Novel Molecular Evidence Related to COVID-19 in Patients with Diabetes Mellitus

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.

Follow-up study of pulmonary sequelae in discharged COVID-19 patients with diabetes or secondary hyperglycemia

“…We also found that the proportions of patients with residual lung abnormalities were significantly higher in the group with diabetes or hyperglycemia than in the control group. Previously, individuals with diabetes or secondary hyperglycemia were shown to be at a high risk of severe COVID-19 due to their impaired immunity and dysfunctional proinflammatory cytokine responses [7] , [27] . Thus, underlying comorbidities are associated with disease severity and, potentially, a slow recovery, which may also lead to a greater degree of residual pulmonary changes.…”

“…Notably, severe acute respiratory syndrome coronavirus (SARS-CoV) has been shown to damage islet cells through its receptors and cause secondary hyperglycemia in patients who were not using any glucocorticoids and who did not have a prior history of diabetes [4] . Several recent studies have shown that hyperglycemia at admission and previously diagnosed diabetes are significant predictors of severe disease and mortality in COVID-19 patients [5] , [6] , [7] . Similar findings were previously observed in patients infected with SARS-CoV [8] and middle east respiratory syndrome coronavirus (MERS-CoV) [9] .…”

Hyperactivated RAGE in Comorbidities as a Risk Factor for Severe COVID-19—The Role of RAGE-RAS Crosstalk

“…Following interaction with SARS-CoV-2, virus-dependent ACE2 downregulation is responsible for the accumulation of ACE1-derived Ang II, which mediates the inflammatory response and parenchymal injury in lungs and other organs by interacting with AT1R and activating NF-κB. ACE2 glycosylation, as occurring under hyperglycemia conditions typical of diabetes, increases the binding affinity of ACE2 to the virus and favors the spreading of the virus to multiple organs [90]. Preventing imbalances in RAS members or favoring the activity of Mas receptor (MasR) or AT2R is a therapeutic strategy to restrain SARS-CoV-2-dependent tissue damage in COVID-19 patients [9].…”

Diabetes mellitus and COVID-19: Understanding the association in light of current evidence

“…A rise in glycosylated ACE-2, ADAM17 and TMPRSS2 expression in pancreatic islets and glycated SARS-CoV-2 S-protein in an individual with DM were observed. Thus, it is predicted that increased TMPRSS2 expression is linked to entry of the virus in humans[ 39 , 48 ]. The role of interferon-induced transmembrane proteins and ADAM17 was also investigated, and a possible association of their expression with SARS-CoV-2 infection and severity was suggested[ 39 , 48 ].…”