Abstract
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly evolved into a global pandemic. The hyperglycemia in patients with diabetes mellitus (DM) substantially compromises their innate immune system. SARS-CoV-2 uses human angiotensin-converting enzyme 2 (ACE2) receptors to enter the affected cell. Uncontrolled hyperglycemia-induced glycosylation of ACE2 and the S protein of SARS-CoV-2 could facilitate the binding of S protein to ACE2, enabling viral entry. Downregulation of ACE2 activity secondary to SARS-CoV-2 infection, with consequent accumulation of angiotensin II and metabolites, eventually leads to poor outcomes. The altered binding of ACE2 with SARS-CoV-2 and the compromised innate immunity of patients with DM increase their susceptibility to COVID-19; COVID-19 induces pancreatic β-cell injury and poor glycemic control, which further compromises the immune response and aggravates hyperglycemia and COVID-19 progression, forming a vicious cycle. Sequential cleavage of viral S protein by furin and transmembrane serine protease 2 (TMPRSS2) triggers viral entry to release the viral genome into the target cell. Hence, TMPRSS2 and furin are possible drug targets. As type 1 DM exhibits a Th1-driven autoimmune process, the relatively lower mortality of COVID-19 in type 1 DM compared to type 2 DM might be attributed to an imbalance between Th1 and Th2 immunity. The anti-inflammatory effects of dipeptidyl peptidase-4 inhibitor may benefit patients with DM and COVID-19. The potential protective effects of sodium–glucose cotransporter-2 inhibitor (SGLT2i), including reduction in lactate level, prevention of lowering of cytosolic pH and reduction in pro-inflammatory cytokine levels may justify the provision of SGLT2i to patients with DM and mild or asymptomatic COVID-19. For patients with DM and COVID-19 who require hospitalization, insulin-based treatment is recommended with cessation of metformin and SGLT2i. Further evidence from randomized or case–control clinical trials is necessary to elucidate the effectiveness and pitfalls of different types of medication for DM.
Highlights
Coronavirus disease 2019 (COVID-19), an infection caused by an enveloped virus with a single-stranded RNA genome, namely novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a global pandemic
Patients with high blood glucose or diabetes mellitus (DM) are at a risk of developing more severe COVID-19, which might be attributed to the hyperglycemia related aberrant glycosylation or hyperglycemia-enhanced nonenzymatic glycation of angiotensin-converting enzyme 2 (ACE2) and SARS-CoV-2 spike protein
SARS-CoV was detected in the pancreas of patients whose death was attributed to SARS [27]. These findings suggest that direct binding of SARS-CoV-2 to ACE2 on pancreatic β-cells might contribute to their damage (Figure 1) and subsequent insulin deficiency and hyperglycemia, as observed previously in patients with SARS-CoV infection [28]
Summary
Coronavirus disease 2019 (COVID-19), an infection caused by an enveloped virus with a single-stranded RNA genome, namely novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a global pandemic. Patients with high blood glucose or DM are at a risk of developing more severe COVID-19, which might be attributed to the hyperglycemia related aberrant glycosylation or hyperglycemia-enhanced nonenzymatic glycation of ACE2 and SARS-CoV-2 spike protein Both RAS and ACE2 play important roles in DM patients with COVID-19, especially through bradykinin being degraded by ACE and angiotensin 1–9 being activated by ACE2. Compared with hospitalized patients with COVID-19 without DM, those with DM have worse clinical profiles and outcomes, such as higher blood glucose, HbA1c, white blood cell count, high-sensitivity C-reactive protein, procalcitonin, ferritin, D-dimer, lactic dehydrogenase, N-terminal pro-brain natriuretic peptide and mortality [35] These findings indicate that patients with COVID-19 with underlying DM had worse glycemic control, more severe infection and myocardial damage. Altered immune response, augmented viral entry and decreased viral clearance in patients with DM contribute to their higher susceptibility to COVID-19
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