key: cord-0944931-cvltwjbz authors: Jeong, In-Kyung; Ho Yoon, Kun; Kyu Lee, Moon title: Diabetes and COVID-19: Global and Regional Perspectives date: 2020-07-03 journal: Diabetes Res Clin Pract DOI: 10.1016/j.diabres.2020.108303 sha: e9ec4823646bcbd8726cee8b02780c5ac7f2c5c7 doc_id: 944931 cord_uid: cvltwjbz Abstract The coronavirus disease-2019 (COVID-19) has been designated as a highly contagious infectious disease caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) since December 2019, when an outbreak of pneumonia cases emerged in Wuhan, China. The COVID-19 pandemic has led to a global health crisis, devastating the social, economic and political aspects of life. Many clinicians, health professionals, scientists, organizations, and governments have actively defeated COVID-19 and shared their experiences of the SARS-CoV2. Diabetes is one of the major risk factors for fatal outcomes from COVID-19. Patients with diabetes are vulnerable to infection because of hyperglycemia; impaired immune function; vascular complications; and comorbidities such as hypertension, dyslipidemia, and cardiovascular disease. In addition, angiotensin-converting enzyme 2 (ACE2) is a receptor for SARS-CoV-2 in the human body. Hence, the use of angiotensin-directed medications in patients with diabetes requires attention. The severity and mortality from COVID-19 was significantly higher in patients with diabetes than in those without. Thus, the patients with diabetes should take precautions during the COVID-19 pandemic. Therefore, we review the current knowledge of COVID-19 including the global and regional epidemiology, virology, impact of diabetes on COVID-19, treatment of COVID-19, and standard of care in the management of diabetes during this critical period. The coronavirus disease-2019 (COVID -19) has been designated as a highly contagious infectious disease caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) since December 2019, when an outbreak of pneumonia cases emerged in Wuhan, Hubei, China [1] . Due to rapid and sustained human-to-human transmission, the COVID-19 pandemic has led to a global health crisis, devastating the social, economic and political aspects of life. Many clinicians, health professionals, scientists, organizations, and governments have actively defeated COVID-19 and shared their experiences and knowledge of the SARS-CoV2. Diabetes is one of the major risk factors for fatal outcomes from COVID-19 [2] . Patients with diabetes are vulnerable to infection because of hyperglycemia; impaired immune function; and comorbidities such as hypertension, dyslipidemia, and cardiovascular disease. In addition, angiotensin-converting enzyme 2 (ACE2) is a receptor for SARS-CoV-2 in the human body [3] . Hence, the use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blockers (ARB) and high level of angiotensin II in patients with diabetes requires attention. In fact, it was reported that the overall proportion of diabetics with COVID-19 was 5.3% to 33.9% in China [4] , Italy [5] , and the USA [6] . The severity and mortality from COVID-19 was significantly higher in patients with diabetes than in those without [7] . Thus, the patients with diabetes should take precautions during the COVID-19 pandemic. In addition, knowledge of the molecular mechanism of viral entry and replication can direct the treatment strategies and future research on targeted antiviral drugs and vaccines. Therefore, we review the current knowledge of COVID-19 including the global and western-Pacific regional epidemiology, virology, impact of diabetes on COVID-19, treatment of COVID-19, and standard of care in the management of diabetes during this critical period. We searched all the articles in PubMed and Google Scholar databases from December 2019 to early May 2020 using keywords: "COVID-19", "SARS-CoV-2", "diabetes", "epidemiology", "pathophysiology", "ACE2", "manifestation", and "treatment". Due to sustained human-to-human transmission, the rapid spread of SARS-CoV-2 resulted in a formidable outbreak in many cities in China, expanding internationally to South Korea[9], Europe [10] , and the United States [11] . The WHO declared the COVID-19 outbreak a pandemic on March 11, 2020 [12] . The case fatality rate (CFR) of COVID-19 is lower than that of SARS-CoV1 and MERS-CoV, which