Long COVID-19 and diabetes mellitus: a short review

Abstract

The persistence of Covid-19 infection for more than four weeks after the acute phase is defined as the long Covid-19 syndrome. This condition, otherwise defined by the persistence of signs and symptoms for more than 12 weeks, shares several features with diabetes mellitus: diabetes mellitus and Covid-19 infections have a pandemic dimension, are characterized by an inflammatory milieu, and show a bidirectional relationship. Diabetic patients appear more likely to develop long Covid-19 syndrome than non-diabetic individuals. The chronicity of Covid-19 favors the development of new cases of diabetes. In this short review, we discuss the evidence supporting the link between Covid-19 and diabetes mellitus, focusing on the epidemiological and pathophysiological aspects of this dangerous relationship.

Highlights

● Patients affected by diabetes both type 1 and type 2 seem more likely to develop a long Covid-19 syndrome compared to non-diabetic subjects;

● Long Covid-19 syndrome is associated with new-onset cases of diabetes, both type 1 and type 2 higher than expected;

● Presence of other comorbidities prior to acute Covid-19 infection favors the development of long Covid-19 syndrome;

● Most frequent symptoms of long Covid-19 in diabetic patients are fatigue, shortness of breath, neurocognitive and neurological manifestations, and cardiovascular sequelae;

● Long Covid-19 can exacerbate microvascular dysfunction in patients with diabetes.

Keywords

Post-COVID / diabetes mellitus / long Covid-19 pathophysiological mechanisms

References

[1] Saeedi P,Salpea P.IDF Diabetes Atlas CommitteeGlobal and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9(th) edition.Diabetes Res Clin Pract2019;157:107843

[2] Wang D,Hu C.Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan.JAMA2020;323:1061-69 PMCID:PMC7042881

[3] Yang X,Xu J.Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.Lancet Respir Med2020;8:475-81 PMCID:PMC7102538

[4] Gupta A,Sehgal K.Extrapulmonary manifestations of COVID-19.Nat Med2020;26:1017-32

[5] Feldman EL,Hayek SS,Kretzler M.COVID-19 and diabetes: a collision and collusion of two diseases.Diabetes2020;69:2549-65 PMCID:PMC7679769

[6] Gianchandani R,Ang L.Managing hyperglycemia in the COVID-19 inflammatory storm.Diabetes2020;69:2048-53

[7] Sudre CH,Varsavsky T.Attributes and predictors of long COVID.Nat Med2021;27:626-31 PMCID:PMC7611399

[8] Chen C,Zimmermann L,Fritsche LG.Global prevalence of post-coronavirus disease 2019 (COVID-19) condition or long COVID: a meta-analysis and systematic review.J Infect Dis2022;226:1593-607 PMCID:PMC9047189

[9] Wu J,Sun X.Influence of diabetes mellitus on the severity and fatality of SARS-CoV-2 (COVID-19) infection.Diabetes Obes Metab2020;22:1907-14 PMCID:PMC7300679

[10] Wu ZH,Cheng Q.Diabetes increases the mortality of patients with COVID-19: a meta-analysis.Acta Diabetol2021;58:139-44 PMCID:PMC7311595

[11] Zhu L,Cheng X.Association of blood glucose control and outcomes in patients with COVID-19 and pre-existing type 2 diabetes.Cell Metab2020;31:1068-1077.e3 PMCID:PMC7252168

[12] Barron E,Kar P.Associations of type 1 and type 2 diabetes with COVID-19-related mortality in England: a whole-population study.Lancet Diabetes Endocrinol2020;8:813-22 PMCID:PMC7426088

[13] Zhang Y,Zhang J.The clinical characteristics and outcomes of patients with diabetes and secondary hyperglycaemia with coronavirus disease 2019: a single-centre, retrospective, observational study in Wuhan.Diabetes Obes Metab2020;22:1443-54 PMCID:PMC7273002

[14] Gupta R.Clinical considerations in patients with diabetes during times of COVID19: an update on lifestyle factors and antihyperglycemic drugs with focus on India.Diabetes Metab Syndr2020;14:1777-81 PMCID:PMC7477599

