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Historical aspects and current understanding of the connections and implications of viruses and diabetes: A narrative review

Open AccessPublished:July 11, 2022DOI:https://doi.org/10.1016/j.cegh.2022.101110

      Abstract

      The continued increase in diabetes indicates it to be a significant global challenge to the health and wellbeing of people. Hyperglycemia is linked to chronic inflammatory processes and diabetes-related vulnerability to infection. There is historic evidence linking viruses and microbes with diabetes and in some instances considered the causative agent. The viral infection causes inflammation and autoimmune destruction of beta cells, which, in turn, give rise to hyperglycemia, finally leading to diabetes. This review considers the historic aspects of viruses and diabetes, immune dysfunction with hyperglycemia, bidirectional relations between COVID-19 virus and diabetes, and new-onset diabetes in COVID-19.

      Keywords

      1. Introduction

      Diabetes is a growing global concern as its incidence is increasing at a rapid rate. Approximately 537 million a dults are living with diabetes as of 2021, and the numbers are projected to rise to 783 million by the year 2045.
      International diabetes foundation atlas.
      In India, the number of people with diabetes is estimated to roughly double from 77 million in the year 2019 to 134 million by the year 2045. One in 10 people worldwide are currently living with diabetes and every sixth person with diabetes in the world is an Indian.
      International diabetes foundation atlas.
      The microbes and viruses have been observed to play a key role as infectious agents linked to diabetic status and also as factors responsible for causing diabetes mellitus.
      • Toniolo A.
      • Cassani G.
      • Puggioni A.
      • et al.
      The diabetes pandemic and associated infections: suggestions for clinical microbiology.

      1.1 History of viruses and diabetes

      In the mid-nineteenth century, Stang mentioned the possibility of a relationship between mumps and diabetes. In 1899, Harris talked about the association of viruses with diabetes in detail. He mentioned a case of glycosuria followed by the onset of a mumps attack. However, it took almost 3 years for that person to develop full-blown diabetes with ketosis. In 1924, Patrick reported an association between mumps and diabetes in sporadic cases. Finally, in 1927, Gundersen published a paper with the title, “Is diabetes of infectious origin?” He suggested that mumps produced pancreatic disease, which resulted in diabetes in young after 3 years of initial infection. Since then, many studies have reported on the connection between mumps and diabetes.
      • Taylor K.W.
      Historical background: earlier studies on the connexion between viruses and diabetes.
      In the United States, approximately 9.4% of people have diabetes and 1.4% of them carry hepatitis C virus (HCV). The risk of type 2 diabetes mellitus (T2DM) is nearly four times greater in HCV-positive individuals than HCV-negative individuals. The association between HCV and diabetes gives a fair idea of the benefits of anti-HCV treatment in T2DM management. Anti-HCV treatment in diabetes has been shown to significantly improve glycemic control and has also been observed to reduce the need for insulin in persons with T2DM. As per the latest in vitro study, the infection of pancreatic islet cells by HCV may alter the cytokine expression, which, in turn, may contribute to insulin deficiency.
      • Toniolo A.
      • Cassani G.
      • Puggioni A.
      • et al.
      The diabetes pandemic and associated infections: suggestions for clinical microbiology.
      The same trends that ushered severe acute respiratory syndrome (SARS) into the human population are prevalent in the current pandemic situation and there are many lessons to draw from the SARS experience:
      • Yang J.K.
      • Feng Y.
      • Yuan M.Y.
      • et al.
      Plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with SARS.
      • History of diabetes and ambient hyperglycemia was found to be independent factors of death and mortality in people with SARS.
      • Hyperglycemia had devastating effects on organ function in people with SARS.
      • Intensive monitoring and optimal metabolic control have been reported to improve the prognosis of people with SARS.

      2. Hyperglycemia and immune dysfunction

      Hyperglycemia is linked to chronic inflammatory processes and diabetes mellitus-related vulnerability to infection. People with diabetes are prone to develop periodontal disease, tuberculosis, lung infection by legionella bacteria, and mucormycosis by the Mucoraceae family of fungi. Impaired functioning of macrophages, dendritic cells, natural killer T cells, and B and T lymphocytes causes defects of the innate response.
      • Toniolo A.
      • Cassani G.
      • Puggioni A.
      • et al.
      The diabetes pandemic and associated infections: suggestions for clinical microbiology.

