Metabolic Syndrome and COVID 19: Endocrine-Immune-Vascular Interactions Shapes Clinical Course

Abstract

The ongoing coronavirus disease 2019 (COVID-19) pandemic is caused by the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Individuals with metabolic syndrome are at increased risk for poor disease outcomes and mortality from COVID-19. The pathophysiologic mechanisms for these observations have not been fully elucidated. A critical interaction between SARS-CoV-2 and the angiotensin-converting enzyme 2 (ACE2) facilitates viral entry into the host cell. ACE2 is expressed in pancreatic islets, vascular endothelium, and adipose tissue, and the SARS-CoV-2 -ACE2 interaction in these tissues, along with other factors, governs the spectrum and the severity of clinical manifestations among COVID-19 patients with metabolic syndrome. Moreover, the pro-inflammatory milieu observed in patients with metabolic syndrome may contribute toward COVID-19-mediated host immune dysregulation, including suboptimal immune responses, hyperinflammation, microvascular dysfunction, and thrombosis. This review describes the spectrum of clinical features, the likely pathophysiologic mechanisms, and potential implications for the management of metabolic syndrome in COVID-19 patients.

Keywords: COVID-19; coronavirus; diabetes; hypertension; metabolic syndrome; obesity.

Figure 1.

Clinical course and innate immunity in coronavirus disease 2019 (COVID-19). Time course of clinical presentation and course, type I interferon (IFN) response (green), and inflammatory monocyte/macrophage recruitment and cytokine production (red). Timely and robust type I IFN response and regulated inflammatory monocyte/macrophage and cytokine levels limits viral replication in patients with mild/moderate COVID-19. High viral load with delayed and suboptimal type I IFN response, exaggerated inflammatory monocyte/macrophage recruitment, and cytokine storm is characteristic of severe COVID-19. Neutrophilia, lymphopenia, elevated lactate dehydrogenase, and high C-reactive protein levels predict severe COVID-19. Created with BioRender.com.

Figure 2.

Cellular entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and initial innate immune mechanisms. The initial step in cellular entry of the virus is the binding of SARS-CoV-2 spike protein to cell surface angiotensin-converting enzyme 2 (ACE2). Cellular proteases such as TMPRSS2 and furin are involved in priming of the S protein, which involves cleavage at the S1/S2 domains. This allows the fusion of the virus to the cell surface. Once inside the cell, SARS-CoV-2 viral sensing involves activation of the Toll-like receptor (TLR7) to stimulate the production of type I interferons. There is also activation of inflammatory monocytes/macrophages and the production of cytokines/chemokines. Angiotensin-converting enzyme (ACE) catalyzes the conversion of angiotensin I to the octapeptide, angiotensin II (AngII), whereas ACE2 converts Ang II to angiotensin_1-7. Ang II, through the activation of Ang II type 1a receptors, induces vasoconstriction and proliferation, but angiotensin_1-7 stimulates vasodilatation and suppresses cell growth. GLP-1 agonist, glucagon-like peptide-1; TMPRSS2, transmembrane protease, serine 2; TZD, thiazolidinedione. Created with BioRender.com.

Figure 3.

Immune and endothelial interactions in COVID-19. SARS-CoV-2 infection of cells stimulates type I IFN response and recruitment of inflammatory monocyte and macrophages. Activated monocytes/macrophages release cytokines/chemokines such as IL-6, TNF-α, IL-8, CCL-2, CCL-4, and CCL-14 leading to hyperinflammation. Infection of endothelial cells and activation by inflammatory cells and cytokines trigger coagulation pathways, stimulates platelet aggregation, induces microvascular dysfunction, and generates microthrombi formation. CCL2, chemokine (C-C motif) ligand 2; CCL4, chemokine ligand 4; CCL14, chemokine ligand 14; IFN-γ, interferon-gamma; IL, interleukin; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TNF-α, tumor necrosis factor-alpha. Created with BioRender.com.

Figure 4.

Management of metabolic syndrome in coronavirus disease 2019 (COVID-19).