[15] Guan WJ,Hu Y.China Medical Treatment Expert Group for Covid-19Clinical characteristics of coronavirus disease 2019 in China.N Engl J Med2020;382:1708-20

[16] Wu Z.Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention.JAMA2020;323:1239-42

[17] Shenoy A,Bajaj M.Diabetes and covid-19: a global health challenge.BMJ Open Diabetes Res Care2020;8:e001450 PMCID:PMC7222578

[18] Zhou F,Du R.Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.Lancet2020;395:1054-62 PMCID:PMC7270627

[19] Mantovani A,Zheng MH.Diabetes as a risk factor for greater COVID-19 severity and in-hospital death: a meta-analysis of observational studies.Nutr Metab Cardiovasc Dis2020;30:1236-48 PMCID:PMC7258796

[20] Stefan N,Schulze MB.Global pandemics interconnected - obesity, impaired metabolic health and COVID-19.Nat Rev Endocrinol2021;17:135-49

[21] COVID-19 rapid guideline: managing the long-term effects of COVID-19. London: National Institute for Health and Care Excellence (NICE); 2020 Dec 18.

[22] WHO. A clinical case definition of post COVID-19 condition by a Delphi consensus, 6 October 2021. Available from: https://www.who.int/publications/i/item/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1 [Last accessed on 30 Mar 2023]

[23] Ayoubkhani DP. Technical article: updated estimates of the prevalence of post-acute symptoms among people with coronavirus (COVID-19) in the UK: 26 April 2020 to 1 August 2021. Available from: https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/articles/technicalarticleupdatedestimatesoftheprevalenceofpostacutesymptomsamongpeoplewithcoronaviruscovid19intheuk/26april2020to1august2021 [Last accessed on 30 Mar 2023]

[24] Tenforde MW,Reese HE.Point prevalence estimates of activity-limiting long-term symptoms among U.S. adults ≥1 month after reported SARS-CoV-2 infection, November 1, 2021.J Infect Dis2022; PMCID:PMC9278232

[25] Sisó-Almirall A,Conangla Ferrín L.Long covid-19: proposed primary care clinical guidelines for diagnosis and disease management.Int J Environ Res Public Health2021;18:4350 PMCID:PMC8073248

[26] Salamanna F,Martini L,Fini M.Post-COVID-19 syndrome: the persistent symptoms at the post-viral stage of the disease. a systematic review of the current data.Front Med (Lausanne)2021;8:653516 PMCID:PMC8129035

[27] Munblit D,Akrami A.PC-COS project steering committeeA core outcome set for post-COVID-19 condition in adults for use in clinical practice and research: an international Delphi consensus study.Lancet Respir Med2022;10:715-24 PMCID:PMC9197249

[28] Roth A,Jonas W.Addressing the long COVID Crisis: integrative health and long COVID.Glob Adv Health Med2021;10:21649561211056597 PMCID:PMC8606968

[29] Greenhalgh T,A’Court C,Husain L.Management of post-acute covid-19 in primary care.BMJ2020;370:m3026

[30] Mittal J,Bhatt SP,Ansari IA.High prevalence of post COVID-19 fatigue in patients with type 2 diabetes: a case-control study.Diabetes Metab Syndr2021;15:102302 PMCID:PMC8462068

[31] Jayasinghe S,Hills AP.Post-COVID-19 syndrome and type 2 diabetes: primacy of exercise in prevention and management.Diabetes Metab Syndr2022;16:102379 PMCID:PMC8714239

[32] Sosale A,Kesavadev J.Steroid use during COVID-19 infection and hyperglycemia - What a physician should know.Diabetes Metab Syndr2021;15:102167 PMCID:PMC8189750

[33] Mechi A,Al-Darraji R.Long-term persistent symptoms of COVID-19 infection in patients with diabetes mellitus.Int J Diabetes Dev Ctries2022;42:49-52 PMCID:PMC8382933