were 9.4% and 34.4%, respectively [13] . However, due to the high transmission rate, the absolute number of fatality is strikingly high. As of May 8 , 2020, the WHO reported 3,759,967 confirmed cases including 259,474 deaths (CFR 6.90%). In the Western Pacific Region, 157,447 confirmed cases including 6,394 deaths (CFR 4.06%) were reported (https://www.who.int/docs/default-source/coronaviruse/situationreports) [14] . Recently, as the countries are moving to less restrictive social distancing measures after successful initial defense, the number of COVID-19 patients has been increasing in Japan, Hong Kong, and Singapore. Thus, careful prevention and treatment of COVID-19 is still needed in the western Pacific region (Fig 1) . The first confirmed case of COVID-19 in the Republic of Korea (South Korea) was a traveler from Wuhan, China on January 19, 2020 [15] . [7] . Therefore, patients with diabetes do not seem to be more susceptible to COVID-19. The severity and mortality of patients with diabetes was higher than those of patients without diabetes infected COVID-19 (Table 1) . A previous early large observational study found that the incidence of diabetes was higher in patients with severe illness (16.3%) than in patients with non-severe illness (6.9%) [28] . Other single-center observational studies showed similar results, i.e., higher (13. A single-center study conducted in Korea reported that 28-day mortality was significantly higher in patients with diabetes than in those without diabetes (17.2% vs. 1.2%). Patients with diabetes showed a higher severity score and inflammation marker levels [46] . In USA, as of March 28, 2020, among a total of 122,653 laboratory-confirmed COVID-19 cases, diabetes mellitus (784, 10.9%) was the most frequently reported condition among 7162 cases whose data on underlying health conditions were available. The percentage of diabetics among cases that resulted in an ICU admission was higher (32%) than that among nonhospitalized cases (6%) or among cases of non-ICU admissions(24%) [47] . Several metaanalyses also found that the incidence of diabetes was two-fold higher in those who developed severe disease than in patients who experienced non-severe disease [7, [48] [49] [50] [51] (Supplementary table 1) . These results suggest an association between diabetes and poor prognosis and increased mortality. Therefore, intensive attention should be paid to patients with diabetes. The reason for the high morbidity and mortality in patients with diabetes should be investigated. Hyperglycemia, low immune function, vascular complications, and comorbidities are contributing factors to fatal outcomes in patients with diabetes. However, few studies have analyzed the effect of hyperglycemia on prognosis. A retrospective single-center study conducted in Korea reported that age was an independent risk factor for severe outcomes among patients with diabetes. Baseline HbA1c and anti-diabetic medication did not affect COVID-19 outcomes [46] . Because baseline HbA1c does not take into account fluctuations in blood glucose levels, glycemic variability is important for evaluating overall glycemic control. [55] , 2015 [56] , and 2017 [57] . The latest isolated SARS-CoV-2 is the seventh corona virus that causes severe and fatal disease in humans ( Table 2 ). The SARS-CoV-2 is a novel β-coronavirus, which is an enveloped, non-segmented positivesense, single-strand RNA virus identified by complete genome sequences of samples from the bronchoalveolar lavage fluid of patients [1] . The SARS-CoV-2 shares 79% sequence identity with SARS-CoV [58] , and 50% similarity with MERS-CoV [59] . It is a spherical particle of 100-160 nm in diameter, which contains a 27-32-kb ssRNA genome. The 5' two-thirds of the genome encodes a polyprotein, pp1ab, which is further cleaved into 16 nonstructural proteins that are involved in genome transcription and replication. The 3' terminus encodes structural proteins, including envelope glycoproteins spike (S), envelope (E), membrane (M), and nucleocapsid (N) [59] . The genome is packaged inside a capsid formed by nucleocapsid protein (N). Membrane protein (M) and envelope protein (E) are both involved in virion assembly, and spike protein (S) mediates entry into host cells [60] . The S protein is characterized by a