      2.1 Immune defects associated with hyperglycemia

      Hyperglycemia is responsible for impeding the production of interleukin-22 (IL-22) and type1 interferon, which, in turn, diminishes the protective effects offered by both the cytokines. Type 1 interferon possesses antiviral activity. IL-22 decreases chronic inflammation and improves antimicrobial immunity and insulin sensitivity.
      • Toniolo A.
      • Cassani G.
      • Puggioni A.
      • et al.
      The diabetes pandemic and associated infections: suggestions for clinical microbiology.
      Hyperglycemia downregulates the expression of cathelicidins in macrophages which further decreased antimicrobial properties and chemotaxis, impaired antibacterial activity, neutrophil degranulation in response to bacterial lipopolysaccharide
      • Toniolo A.
      • Cassani G.
      • Puggioni A.
      • et al.
      The diabetes pandemic and associated infections: suggestions for clinical microbiology.
      Hyperglycemia causes nonenzymatic glycation of multiple proteins, including those of the complement system involved in the opsonization of pathogens. Glycation stops complement activation through the mannan-binding lectin pathway as well as functions of the CD59 inhibitor of the membrane attack complex.
      • Toniolo A.
      • Cassani G.
      • Puggioni A.
      • et al.
      The diabetes pandemic and associated infections: suggestions for clinical microbiology.

      2.2 Mechanisms of beta-cell destruction associated with viral infections

      The direct effects of viral infections on beta cells include different cytolytic effects in pancreatic beta cells. The viral infection causes inflammation and autoimmune destruction of beta cells, which, in turn, give rise to hyperglycemia, finally leading to diabetes.
      • Jaeckel E.
      • Manns M.
      • Von Herrath M.
      Viruses and diabetes.
      The various indirect effects of viral infections on beta cells include the following: Viral antigens expressed in beta cells cause infection; the release of substances toxic to beta cells destroys surrounding tissues; altered expression of major histocompatibility complex and costimulatory molecules; bystander activation of autoreactive lymphocytes by cytokines, antigen-presenting cells, and beta cells; virally encoded antigens activate and expand autoreactive T cells; molecular mimicry of viral antigens with beta-cell antigens; altered immune regulation; and altered repertoire of memory T cells.
      • Jaeckel E.
      • Manns M.
      • Von Herrath M.
      Viruses and diabetes.

      2.3 Viral infections implicated in diabetes

      Multiple varieties of viruses have a possible role as a major environmental factor in inducing diabetes.
      • Jaeckel E.
      • Manns M.
      • Von Herrath M.
      Viruses and diabetes.
      Viruses for which there is extensive evidence for association with diabetes are Enterovirus including Coxsackie B strains,
      • Hyöty H.
      • Taylor K.W.
      The role of viruses in human diabetes.
      and Rubella.
      • Forrest J.M.
      • Menser M.A.
      • Burgess J.A.
      High frequency of diabetes mellitus in young adults with congenital rubella.
      Viruses less commonly associated with diabetes are Cytomegalovirus,
      • Pak C.Y.
      • Eun H.M.
      • McArthur R.G.
      • Yoon J.W.
      Association of cytomegalovirus infection with autoimmune type 1 diabetes.
      Epstein-Barr virus,
      • Jun H.S.
      • Yoon J.W.
      A new look at viruses in type 1 diabetes.
      Mumps,
      • Hyöty H.
      • Leinikki P.
      • Reunanen A.
      • et al.
      Mumps infections in the etiology of type 1 (insulin-dependent) diabetes.
      Rota virus
      • Honeyman M.C.
      • Coulson B.S.
      • Stone N.L.
      • et al.
      Association between rotavirus infection and pancreatic islet autoimmunity in children at risk of developing type 1 diabetes.
      and Retro virus.
      • Hyöty H.
      • Taylor K.W.
      The role of viruses in human diabetes.
      Multiple viruses including RNA and DNA viruses implicated in diabetes
      • Jaeckel E.
      • Manns M.
      • Von Herrath M.
      Viruses and diabetes.
      is shown in Fig. 1.