[34] Ceriello A,Catrinoiu D.Diabetes and Cardiovascular Disease (D&CVD) EASD Study GroupIssues of cardiovascular risk management in people with diabetes in the COVID-19 era.Diabetes Care2020;43:1427-32

[35] Montalvan V,Bueso T,Rivas K.Neurological manifestations of COVID-19 and other coronavirus infections: a systematic review.Clin Neurol Neurosurg2020;194:105921 PMCID:PMC7227498

[36] Raveendran AV.Post COVID-19 Syndrome (“Long COVID”) and diabetes: challenges in diagnosis and management.Diabetes Metab Syndr2021;15:102235 PMCID:PMC8317446

[37] CDC. Long-term effects of COVID-19; 2020. Available from: https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/index.html [Last accessed on 30 Mar 2023]

[38] Shin J,Nishitani S.Possible involvement of adipose tissue in patients with older age, obesity, and diabetes with SARS-CoV-2 infection (COVID-19) via GRP78 (BIP/HSPA5): significance of hyperinsulinemia management in COVID-19.Diabetes2021;70:2745-55 PMCID:PMC8660985

[39] Stefan N.Metabolic disorders, COVID-19 and vaccine-breakthrough infections.Nat Rev Endocrinol2022;18:75-6 PMCID:PMC8647056

[40] Liang L,Jiang N.Three-month follow-up study of survivors of coronavirus disease 2019 after discharge.J Korean Med Sci2020;35:e418 PMCID:PMC7721559

[41] Huang C,Wang Y.6-month consequences of COVID-19 in patients discharged from hospital: a cohort study.Lancet2021;397:220-32 PMCID:PMC7833295

[42] Pavli A,Maltezou HC.Post-COVID syndrome: incidence, clinical spectrum, and challenges for primary healthcare professionals.Arch Med Res2021;52:575-81 PMCID:PMC8093949

[43] Banerjee M,Dutta S.Risk of incident diabetes post-COVID-19: a systematic review and meta-analysis.Prim Care Diabetes2022;16:591-3 PMCID:PMC9148988

[44] Simani L,Darazam IA.Prevalence and correlates of chronic fatigue syndrome and post-traumatic stress disorder after the outbreak of the COVID-19.J Neurovirol2021;27:154-9 PMCID:PMC7852482

[45] Fernández-de-Las-Peñas C,Gómez-Mayordomo V,Palacios-Ceña D.Proposed integrative model for post-COVID symptoms.Diabetes Metab Syndr2021;15:102159 PMCID:PMC8168334

[46] Seiglie J,Cromer SJ.Diabetes as a risk factor for poor early outcomes in patients hospitalized with COVID-19.Diabetes Care2020;43:2938-44 PMCID:PMC7770271

[47] Fang L,Roth M.Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?.Lancet Respir Med2020;8:e21 PMCID:PMC7118626

[48] Estiri H,Brat GA,Patel CJ.Consortium for Characterization of COVID-19 by EHR (4CE)Evolving phenotypes of non-hospitalized patients that indicate long Covid.medRxiv2021:2021 PMCID:PMC8095212

[49] Yaksi N,Imre A.Long COVID in hospitalized COVID-19 patients: A Retrospective Cohort Study.Iran J Public Health2022;51:88-95 PMCID:PMC8837882

[50] Steenblock C,Khan EG.Diabetes and COVID-19: short- and long-term consequences.Horm Metab Res2022;54:503-9 PMCID:PMC9363150

[51] Thompson EJ,Walker AJ.OpenSAFELY CollaborativeLong COVID burden and risk factors in 10 UK longitudinal studies and electronic health records.Nat Commun2022;13:3528 PMCID:PMC9240035

[52] Cariou B,Wargny M.CORONADO investigatorsPhenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study.Diabetologia2020;63:1500-15 PMCID:PMC7256180

[53] Bonyek-Silva I,Nunes S.Prediabetes induces more severe acute COVID-19 associated with IL-6 production without worsening long-term symptoms.Front Endocrinol (Lausanne)2022;13:896378 PMCID:PMC9311489