receptorbinding domain (RBD) S1 subunit that facilitates binding to the host angiotensin-converting enzyme 2 (ACE2) receptor for both SARS-CoV and SARS-CoV-2 and an S2 subunit that is responsible for membrane fusion [3] . The RBD of MERS-CoV attaches to the host cells via dipeptidyl peptidase 4 (DPP4) rather than ACE2 [61] . A recent study demonstrated that the RBD unique to SARS-CoV-2 enhanced ACE2 receptor-binding affinity as compared to SARS-CoV [62] . After binding of ACE2, host cell factors further mediate viral entry through two serine proteases, transmembrane protease serine 2 (TMPRSS2) and furin, which cleave the S protein for membrane fusion and assist in viral processing, respectively [56] [57] [58] [59] [60] . Upon membrane fusion, the viral RNA is translated, replicated, and amplified. Upon amplification of the viral RNA, viral structural and nonstructural proteins are generated, which interact with viral RNA on the membrane of the ER and Golgi apparatus and finally result in viral budding and exocytosis [63] . Angiotensin-converting enzyme 2 (ACE2) protein The reason why the ACE2 molecule is the subject of much attention is because it is the receptor for SARS-CoV-2 viral entry as well as an important element in the cardiovascular system, use of ACEI or ARB medication for cardiovascular disease, and severe clinical course of patients with cardiovascular comorbidity and SARS-CoV-2 infection. ACE2 is a single-pass transmembrane protein with protease activity and is found in the type II pneumocytes of the lower respiratory tract, myocardium, endothelium, gastrointestinal tract, pancreatic islets, bone marrow, kidney, and spleen [64] . This broad expression of ACE2 may explain the multi-organ injury observed with COVID-19. The role of ACE2 in the cardiovascular system is that ACE2 converts angiotensin I (Ang I) into angiotensin 1-9 (Ang 1-9) and also converts angiotensin II (Ang II) into angiotensin (Ang 1-7), which acts on the Mas receptor to modestly lower blood pressure through vasodilation and by promoting sodium and water excretion through the kidney and to attenuate inflammation through the production of nitric oxide[65]. ACE2 is a counter-regulatory enzyme to ACE1. ACE1 converts Ang I into Ang II, which acts at the angiotensin II type-1 receptor (AT1R) to increase blood pressure by inducing vasoconstriction, increasing reabsorption of sodium and water in the kidney, and increasing oxidative stress to promote inflammation and fibrosis [66] (Fig 3) . Thus, the balance between ACE-Ang II and ACE2-Ang-(1-7) determines whether acute lung injury will be aggravated or alleviated. There are controversies regarding whether renin-angiotensin system (RAS) inhibition is harmful or protective in COVID- 19[67] . Even though ACE inhibitors and angiotensinreceptor blockers (ARB) do not directly inhibit ACE2 [68] , ACE inhibitors affect the expression of ACE2 in the heart and kidney, and ARB could increase ACE2 abundance and enhance viral entry. However, there are no data to support the notion that ACE inhibitors or AT1R blockers facilitate coronavirus entry by increasing ACE2 expression. Regarding the protective view, diminishing production of Ang II with an ACE inhibitor or blocking Ang II-AT1R actions with an ARB enhances the generation of Ang-(1-7) by ACE2 and activation of the Mas receptor (MasR), which attenuates inflammation, fibrosis, and lung injury. Interestingly, the administration of losartan, an AT1R blocker alleviated the exacerbating effects of SARS-CoV spike protein in an animal model of acute respiratory distress syndrome (ARDS) [69] . Losartan also ameliorated influenza virus-induced acute lung injury in mice [70] . Fortunately, a retrospective single-center study conducted in Korea showed that ARB or ACEI medication was associated with a protective effect against cardiac injury, and it was an independent factor of favorable outcomes in patients with COVID-19 [46] . Angiotensin inhibitors improve blood pressure and might help restore pulmonary function through the MAS receptor pathway. Soluble ACE2 is released into the blood through cleavage by the membrane-bound protease, A disintegrin and metalloprotease 17 (ADAM17) [71] . result from direct viral cytotoxicity of the pulmonary system due to inflammatory activation. If the host cannot remove