      3. Bidirectional relationship between COVID-19 and diabetes

      Diabetes has been reported to be one of the common comorbidities in persons infected with coronavirus disease 2019 (COVID-19). This has generated interest in exploring the two-way relationship between diabetes and COVID-19.
      • Balasubramanyam M.
      Does COVID-19 warn us to revisit virus-induced diabetes?.
      • Newer emerging evidence suggests that the coronavirus might trigger diabetes. Increased risk of development of new-onset hyperglycemia in infected individuals
        • Mallapaty S.
        Mounting clues suggest the coronavirus might trigger diabetes.
        ,
        • Unnikrishnan R.
        • Misra A.
        Diabetes and COVID19: a bidirectional relationship.
      • Moreover, COVID-19 infection in people with diabetes causes virus exploitation in multiple organs due to multiple mechanisms, such as altered angiotensin-converting enzyme 2 (ACE2) activity,
        • Ni W.
        • Yang X.
        • Yang D.
        • et al.
        Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19.
        breakdown of Ca2+ homeostasis, activation of the renin-angiotensin–aldosterone system (RAAS),
        • Dean R.G.
        • Burrell L.M.
        ACE2 and diabetic complications.
        pre-existing diabetes-related organ damage, impairment of sympathetic nervous system, and raised oxidative stress.
        • Boddu S.K.
        • Aurangabadkar G.
        • Kuchay M.S.
        New onset diabetes, type 1 diabetes and COVID-19.
        ,
        • Müller J.A.
        • Groß R.
        • Conzelmann C.
        • et al.
        SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas.
      • Several studies have also reported that COVID-19 may induce diabetes by causing beta-cell destruction, hepatic manifestations, increased stress, and changes in the pancreas–liver–gut-brain axis in people without diabetes.
        • Balasubramanyam M.
        Does COVID-19 warn us to revisit virus-induced diabetes?.
        • Mallapaty S.
        Mounting clues suggest the coronavirus might trigger diabetes.
        • Unnikrishnan R.
        • Misra A.
        Diabetes and COVID19: a bidirectional relationship.
      Yang et al. evaluated whether the multiorgan damage (mainly in the pancreas) was related to the expression of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor, ACE2 (Fig. 2). As per the study findings, the organ expression of SARS was linked to the organ expression of ACE2. The localization of ACE2 expression in the part of the pancreas confirmed that SARS-CoV-2 binds to the ACE2 receptor and damages the islet cells in the pancreas, further resulting in acute diabetes.
      • Yang J.K.
      • Lin S.S.
      • Ji X.J.
      • et al.
      Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes.
      ACE2 is a functional receptor for SARS-CoV-2. The basic mechanism of engagement of RAAS with SARS-CoV-2 is given below.
      • Onweni C.L.
      • Zhang Y.S.
      • Caulfield T.
      • et al.
      ACEI/ARB therapy in COVID-19: the double-edged sword of ACE2 and SARS-CoV-2 viral docking.
      • SARS-CoV-2 binds to ACE2 and thus promotes the internalization of the viral receptor.
      • ACE2-mediated production of angiotensin (1–7) gets disturbed and production of angiotensin II (1–8) increases.
      • The alteration in the levels of angiotensin further changes the target receptor activity in selected tissues.
      Fig. 2
      Fig. 2The binding of SARS-CoV-2 to ACE2 receptor damages islet cells in the pancreas and causes acute diabetes
      SARS-Cov: Severe acute respiratory syndrome coronavirus, ACE: Angiotensin-converting enzyme.

      3.1 Angiotensin-converting enzyme-2: double-edged sword for people with diabetes

      There has been an ongoing debate regarding the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in people with COVID-19. It is important to understand how ACE2 acts as a double-edged sword for people with diabetes.
      • ACE2, an extracellular transmembrane enzyme, is responsible for converting angiotensin II into the angiotensin (1–7) heptapeptide.
        • Onweni C.L.
        • Zhang Y.S.
        • Caulfield T.
        • et al.
        ACEI/ARB therapy in COVID-19: the double-edged sword of ACE2 and SARS-CoV-2 viral docking.
      • ACE2 is the main receptor for binding and uptake of SARS-CoV-2 into the cell.
        • Onweni C.L.
        • Zhang Y.S.
        • Caulfield T.
        • et al.
        ACEI/ARB therapy in COVID-19: the double-edged sword of ACE2 and SARS-CoV-2 viral docking.
      • Viral binding causes internalization and enzymatic degradation of ACE2, hence resulting in hypertensive effects due to enhanced angiotensin II levels.
        • Cristelo C.
        • Azevedo C.
        • Marques J.M.
        • et al.
        SARS-CoV-2 and diabetes: new challenges for the disease.
      • ACEIs and ARBs lead to overexpression of ACE2 and thus persons treated with ACEIs and ARBs could be at risk of developing COVID-19.
        • Cristelo C.
        • Azevedo C.
        • Marques J.M.
        • et al.
        SARS-CoV-2 and diabetes: new challenges for the disease.

