Commentary: COVID-19 and diabetes mellitus: What we know, how our patients should be treated now, and what should happen next
Authors: Angeliki M. Angelidi, Matthew J. Belanger, Christos S. Mantzoros
Journal: Metabolism (2020)

The novel coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into a worldwide crisis and was declared a global pandemic by the World Health Organization (WHO) on March 11, 2020 [[1]WHO Director-General's opening remarks at the media briefing on COVID-19 - 11 March 2020.https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020/Date: 2020Date accessed: April 13, 2020Google Scholar]. The rate of spread, range of clinical manifestations, morbidity, and mortality associated with COVID-19 has prompted special interest in understanding the factors that predispose individuals to infection and severe forms of the disease. Many of the early studies from China overlapped in finding that, in addition to older age, certain chronic medical conditions including hypertension, type 2 diabetes, and cardiovascular disease, are a risk factor for severe illness with COVID-19 [2Yang X. Yu Y. Xu J. Shu H. Xia J. Liu H. 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; https://doi.org/10.1016/s2213-2600(20)30079-5Abstract Full Text Full Text PDF Google Scholar, 3Guan W.J. Ni Z.Y. Hu Y. Liang W.H. Ou C.Q. He J.X. et al.Clinical characteristics of coronavirus disease 2019 in China.N Engl J Med. 2020; https://doi.org/10.1056/NEJMoa2002032Crossref Scopus (20093) Google Scholar, 4Zhang J.J. Dong X. Cao Y.Y. Yuan Y.D. Yang Y.B. Yan Y.Q. et al.Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China.Allergy. 2020; https://doi.org/10.1111/all.14238Crossref Scopus (2534) Google Scholar, 5Li B. Yang J. Zhao F. Zhi L. Wang X. Liu L. et al.Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China.Clin Res Cardiol. 2020; https://doi.org/10.1007/s00392-020-01626-9Crossref Scopus (1336) Google Scholar]. Of note, according to a recent study, diverse haplotypes of SARS-CoV-2 were identified in distinct areas, probably due to different sources of exposure [[6]Gudbjartsson D.F. Helgason A. Jonsson H. Magnusson O.T. Melsted P. Norddahl G.L. et al.Spread of SARS-CoV-2 in the Icelandic population.N Engl J Med. 2020; https://doi.org/10.1056/NEJMoa2006100Crossref PubMed Scopus (851) Google Scholar]. However, no evidence exists whether these haplotypes are responsible for differences in clinical manifestations of the disease. The pandemic has spread worldwide, affecting >200 countries and territories. As of April 13, 2020, the number of global cases has surpassed 1.7 million, including over 110,000 deaths; the United States alone has reported over 500,000 cases and 20,444 deaths [[7]WHO Coronavirus disease 2019 (COVID-19): situation report—84.https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200413-sitrep-84-covid-19.pdf?sfvrsn=44f511ab_2/Date: 2020Date accessed: April 13, 2020Google Scholar]. According to a recent study in Iceland, the percentage of people at high risk for infection (mainly patients with symptoms, those who had close contact with infected persons, and those who had recently traveled to areas where there is major community spread) who tested positive for SARS-CoV-2 infection was approximately 13%. In comparison, the percentage of infected individuals in the general population was 0.8%, which remained stable over the course of 20 days. It should be noted that children under ten years of age and females had a lower incidence of SARS-CoV-2 infection compared to adolescents or adults and males [[6]Gudbjartsson D.F. Helgason A. Jonsson H. Magnusson O.T. Melsted P. Norddahl G.L. et al.Spread of SARS-CoV-2 in the Icelandic population.N Engl J Med. 2020; https://doi.org/10.1056/NEJMoa2006100Crossref PubMed Scopus (851) Google Scholar]. These initial data on incidence and prevalence are likely to change significantly over time with the progression of the pandemic and with the expected availability of better tests to confirm diagnosis as well as short and long-term immunity. Emerging literature from Italy and the United States has also pointed to a higher burden of severe disease in individuals with chronic medical conditions. Preliminary data in the United States identified diabetes as the most common risk factor for SARS-CoV-2 infection [[8]CDC Preliminary estimates of the prevalence of selected underlying health conditions among patients with coronavirus disease 2019 - United