the virus via a protective immune response, COVID-19 progresses to stage III which is a severe status with multi-organ dysfunction and cytokine storm with immune dysregulation (Fig 4) . Accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have a cytokine storm syndrome and strong inflammatory response could be linked with uncontrolled pulmonary inflammation and consequent COVID-19 lethality [76] . ICU patients in the severe stage of COVID-19 had high plasma levels of interleukin (IL)-2, IL-7, granulocyte colony-stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumor necrosis factor-α than non-ICU patients, suggesting the presence of a hyper-inflammatory condition also known as a cytokine storm [77] . In particular, diabetes was identified as a risk days after they were vacated and before disinfection procedure [79] . Live virus has also been isolated and cultured from fecal specimens raising the possibility of oro-fecal transmission, but corroborating clinical evidence of this transmission is lacking [80] . Therefore, it is recommended that precautions to reduce airborne transmission, with the use of N-95 masks, should be implemented in these aerosol-producing settings [81] . Human-to-human transmission is now well established for COVID-19 with an R 0 (the expected number of secondary cases produced by a single [typical] infection in a completely susceptible population) of 1.4-2.5, as estimated by the WHO [82] . For comparison, seasonal flu has a median R 0 of 1.28 (IQR 1.19-1.37) [83] , while measles has an R 0 of 12-18 [84] . However, the COVID-19 R 0 was calculated from incomplete data and may change as further information becomes available. The clinical spectrum of SARS-CoV-2 infection appears to be wide, encompassing asymptomatic infection, mild upper respiratory tract illness, and severe viral pneumonia with respiratory failure and even death. The prevalence of asymptomatic patients from exposure to admission was as much as one-fifth among participants from a community facility designated for isolation of patients without moderate-to-severe symptoms in South Korea [85] . Most cases are reported to experience a mild course [24] . The most common symptoms of mild COVID-19 patients were cough, hyposmia, and sputum, and not fever. However, the most common symptoms of hospitalized patients were fever, cough, fatigue, dyspnea or chest tightness, sore throat, and headache [4, 9] . In addition, some patients manifested gastrointestinal symptoms, with diarrhea and vomiting. The average length of hospital stay was 12.7 days (range: 8-19 days) [9] . Based on the current information, the elderly and those with chronic underlying diseases were in critical condition and their hospital stay was long. Chest computed tomography showed ground-glass opacities and patchy bilateral shadowing [4, 9] . However, clinicians should be aware that some patients with COVID-19 also had normal computed tomography findings. Complications of COVID-19 are ARDS, arrhythmia, shock, acute kidney injury, acute cardiac injury, liver dysfunction, secondary infection, and multiple organ dysfunction. The disease can quickly progress to a severe condition in the elderly or people with comorbidities such as diabetes, hypertension, cardiovascular disease, cerebrovascular disease, chronic obstructive pulmonary disease, asthma, immunocompromised state, chronic kidney disease, chronic liver disease, and severe obesity (Fig 4) . Samples from nasal and throat swab or other respiratory tract are used to test for the virus. clinical diagnostic method for COVID-19 around the world [86] . If the test result is positive, the diagnosis of SARSCoV-2 is confirmed. The WHO currently recommends that negative results in the presence of clinical symptoms or exposure to infected patients must be treated with suspicion; the test can be repeated using additional samples from the lower respiratory tract [87] . Also, it would be interesting to examine the cases of positive converters after initial Metformin [93] , pioglitazone [94] , liraglutide [95] , sodium-glucose cotransporter-2 inhibitor (SGLT2) inhibitor [96] , and insulin [97] increased ACE2 expression in animal study. However, metformin showed immune-modulating activity [98] . Pioglitazone reduced the lung fibrotic reaction to silica in rats, which