org/10.1136/bmjdrc-2020-001343] [PMID: 32345579]
[47]
Lu M, Zuo Y, Guo J, Wen X, Kang Y. Continuous glucose monitoring system can improve the quality of glucose control and glucose variability compared with point-of-care measurement in critically ill patients. Medicine (Baltimore) 2018; 97(36): e12138.
[http://dx.doi.org/10.1097/MD.0000000000012138] [PMID: 30200106]
[http://dx.doi.org/10.1097/MD.0000000000012138] [PMID: 30200106]
[48]
Sardu C, D’Onofrio N, Balestrieri ML, et al. Outcomes in patients with hyperglycemia affected by COVID-19: Can we do more on glycemic control? Diabetes Care 2020; 43(7): 1408-15.
[http://dx.doi.org/10.2337/dc20-0723] [PMID: 32430456]
[http://dx.doi.org/10.2337/dc20-0723] [PMID: 32430456]
[49]
Sinclair A, Dhatariya K, Burr O, et al. Guidelines for the management of diabetes in care homes during the Covid-19 pandemic. Diabet Med 2020; 37(7): 1090-3.
[http://dx.doi.org/10.1111/dme.14317] [PMID: 32369634]
[http://dx.doi.org/10.1111/dme.14317] [PMID: 32369634]
[50]
Iacobellis G. COVID-19 and diabetes: Can DPP4 inhibition play a role? Diabetes Res Clin Pract 2020; 162: 108125.
[http://dx.doi.org/10.1016/j.diabres.2020.108125] [PMID: 32224164]
[http://dx.doi.org/10.1016/j.diabres.2020.108125] [PMID: 32224164]
[51]
Maddaloni E, Buzzetti R. Covid-19 and diabetes mellitus: Unveiling the interaction of two pandemics. Diabetes Metab Res Rev 2020; 36(7): e33213321.
[http://dx.doi.org/10.1002/dmrr.3321] [PMID: 32233018]
[http://dx.doi.org/10.1002/dmrr.3321] [PMID: 32233018]
[52]
Lee YS, Park MS, Choung JS, et al. Glucagon-like peptide-1 inhibits adipose tissue macrophage infiltration and inflammation in an obese mouse model of diabetes. Diabetologia 2012; 55(9): 2456-68.
[http://dx.doi.org/10.1007/s00125-012-2592-3] [PMID: 22722451]
[http://dx.doi.org/10.1007/s00125-012-2592-3] [PMID: 22722451]
[53]
Lee YS, Jun HS. Anti-inflammatory effects of GLP-1-based therapies beyond glucose control. Mediators Inflamm 2016; 2016: 1-11.
[http://dx.doi.org/10.1155/2016/3094642] [PMID: 27110066]
[http://dx.doi.org/10.1155/2016/3094642] [PMID: 27110066]
[54]
Maranta F, Cianfanelli L, Rizzo M, Cianflone D. Filling the gap between Guidelines and Real World in the cardiovascular approach to the diabetic patients: The need for a call to action. Int J Cardiol 2021; 329: 205-7.
[http://dx.doi.org/10.1016/j.ijcard.2020.12.074] [PMID: 33388398]
[http://dx.doi.org/10.1016/j.ijcard.2020.12.074] [PMID: 33388398]
[55]
Couselo-Seijas M, Agra-Bermejo RM, Fernández AL, et al. High released lactate by epicardial fat from coronary artery disease patients is reduced by dapagliflozin treatment. Atherosclerosis 2020; 292: 60-9.
[http://dx.doi.org/10.1016/j.atherosclerosis.2019.11.016] [PMID: 31783199]
[http://dx.doi.org/10.1016/j.atherosclerosis.2019.11.016] [PMID: 31783199]
[56]
Hahn K, Ejaz AA, Kanbay M, Lanaspa MA, Johnson RJ. Acute kidney injury from SGLT2 inhibitors: Potential mechanisms. Nat Rev Nephrol 2016; 12(12): 711-2.
[http://dx.doi.org/10.1038/nrneph.2016.159] [PMID: 27847389]
[http://dx.doi.org/10.1038/nrneph.2016.159] [PMID: 27847389]
[57]
Pang J, Liu M, Ling W, Jin T. Friend or foe? ACE2 inhibitors and GLP-1R agonists in COVID-19 treatment. Obes Med 2021; 22: 100312.
[http://dx.doi.org/10.1016/j.obmed.2020.100312] [PMID: 33426364]
[http://dx.doi.org/10.1016/j.obmed.2020.100312] [PMID: 33426364]