States, February 12–March 28, 2020.MMWR Morb Mortal Wkly Rep. 2020; 69: 382-386https://doi.org/10.15585/mmwr.mm6913e2Crossref PubMed Google Scholar]. In this editorial, we review the clinical observations related to diabetes and COVID-19 in China, Italy, and the United States. We next review the pathogenesis of and immune response to SARS-CoV-2 infection. We then outline proposed mechanisms that may predispose individuals with diabetes both to infection and severe disease. Finally, we highlight areas that warrant further investigation and discuss management considerations for clinicians. The first cluster of cases of pneumonia of unknown etiology appeared in Wuhan, China, in late December of 2019 [[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; 395: 497-506https://doi.org/10.1016/s0140-6736(20)30183-5Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Subsequent analysis identified the novel betacoronavirus, SARS-CoV-2, the seventh member of the coronavirus family that infects humans and includes severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), as the causative agent of COVID-19 [[10]Yang P. Wang X. COVID-19: a new challenge for human beings.Cell Mol Immunol. 2020; https://doi.org/10.1038/s41423-020-0407-xCrossref Scopus (290) Google Scholar]. An early single-center observational study in Wuhan of individuals with severe COVID-19 pneumonia described a high prevalence of chronic illness and a 22% prevalence of type 2 diabetes in individuals who did not survive the infection [[2]Yang X. Yu Y. Xu J. Shu H. Xia J. Liu H. 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; https://doi.org/10.1016/s2213-2600(20)30079-5Abstract Full Text Full Text PDF Google Scholar]. Another early large observational study identified type 2 diabetes as a common underlying condition in patients with severe illness (16.2%), second only to hypertension (23.7%) [[3]Guan W.J. Ni Z.Y. Hu Y. Liang W.H. Ou C.Q. He J.X. et al.Clinical characteristics of coronavirus disease 2019 in China.N Engl J Med. 2020; https://doi.org/10.1056/NEJMoa2002032Crossref Scopus (20093) Google Scholar]. A meta-analysis that included these and other studies found that the incidence of diabetes was two-fold higher in those that developed severe disease compared with patients that experienced non-severe disease [[5]Li B. Yang J. Zhao F. Zhi L. Wang X. Liu L. et al.Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China.Clin Res Cardiol. 2020; https://doi.org/10.1007/s00392-020-01626-9Crossref Scopus (1336) Google Scholar]. Subsequent studies have demonstrated an association between diabetes and poor prognosis and increased mortality. A recent retrospective cohort study of 174 patients admitted to Wuhan Union Hospital with COVID-19 found that 21.2% of patients had diabetes and further identified diabetes as a risk factor for severe disease based on radiographic findings and biomarkers of inflammation and end-organ damage [[11]Guo W. Li M. Dong Y. Zhou H. Zhang Z. Tian C. et al.Diabetes is a risk factor for the progression and prognosis of COVID-19.Diabetes Metab Res Rev. 2020; e3319https://doi.org/10.1002/dmrr.3319Crossref PubMed Scopus (924) Google Scholar]. These findings are consistent with a summary report of over 72,000 cases across China from the Chinese Center for Disease Control (CDC) that showed an increased fatality rate of 7.3% in individuals with diabetes compared to an overall fatality rate of 2.3% [[12]Wu Z. McGoogan J.M. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention.JAMA. 2020; https://doi.org/10.1001/jama.2020.2648Crossref Scopus (12457) Google Scholar]. Additionally, a recent multicenter retrospective cohort study of COVID-19 confirmed inpatients from Jinyintan Hospital and Wuhan Pulmonary Hospital found a statistically significant association between diabetes and increased mortality [[13]Zhou F. Yu T. Du R. Fan G. Liu Y. Liu Z. 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: 1054-1062https://doi.org/10.1016/s0140-6736(20)30566-3Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. In Italy, the severity of disease and strain on the healthcare system related to COVID-19 has been noteworthy, with one recent estimated case fatality rate of 7.2% [[14]Onder G. Rezza G. Brusaferro S. Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy.JAMA. 2020; https://doi.org/10.1001/jama.2020.4683Crossref PubMed Scopus (2971) Google Scholar]. While factors unique to the Italian population may contribute to the higher case fatality rate, such as a relatively older population, emerging data has also highlighted the role that underlying chronic cardiometabolic disease has on the severity of illness. A retrospective case series of patients admitted to the intensive care unit (ICU) with COVID-19 in the Lombardy region found hypertension (49%), cardiovascular disease (21%), and diabetes (17%) to be common underlying medical conditions [[15]Grasselli G. Zangrillo A. Zanella A. Antonelli M. Cabrini L. Castelli A. et al.Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region, Italy.JAMA. 2020; https://doi.org/10.1001/jama.2020.5394Crossref Scopus (3793) Google Scholar]. The Italian National Institute of Health reported the prevalence of diabetes in patients that died while infected with SARS-CoV-2 to be 35.5%, suggesting that diabetes may be a significant risk factor for mortality [[16]Fadini G.P. Morieri M.L. Longato E. Avogaro A. Prevalence and impact of diabetes among people infected with SARS-CoV-2.J Endocrinol Invest. 2020; https://doi.org/10.1007/s40618-020-01236-2Crossref Scopus (327) Google Scholar]. The first case of COVID-19 in the United States was confirmed on January 20, 2020, in Snohomish County, Washington [[17]Holshue M.L. DeBolt C. Lindquist S. Lofy K.H. Wiesman J. Bruce H. et al.First case of 2019 novel coronavirus in the United States.N Engl J Med. 2020; 382: 929-936https://doi.org/10.1056/NEJMoa2001191Crossref PubMed Scopus (4257) Google Scholar]. Two early case series of critically ill patients admitted to ICUs in the Seattle-area found an incidence of diabetes of 58% and 33.3%, respectively [[18]Bhatraju P.K. Ghassemieh B.J. Nichols M. Kim R. Jerome K.R. Nalla A.K. et al.Covid-19 in critically ill patients in the Seattle region - case series.N Engl J Med. 2020; https://doi.org/10.1056/NEJMoa2004500Crossref PubMed Scopus (1797) Google Scholar,[19]Arentz M. Yim E. Klaff L. Lokhandwala S. Riedo F.X. Chong M. et al.Characteristics and outcomes of 21 critically ill patients with COVID-19 in Washington State.JAMA. 2020; https://doi.org/10.1001/jama.2020.4326Crossref PubMed Scopus (1604) Google Scholar]. While more robust studies need to be completed, preliminary data from the United States CDC on March 28, 2020, estimated diabetes to be the most prevalent underlying health condition in individuals infected with SARS-CoV-2 at 10.9%, and further estimated that 32% of patients requiring ICU admission had diabetes [[8]CDC Preliminary estimates of the prevalence of selected underlying health conditions among patients with coronavirus disease 2019 - United States, February 12–March 28, 2020.MMWR Morb Mortal Wkly Rep. 2020; 69: 382-386https://doi.org/10.15585/mmwr.mm6913e2Crossref PubMed Google Scholar]. What remains to be fully elucidated, given the nature and study designs of initial reports, is whether the associations are independent from potential confounding factors such as gender and age that are associated with both COVID-19 and diabetes. Additionally, the extent that admission to the hospital or ICU, or medications used in the ICU (such as steroids), may be contributing to the increased prevalence of diabetes and other metabolic syndrome-related comorbidities needs to be determined. Coronaviruses are positive-sense, single-stranded RNA viruses, with a large 27 to 32 kilobase genome packaged inside a capsid formed by nucleocapsid protein (N). An envelope surrounds this helical structure and is associated with three structural proteins: membrane protein (M) and envelope protein (E), which are both involved in virion assembly, and spike protein (S), which mediates entry into host cells [[20]Li G. Fan Y. Lai Y. Han T. Li Z. 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Hypothesis for potential pathogenesis of SARS-CoV-2 infection-a review of immune changes in patients with viral pneumonia.Emerg Microbes Infect. 2020; 9: 727-732https://doi.org/10.1080/22221751.2020.1746199Crossref PubMed Scopus (615) Google Scholar]. The innate immune response involves the recognition of viral pathogen-associated molecular patterns by pattern recognition receptors (i.e., Toll-like receptors), resulting in the expression of type I interferons and inflammatory factors that potentiate macrophage and natural killer cell defense mechanisms [[20]Li G. Fan Y. Lai Y. Han T. Li Z. Zhou P. et al.Coronavirus infections and immune responses.J Med Virol. 