is normally characterized by overproduction of TNFa [99] . Cardiology [102] . Calcium-channel blockers (CCBs) have no effect on ACE2 expression. Since CCB has been shown to reduce severity and mortality in patients with pneumonia, its use has been proposed for patients with COVID19 and hypertension[103]. Because SARS-CoV-2 has rapidly spread globally, there are no approved and evidence-based (3) (Hydroxy-)chloroquine, (potentially in combination with azithromycin) accelerated viral clearance in small French pilot study [106] . (4) Nucleoside analogues (remdesivir, favipiravir, geldesivir, and ribavirin etc.) can limit virus replication. Remdesivir was originally developed for the treatment of Ebola virus. Remdesivir successfully treated the first US case of COVID-19 in January 2020 [107] . (5) Protease inhibitors (lopinavir, ritonavir, etc.) have been used to treat infection with human immunodeficiency virus (HIV) [108] and could improve the outcomes of MERS-CoV [109] and SARS-CoV [110] patients. SARS-CoV-2 viral loads of patients in South Korea significantly decreased after lopinavir/ritonavir treatment [111] . (6) Type 1 interferons induce anti-viral cellular programs through immune modulation [112] . (7) The recombinant IL-6 receptor antagonist tocilizumab has been used successfully in patients with COVID-19 [113] . The recombinant IL-1 receptor antagonist anakinra is being trialed in children and adults with COVID-19 associated cytokine storm syndrome in China (NCT02780583) [114] .(8) Inhibitors of janus kinases (JAK) modulate cytokine receptor signaling, including the IL-6 receptor as well as type 1 and type 2 IFN receptors [115] . Clinical trials on severe COVID-19 are ongoing (ChiCTR2000030170, ChiCTR2000029580) [116] . (9) Corticosteroids can control inflammation in ARDS. However, preliminary data on COVID-19 showed that high-dose steroids did not have beneficial effects on lung injury, but were associated with complications. Thus, high-dose corticosteroids cannot be generally recommended for the treatment of COVID-19 [117] . Management of glycemic control during the pandemic period Telemedicine has been very helpful and useful the during the COVID-19 pandemic [122] . Wearable health systems to monitor blood glucose, blood pressure, physical activity, caloric intake, eating behavior, sleep pattern, and adherence to medication will be helpful for comprehensive management for patients with diabetes. ACE2 converts Ang I to Ang-(1-9) and Ang II (angiotensin II) to Ang-(1-7), which acts on the Mas receptor (MasR) to lower blood pressure through vasodilation but also to attenuate inflammation and fibrosis. ACE1 converts Ang I into Ang II, which acts at the angiotensin II type 1 receptor (AT1R) to increase blood pressure by inducing vasoconstriction, increasing kidney reabsorption of sodium and water, and increasing oxidative stress to promote inflammation and fibrosis. ACE2 also binds to and internalizes SARS-CoV-2 after priming by the serine protease TMPRSS2 (transmembrane protease,serine-2  Even though angiotensin-converting enzyme (ACE) 2 molecule is a receptor for SARS-CoV-2 viral entry, there is no evidence for the deleterious influence of ACE inhibitor or angiotensin receptor blocker (ARB) medication on the COVID-19 outcomes. It is strongly recommended that ACE inhibitor or ARBs should not be withdrawn without consultation of physician or healthcare provider.  Optimal glucose control is necessary for critically ill patients with diabetes. Also, antidiabetic medications should be individualized according to the degree of hyperglycemia, contraindications, adverse reactions, and severity of COVID-19.  Various online services of glucose management such as remote consultation, wearable monitoring system, and educational tools will be helpful for comprehensive management for patients with diabetes during pandemic period.  South Korea's strategies for favorable outcomes are early recognition, transparent and prompt sharing of information, rapid establishment of extensive diagnostic testing facilities, implementing innovative and aggressive measures for control and preventing community transmission, redesigning the triage and treatment system, mobilizing the necessary resources for clinical care. 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