[54] Al-Aly Z,Bowe B.High-dimensional characterization of post-acute sequelae of COVID-19.Nature2021;594:259-64

[55] Xie Y.Risks and burdens of incident diabetes in long COVID: a cohort study.Lancet Diabetes Endocrinol2022;10:311-21 PMCID:PMC8937253

[56] Sathish T,Cao Y,Zimmet P.Proportion of newly diagnosed diabetes in COVID-19 patients: a systematic review and meta-analysis.Diabetes Obes Metab2021;23:870-4 PMCID:PMC7753574

[57] Zhang J,Zhu R,Zhang B.The long-term effect of COVID-19 disease severity on risk of diabetes incidence and the near 1-year follow-up outcomes among postdischarge patients in Wuhan.J Clin Med2022;11:3094 PMCID:PMC9181214

[58] Barrett CE,Alvarez P.Risk for newly diagnosed diabetes >30 days after SARS-CoV-2 infection among persons aged <18 years - United States, March 1, 2020-June 28, 2021.MMWR Morb Mortal Wkly Rep2022;71:59-65 PMCID:PMC8757617

[59] The OpenSAFELY Collaborative,Alex J Walker. Rates of serious clinical outcomes in survivors of hospitalisation with COVID-19: a descriptive cohort study within the OpenSAFELY platform. medRxiv. Available from: https:// www.medrxiv.org/content/10.1101/2021.01.22.21250304v2 [Last accessed on 30 Mar 2023]

[60] Ayoubkhani D,Nafilyan V.Post-covid syndrome in individuals admitted to hospital with covid-19: retrospective cohort study.BMJ2021;372:n693 PMCID:PMC8010267

[61] Gentile S,Mambro A.COVID-19, ketoacidosis and new-onset diabetes: Are there possible cause and effect relationships among them?.Diabetes Obes Metab2020;22:2507-8 PMCID:PMC7436911

[62] Rubino F,Zimmet P.New-onset diabetes in Covid-19.N Engl J Med2020;383:789-90 PMCID:PMC7304415

[63] Li H,Chen T.Newly diagnosed diabetes is associated with a higher risk of mortality than known diabetes in hospitalized patients with COVID-19.Diabetes Obes Metab2020;22:1897-906 PMCID:PMC7283710

[64] Zhou W,Wang W,Hu Q.Clinical features of COVID-19 patients with diabetes and secondary hyperglycemia.J Diabetes Res2020;2020:3918723 PMCID:PMC7545437

[65] Wang S,Zhang S.Fasting blood glucose at admission is an independent predictor for 28-day mortality in patients with COVID-19 without previous diagnosis of diabetes: a multi-centre retrospective study.Diabetologia2020;63:2102-11 PMCID:PMC7347402

[66] Yi H,Jin X.Clinical characteristics and outcomes of coronavirus disease 2019 infections among diabetics: a retrospective and multicenter study in China.J Diabetes2020;12:919-28

[67] Fadini GP,Boscari F.Newly-diagnosed diabetes and admission hyperglycemia predict COVID-19 severity by aggravating respiratory deterioration.Diabetes Res Clin Pract2020;168:108374 PMCID:PMC7428425

[68] Lampasona V,Scavini M.Antibody response to multiple antigens of SARS-CoV-2 in patients with diabetes: an observational cohort study.Diabetologia2020;63:2548-58 PMCID:PMC7541098

[69] Smith SM,Traupman JA.Impaired glucose metabolism in patients with diabetes, prediabetes, and obesity is associated with severe COVID-19.J Med Virol2021;93:409-15 PMCID:PMC7361926

[70] Montori VM.Patients surviving COVID-19 had increased risk for incident diabetes vs. persons without COVID-19.Ann Intern Med2022;175:JC93

[71] Frere JJ.Cardiometabolic syndrome - an emergent feature of Long COVID?.Nat Rev Immunol2022;22:399-400 PMCID:PMC9127811