      3.2 Diabetes: a strong risk factor for COVID-19 severity

      Research has indicated a higher risk of severe COVID-19 in individuals with comorbidities:
      • Pre-existing T2DM has been reported to be independently associated with poor outcomes in people with SARS.
        • Yang J.K.
        • Feng Y.
        • Yuan M.Y.
        • et al.
        Plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with SARS.
      • As per the study by Algahtani et al., T2DM was found to be the primary comorbidity linked to severe or lethal Middle East respiratory syndrome-related coronavirus infections.
        • Alqahtani F.Y.
        • Aleanizy F.S.
        • Ali El Hadi Mohamed R.
        • et al.
        Prevalence of comorbidities in cases of Middle East respiratory syndrome coronavirus: a retrospective study.
      • Diabetes status has been associated with an increase in the requirement of medical interventions during COVID-19 and also escalated mortality risk of people with COVID-19.
        • Zhu L.
        • She Z.G.
        • Cheng X.
        • et al.
        Association of blood glucose control and outcomes in patients with COVID-19 and pre-existing type 2 diabetes.
      Several mechanisms explain that diabetes could be a strong risk factor for COVID-19. The major mechanisms are those linked directly to hyperglycemia and the associated imbalances in pathways involved in virus entry into the cell as well as in the immune and inflammatory response. Also, the diabetes-related comorbidities/complications with poor prognosis mediate certain effects of diabetes in people with COVID-19.
      • Pugliese G.
      • Vitale M.
      • Resi V.
      • et al.
      Is diabetes mellitus a risk factor for coronavirus disease 19 (COVID-19)?.

      3.3 New-onset diabetes in COVID-19

      Clinical evidence is being accumulated regarding new-onset diabetes in COVID-19:
      • A bidirectional relationship between COVID-19 and diabetes has emerged.
        • Balasubramanyam M.
        Does COVID-19 warn us to revisit virus-induced diabetes?.
      • Recent evidence shows that coronavirus may trigger diabetes.
        • Mallapaty S.
        Mounting clues suggest the coronavirus might trigger diabetes.
      • Many studies have reported new-onset diabetes and severe complications of pre-existing diabetes, such as diabetic ketoacidosis and hyperosmolarity in people with COVID-19.
        • Chee Y.J.
        • Ng S.J.H.
        • Yeoh E.
        Diabetic ketoacidosis precipitated by Covid-19 in a patient with newly diagnosed diabetes mellitus.
        • Li J.
        • Wang X.
        • Chen J.
        • et al.
        COVID-19 infection may cause ketosis and ketoacidosis.
        • Heaney A.I.
        • Griffin G.D.
        • Simon E.L.
        Newly diagnosed diabetes and diabetic ketoacidosis precipitated by COVID-19 infection.
      • People with COVID-19 with increased blood sugar and no prior history of diabetes should be tested for new-onset diabetes mellitus and diabetic ketoacidosis.
        • Jaeckel E.
        • Manns M.
        • Von Herrath M.
        Viruses and diabetes.
      SARS-CoV-2 after binding to ACE2 may lead to pleiotropic changes in glucose metabolism. This, in turn, complicates the pathophysiology of already existing diabetes or results in new mechanisms of disease.
      • Rubino F.
      • Amiel S.A.
      • Zimmet P.
      • et al.
      New-onset diabetes in covid-19.
      Previous research has also indicated high incidences of fasting glycemia and acute-onset diabetes in people infected with SARS coronavirus 1 pneumonia.
      • Yang J.K.
      • Lin S.S.
      • Ji X.J.
      • et al.
      Binding of SARS coronavirus to its receptor damage islets and causes acute diabetes.