2020; 92: 424-432https://doi.org/10.1002/jmv.25685Crossref PubMed Scopus (1263) Google Scholar]. Dendritic cells are tissue phagocytes that bridge the innate and adaptive immune response by activating T-lymphocytes and B-lymphocytes through antigen presentation [[20]Li G. Fan Y. Lai Y. Han T. Li Z. Zhou P. et al.Coronavirus infections and immune responses.J Med Virol. 2020; 92: 424-432https://doi.org/10.1002/jmv.25685Crossref PubMed Scopus (1263) Google Scholar]. The adaptive immune system is essential for control of the persistent phase of infection and involves the production of neutralizing monoclonal antibodies to viral envelope glycoproteins by CD4+ T cells and the killing of viral-infected cells by cytotoxic CD8+ T cells [[20]Li G. Fan Y. Lai Y. Han T. Li Z. Zhou P. et al.Coronavirus infections and immune responses.J Med Virol. 2020; 92: 424-432https://doi.org/10.1002/jmv.25685Crossref PubMed Scopus (1263) Google Scholar]. In the acute phase of infection, SARS-CoV and SARS-CoV-2 invade CD4+ and CD8+ T-lymphocytes resulting in apoptosis and lymphocytopenia, a marker that is associated with severe outcomes [[22]Muniyappa R. Gubbi S. COVID-19 pandemic, corona viruses, and diabetes mellitus.Am J Physiol Endocrinol Metab. 2020; https://doi.org/10.1152/ajpendo.00124.2020Crossref PubMed Scopus (537) Google Scholar,[27]Lin L. Lu L. Cao W. Li T. Hypothesis for potential pathogenesis of SARS-CoV-2 infection-a review of immune changes in patients with viral pneumonia.Emerg Microbes Infect. 2020; 9: 727-732https://doi.org/10.1080/22221751.2020.1746199Crossref PubMed Scopus (615) Google Scholar]. The specifics of the humoral response to SARS-CoV-2 infection are under investigation. A study of 173 hospitalized patients with reverse transcription polymerase chain reaction (RT-PCR) confirmed SARS-CoV-2 infection showed a seroconversion rate for total antibody, IgM, and IgG of 93.1%, 82.7%, and 64.7%, respectively, and noted that the few patients with negative antibody findings did not have later stage blood samples available for analysis [[28]Zhao J. Yuan Q. Wang H. Liu W. Liao X. Su Y. et al.Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019.Clin Infect Dis. 2020; https://doi.org/10.1093/cid/ciaa344Crossref Scopus (1821) Google Scholar]. However, a subsequent study that analyzed the plasma of 175 patients who had recovered from mild COVID-19 illness showed that 30% of participants generated a very low level of neutralizing antibody and that elderly patients were more likely to generate a robust antibody response than younger patients [[29]Wu F. Wang A. Liu M. Wang Q. Chen J. Xia S. et al.Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications.medRxiv. 2020; (2020.03.30.20047365)https://doi.org/10.1101/2020.03.30.20047365Crossref Scopus (0) Google Scholar]. The implications of this regarding susceptibility to recurrent infection warrants further investigation and ongoing studies are expected to shed more light on this topic. Individuals with diabetes are more susceptible to a broad range of infections [[30]Joshi N. Caputo G.M. Weitekamp M.R. Karchmer A.W. Infections in patients with diabetes mellitus.N Engl J Med. 1999; 341: 1906-1912https://doi.org/10.1056/nejm199912163412507Crossref PubMed Scopus (0) Google Scholar]. In addition, several infections may result in less well-controlled diabetes. Numerous factors contribute to the immune dysfunction in individuals with diabetes, including hyperglycemia, inhibition of neutrophil chemotaxis, altered cytokine production, phagocytic cell dysfunction, impaired T cell-mediated immune responses, and ineffective microbial clearance [31Geerlings S.E. Hoepelman A.I. Immune dysfunction in patients with diabetes mellitus (DM).FEMS Immunol Med Microbiol. 1999; 26: 259-265https://doi.org/10.1111/j.1574-695X.1999.tb01397.xCrossref PubMed Google Scholar, 32Berbudi A. Rahmadika N. Cahyadi A.I. Ruslami R. 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For example, to understand the immune system response to MERS-CoV in individuals with diabetes, Kulcsar et al. created a transgenic mouse model that expressed human DPP4 (DPP4H/M), the cellular binding site for MERS-CoV, and induced diabetes through a high-fat diet [[37]Kulcsar K.A. Coleman C.M. Beck S.E. Frieman M.B. Comorbid diabetes results in immune dysregulation and enhanced disease severity following MERS-CoV infection.JCI Insight. 