[72] Unsworth R,Oliver NS.New-onset type 1 diabetes in children during COVID-19: multicenter regional findings in the U.K.Diabetes Care2020;43:e170-1

[73] Vlad A,Timar R.Increased incidence of type 1 diabetes during the COVID-19 pandemic in romanian children.Medicina (Kaunas)2021;57:973 PMCID:PMC8470921

[74] Tittel SR,Kamrath C.DPV InitiativeDid the COVID-19 lockdown affect the incidence of pediatric type 1 diabetes in Germany?.Diabetes Care2020;43:e172-3 PMCID:PMC7576433

[75] Kamrath C,Eckert AJ.Incidence of type 1 diabetes in children and adolescents during the COVID-19 Pandemic in Germany: results from the DPV registry.Diabetes Care2022;45:1762-71

[76] Scherer PE,Rosen CJ.Post-acute sequelae of COVID-19: A metabolic perspective.Elife2022;11 PMCID:PMC8942467

[77] Lim S,Kwon HS.COVID-19 and diabetes mellitus: from pathophysiology to clinical management.Nat Rev Endocrinol2021;17:11-30 PMCID:PMC7664589

[78] Castanares-Zapatero D,Kohn L.Pathophysiology and mechanism of long COVID: a comprehensive review.Ann Med2022;54:1473-87 PMCID:PMC9132392

[79] Zollner A,Jukic A.Postacute COVID-19 is Characterized by gut viral antigen persistence in inflammatory bowel diseases.Gastroenterology2022;163:495-506.e8 PMCID:PMC9057012

[80] Xiao F,Zheng X,Li X.Evidence for gastrointestinal infection of SARS-CoV-2.Gastroenterology2020;158:1831-1833.e3 PMCID:PMC7130181

[81] Müller JA,Conzelmann C.SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas.Nat Metab2021;3:149-65

[82] Suwanwongse K.Newly diagnosed diabetes mellitus, DKA, and COVID-19: Causality or coincidence?.J Med Virol2021;93:1150-3 PMCID:PMC7404645

[83] Nalbandian A,Gupta A.Post-acute COVID-19 syndrome.Nat Med2021;27:601-15 PMCID:PMC8893149

[84] Montefusco L,D'Addio F.Acute and long-term disruption of glycometabolic control after SARS-CoV-2 infection.Nat Metab2021;3:774-85 PMCID:PMC9931026

[85] Apicella M,Mantuano M,Coppelli A.COVID-19 in people with diabetes: understanding the reasons for worse outcomes.Lancet Diabetes Endocrinol2020;8:782-92 PMCID:PMC7367664

[86] Tang Y,Zhang D,Ji J.Cytokine Storm in COVID-19: the current evidence and treatment strategies.Front Immunol2020;11:1708 PMCID:PMC7365923

[87] Zhang Y,Shen M.medical team from Xiangya Hospital to support HubeiChinaAssociation of diabetes mellitus with disease severity and prognosis in COVID-19: a retrospective cohort study.Diabetes Res Clin Pract2020;165:108227 PMCID:PMC7996087

[88] Donath MY.Targeting inflammation in the treatment of type 2 diabetes: time to start.Nat Rev Drug Discov2014;13:465-76

[89] Hotamisligil GS,Caro JF,Spiegelman BM.Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance.J Clin Invest1995;95:2409-15 PMCID:PMC295872

[90] Prattichizzo F,Spiga R.Inflammageing and metaflammation: the yin and yang of type 2 diabetes.Ageing Res Rev2018;41:1-17

[91] Wu CT,Xiao Y.SARS-CoV-2 infects human pancreatic β cells and elicits β cell impairment.Cell Metab2021;33:1565-1576.e5 PMCID:PMC8130512

[92] Paneni F.Increased risk of incident diabetes in patients with long COVID.Eur Heart J2022;43:2094-5

[93] Bansal R,Koch CA.COVID-19 and chronic fatigue syndrome: an endocrine perspective.J Clin Transl Endocrinol2022;27:100284 PMCID:PMC8641402

