Why Is COVID-19 More Severe in Patients With Diabetes? The Role of Angiotensin-Converting Enzyme 2, Endothelial Dysfunction and the Immunoinflammatory System

Abstract

Meta-analyses have indicated that individuals with type 1 or type 2 diabetes are at increased risk of suffering a severe form of COVID-19 and have a higher mortality rate than the non-diabetic population. Patients with diabetes have chronic, low-level systemic inflammation, which results in global cellular dysfunction underlying the wide variety of symptoms associated with the disease, including an increased risk of respiratory infection. While the increased severity of COVID-19 amongst patients with diabetes is not yet fully understood, the common features associated with both diseases are dysregulated immune and inflammatory responses. An additional key player in COVID-19 is the enzyme, angiotensin-converting enzyme 2 (ACE2), which is essential for adhesion and uptake of virus into cells prior to replication. Changes to the expression of ACE2 in diabetes have been documented, but they vary across different organs and the importance of such changes on COVID-19 severity are still under investigation. This review will examine and summarise existing data on how immune and inflammatory processes interplay with the pathogenesis of COVID-19, with a particular focus on the impacts that diabetes, endothelial dysfunction and the expression dynamics of ACE2 have on the disease severity.

Keywords: COVID-19; SARS– CoV– 2; angiotensin converting enzyme-2; diabetes; endothelium; immune response; inflammation; oxidative stress.

Figure 1

SARS-CoV-2 genomic and virion structures. (A) Genome schematic of SARS-CoV-2. The asterisk marks the overlapping reading frames of ORF1a and ORF1b, which encode a variety of non-structural proteins, including helicases, proteases, and an RNA-dependent RNA polymerase. The S protein is encoded by nt. 21,563-25,384; the E protein is encoded by nt. 26,245-26472; the M protein is encoded by nt. 26,523-27,191; and the N protein is encoded by nt. 28,274-29,533. Accessory proteins not shown. Adapted from Alanagreh et al. (91). (B) Schematic representation of the SARS-CoV-2 virion structure. This figure is not to scale, and relative abundances of the proteins shown are arbitrary.

Figure 2

SARS-CoV-2 S interfacing with ACE2. Various orientations of an X-ray crystallography-derived cartoon representation of the Spike protein S1 subunit of SARS-CoV-2 (cyan) bound to an extracellular portion of ACE2 (residues 1-597; pink). (B) Is a 90° anticlockwise rotation, along the z-axis, of (A), while (C) is angled to highlight the shape of the binding interface between ACE2 and SARS-CoV-2 S, ~90° clockwise along the z-axis, and ~45° counter-clockwise along the x-axis, relative to A. Figure was created using *Mol. PDB ID: 6M0J, Crystal Structure of SARS-CoV-2 spike receptor-binding domain bound with ACE2 (97, 98).

Figure 3

RAAS schematic. Simplified schematic focusing on the activity of ACE and ACE2 and the resulting receptor activation. The vasoconstrictive activity of this pathway is mediated by AT₁R activation, which also causes increased oxidative stress; MasR and AT₂R activation leads to vasodilation and a reduction in oxidative stress. Receptors are in boxes; enzymes that processes signalling peptides are in ovals.

Figure 4

ACE2 protein schematic. An annotated schematic of the primary structure of ACE2. Arg273 is essential for substrate binding, by facilitating the formation of a salt-bridge. His345 and His505 assist with stabilising the substrates transition state during catalysis (118). The cleavage sites for the in vivo production of sACE2 are Arg697 and Lys716.

Figure 5

Potential temporal impact of COVID-19 on the RAAS. Hypothetical impact of SARS-CoV-2 on local expression of ACE/ACE-2 enzymes and the possible outcome in terms of angiotensin-II, angiotensin 1–7, angiotensin 1–9 and bradykinin (BK) concentrations, as well as the vascular impact.

Figure 6

Interaction between diabetes and COVID-19 with respect to the RAAS. Illustration of the complex interactions associated with diabetes and COVID-19. The green box illustrates the appropriate response to SARS-CoV-2, resulting in only mild symptoms. The alternative pathways illustrate some of the dysregulation that might be primed by diabetes, resulting in acute (pulmonary hypoperfusion and oedema) and chronic (fibrosis) outcomes.

Figure 7

Alveolar and capillary pathophysiology relevant to COVID-19 and diabetes compared to the healthy scenario. This figure highlights some of the key cells that become activated in COVID-19 (middle segment) and diabetes (right segment) that have the potential to drive dysfunction in endothelial (diabetes and COVID-19) and alveolar epithelial (COVID-19 only) cells. The pathophysiological consequences are highlighted in the red boxes.