2019; 4https://doi.org/10.1172/jci.insight.131774Crossref PubMed Scopus (244) Google Scholar]. The diabetic DPP4H/M mice developed more severe disease and were found to have a dysregulated immune response after infection characterized by delayed and decreased recruitment of CD4+ T cells and inflammatory monocytes and macrophages in lung tissue. In addition to the decreased overall CD4+ T cell response, infected diabetic mice also displayed a more prominent Th17 response with increased levels of IL-17a, indicating that an alteration in cytokine profiles could be partly responsible for disease severity. This study is consistent with prior evidence that diabetes results in a shift toward Th17 responses and diminished regulatory T cells resulting in exaggerated inflammatory cascades [[22]Muniyappa R. Gubbi S. COVID-19 pandemic, corona viruses, and diabetes mellitus.Am J Physiol Endocrinol Metab. 2020; https://doi.org/10.1152/ajpendo.00124.2020Crossref PubMed Scopus (537) Google Scholar,[34]Hodgson K. Morris J. Bridson T. Govan B. Rush C. Ketheesan N. Immunological mechanisms contributing to the double burden of diabetes and intracellular bacterial infections.Immunology. 2015; 144: 171-185https://doi.org/10.1111/imm.12394Crossref PubMed Scopus (245) Google Scholar]. Notably, some patients with COVID-19 have developed a fatal hyperinflammatory syndrome resembling secondary hemophagocytic lymphohistiocytosis thought to be mediated by pro-inflammatory cytokines, such as IL-2, IL-6, IL-12, TNF-α, and IFN-γ [[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; 395: 497-506https://doi.org/10.1016/s0140-6736(20)30183-5Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,[38]Mehta P. McAuley D.F. Brown M. Sanchez E. Tattersall R.S. Manson J.J. COVID-19: consider cytokine storm syndromes and immunosuppression.Lancet. 2020; 395: 1033-1034https://doi.org/10.1016/s0140-6736(20)30628-0Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Another area of both scientific and clinical interest has centered on the relationship between ACE2 receptor expression and specific diseases such as diabetes. ACE2 is a transmembrane glycoprotein expressed on cells throughout the human body, including upper respiratory tract epithelial cells, type II alveolar pneumocytes, cardiac myocytes, and pancreatic islet cells. The renin-angiotensin-aldosterone (RAAS) signaling pathway comprises both angiotensin-converting enzyme (ACE), which metabolizes angiotensin I (Ang I) to angiotensin II (Ang II), and ACE2, which converts Ang II to angiotensin(1–7) (Ang 1–7) [[39]Tikellis C. Thomas M.C. Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in health and disease.Int J Pept. 2012; 2012: 256294https://doi.org/10.1155/2012/256294Crossref PubMed Scopus (433) Google Scholar]. Ang II has both vasoconstrictive and inflammatory properties, which are counter-balanced by the vasodilatory and anti-inflammatory properties of Ang 1–7 [[39]Tikellis C. Thomas M.C. Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in health and disease.Int J Pept. 2012; 2012: 256294https://doi.org/10.1155/2012/256294Crossref PubMed Scopus (433) Google Scholar,[40]AlGhatrif M. Cingolani O. Lakatta E.G. The dilemma of coronavirus disease 2019, aging, and cardiovascular disease: insights from cardiovascular aging science.JAMA Cardiol. 2020; https://doi.org/10.1001/jamacardio.2020.1329Crossref PubMed Scopus (162) Google Scholar]. The ratio of the activity of ACE and ACE2, which are both highly expressed in the lung, has been shown to have implications on lung oxygenation and lung injury in acute respiratory distress syndrome (ARDS) [[39]Tikellis C. Thomas M.C. Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in health and disease.Int J Pept. 2012; 2012: 256294https://doi.org/10.1155/2012/256294Crossref PubMed Scopus (433) Google Scholar,[41]Kiely D.G. Cargill R.I. Wheeldon N.M. 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Experimental models have primarily focused on ACE2 in the kidney of type 1 and type 2 diabetic mice and have shown increased ACE2 expression in early disease followed by decreased expression in later disease that coincides with the development of nephropathy [44Tikellis C. Johnston C.I. Forbes J.M. Burns W.C. Burrell L.M. Risvanis J. et al.Characterization of renal angiotensin-converting enzyme 2 in diabetic nephropathy.Hypertension. 2003; 41: 392-397https://doi.org/10.1161/01.Hyp.0000060689.38912.CbCrossref PubMed Scopus (0) Google Scholar, 45Ye M. Wysocki J. Naaz P. Salabat M.R. LaPointe M.S. Batlle D. Increased ACE 2 and decreased ACE protein