[94] Sathish T,Cooper ME.Potential metabolic and inflammatory pathways between COVID-19 and new-onset diabetes.Diabetes Metab2021;47:101204 PMCID:PMC7591867

[95] Fignani D,Brusco N.SARS-CoV-2 receptor angiotensin i-converting enzyme type 2 (ACE2) is expressed in human pancreatic β-cells and in the human pancreas microvasculature.Front Endocrinol (Lausanne)2020;11:596898 PMCID:PMC7691425

[96] Yang JK,Ji XJ.Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes.Acta Diabetol2010;47:193-9 PMCID:PMC7088164

[97] Coate KC,Shrestha S.HPAP ConsortiumSARS-CoV-2 cell entry factors ACE2 and TMPRSS2 are expressed in the microvasculature and ducts of human pancreas but are not enriched in β cells.Cell Metab2020;32:1028-1040.e4 PMCID:PMC7664344

[98] Daly JL,Klein K.Neuropilin-1 is a host factor for SARS-CoV-2 infection.Science2020;370:861-5 PMCID:PMC7612957

[99] Hayden MR.An Immediate and Long-Term Complication of COVID-19 may be type 2 diabetes mellitus: the central role of β-cell dysfunction, apoptosis and exploration of possible mechanisms.Cells2020;9:2475 PMCID:PMC7697826

[100] Govender N,Moodley J.Insulin resistance in COVID-19 and diabetes.Prim Care Diabetes2021;15:629-34 PMCID:PMC8031259

[101] Russo B,Borboni P,Frontoni S.Autonomic nervous system in obesity and insulin-resistance-the complex interplay between leptin and central nervous system.Int J Mol Sci2021;22:5187 PMCID:PMC8156658

[102] Phetsouphanh C,Wilson DB.Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection.Nat Immunol2022;23:210-6

[103] McKeigue PM,Blackbourn L.Relation of incident type 1 diabetes to recent COVID-19 infection: cohort study using e-health record linkage in Scotland.Diabetes Care2022:dc220385

[104] Alaqeel A,Alsuhaibani M.The impact of COVID-19 pandemic lockdown on the incidence of new-onset type 1 diabetes and ketoacidosis among saudi children.Front Endocrinol (Lausanne)2021;12:669302 PMCID:PMC8049603

[105] Mameli C,Macedoni M.Type 1 diabetes onset in Lombardy region, Italy, during the COVID-19 pandemic: The double-wave occurrence.EClinicalMedicine2021;39:101067 PMCID:PMC8365462

[106] Østergaard L.SARS CoV-2 related microvascular damage and symptoms during and after COVID-19: Consequences of capillary transit-time changes, tissue hypoxia and inflammation.Physiol Rep2021;9:e14726 PMCID:PMC7849453

[107] Dagan N,Kepten E.BNT162b2 mRNA Covid-19 vaccine in a nationwide mass vaccination setting.N Engl J Med2021;384:1412-23 PMCID:PMC7944975

[108] Cheng Y,Tao Y.Reduced antibody response to COVID-19 vaccine composed of inactivated SARS-CoV-2 in diabetic individuals.Front Public Health2022;10:1025901 PMCID:PMC9773130

[109] Richard SA,Fries AC.EpidemiologyImmunologyand Clinical Characteristics of Emerging Infectious Diseases With Pandemic Potential (EPICC) COVID-19 Cohort Study GroupPersistent COVID-19 symptoms at 6 months after onset and the role of vaccination before or after SARS-CoV-2 infection.JAMA Netw Open2023;6:e2251360

[110] Chourasia P,Kansal D.Risk of new-onset diabetes mellitus as a Post-COVID-19 condition and possible mechanisms: a scoping review.J Clin Med2023;12:1159 PMCID:PMC9917823

[111] Ayoubkhani D,Pouwels KB.Trajectory of long covid symptoms after covid-19 vaccination: community based cohort study.BMJ2022;377:e069676 PMCID:PMC9115603