      3.4 COVID-19 and thrombotic microangiopathy

      Recent evidence suggests that signs and symptoms of COVID-19 infection resemble more the pathophysiology and phenotype of complement-mediated thrombotic microangiopathies (TMA). Thrombotic microangiopathies are characterized by microvascular thrombosis with thrombocytopenia, hemolytic anemia, and red blood cell fragmentation:
      • Benz K.
      • Amann K.
      Thrombotic microangiopathy: new insights.
      • Pre-existing TMA and its markers (poor glycemic control and duration of diabetes) are risk factors for the severity of the disease.
        • Sharma S.
        • Schaper D.
        • Rayman G.
        Microangiopathy: is it relevant to wound healing in diabetic foot disease?.
      • Thrombotic microangiopathies have been reported to be a common event in people with COVID-19 and possibly involve endothelium-mediated complement activation.
        • Gavriilaki E.
        • Brodsky R.A.
        Severe COVID-19 infection and thrombotic microangiopathy: success does not come easily.
      • Due to overexpression of ACEs in endothelial cells and podocytes, endothelium-mediated complement activation could be considered as a single mechanism of viral action in susceptible organs.
        • Varga Z.
        • Flammer A.J.
        • Steiger P.
        • et al.
        Endothelial cell infection and endothelins in COVID-19.
      • As per the latest clinical observations, SARS-CoV-2 infection causes induction of endothelins in several organs.
        • Kahwash Rami Campbell Courtney M.
        Will complement inhibition be the new target in treating COVID-19–related systemic thrombosis?.
      • Endotheliitis may result in life-threatening complications and even multiple organ failure.
        • Leisman D.E.
        • Deutschman C.S.
        • Legrand M.
        Facing COVID-19 in the ICU: vascular dysfunction, thrombosis, and dysregulated inflammation.
      • Increased Inflammatory response could be the reason for COVID-19–associated coagulopathy.
        • Becker R.C.
        COVID-19 update: covid-19-associated coagulopathy.

      3.5 Time to rethink diabetes management in COVID-19

      The clinical management of diabetes is extremely challenging in the current COVID-19 times as the pathophysiology of COVID-19–related diabetes is complex. People with diabetes carry an increased risk of severe COVID-19. In people with COVID-19, high doses of insulin are needed for new-onset diabetes and related complications.
      • Chee Y.J.
      • Ng S.J.H.
      • Yeoh E.
      Diabetic ketoacidosis precipitated by Covid-19 in a patient with newly diagnosed diabetes mellitus.
      ,
      • Ren H.
      • Yang Y.
      • Wang F.
      • et al.
      Association of the insulin resistance marker TyG index with the severity and mortality of COVID-19.
      SARS-CoV-2 is related to multiorgan damage with the most affected organs being kidneys, lungs, and heart. The severity of COVID-19 is directly related to old age, thrombocytopenia, and hyperglycemia. As SARS-CoV-2 causes ACE2-dependent damage to pancreatic cells, hyperglycemia could be the final consequence. Hyperglycemia, if left untreated, could result in various complications, such as limb amputations, kidney failure, blindness, and cardiovascular disease.
      • Taylor K.W.
      Historical background: earlier studies on the connexion between viruses and diabetes.
      Therefore, it is important to regulate blood glucose levels.
      • Yang J.K.
      • Lin S.S.
      • Ji X.J.
      • et al.
      Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes.
      ,
      • Rao Kondapally Seshasai S.
      • Kaptoge S.
      • Thompson A.
      • et al.
      Diabetes mellitus, fasting glucose, and risk of cause-specific death.

      4. Conclusion

      Viral infections are a major environmental factor in the etiology of diabetes mellitus. Recent evidence indicates the bidirectional relationship between COVID-19 and diabetes. People infected with COVID-19 with elevated blood sugar levels and no history of diabetes should be evaluated for the possibility of new-onset diabetes mellitus. Complement-mediated thrombotic microangiopathies should be watched in persons with COVID-19. A multidisciplinary approach should be looked into while managing diabetes in persons with COVID-19.

      Source funding

      The author received no financial support from any institution for the research, authorship, and/or publication of this article.

      Ethical approval

      Not required.

      Declaration of competing interest

      None declared.

      Acknowledgment

      The author would like to thank BioQuest Solutions for their editorial assistance and Dr. S Amarnath for editorial and scientific support.

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