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.

Umbilical Cord Mesenchymal Stromal Cells as Critical COVID-19 Adjuvant Therapy: A Randomized Controlled Trial

“…With endothelial conditions that are already compromised by this process, it cannot be denied that endothelial dysfunction will worsen with COVID-19, particularly in older patients. 13 thrombin-antithrombin-complex and D-dimer after administration of 4 Â 10 6 cells/kg body weight AT-MSCs; thus, an application dose less than 4 Â 10 6 cells/kg body weight is recommended. 16 Not analyzing the TF/CD142, we used UC-MSCs with 1 Â 10 6 /kg body weight dose.…”

“…Endothelial dysfunction occurs in patients with diabetes because of oxidative stress processes and chronic inflammation. With endothelial conditions that are already compromised by this process, it cannot be denied that endothelial dysfunction will worsen with COVID‐19, particularly in older patients 13 …”

Impaired Glucose-Insulin Metabolism in Multisystem Inflammatory Syndrome Related to SARS-CoV-2 in Children

“…As reported in the literature, an interaction between COVID-19 and glucose-insulin metabolic disorders is postulated in adults [1,29] and not excluded in pediatrics [30,31]. In particular, the relationship between COVID-19 and type 2 diabetes mellitus (T2DM) has been extensively described in adults [1,2,30] and a relationship between SARS-CoV-2 infection and type 1 diabetes mellitus (T1DM) has also been discussed in children [30][31][32][33][34][35][36]. This is possibly the first up-to-date study on the relationship between IR and glycemic fluctuation in normal weight children without glycemic disorders.…”

Association between Hyperglycemia at Hospital Presentation and Hospital Outcomes in COVID-19 Patients with and without Type 2 Diabetes: A Retrospective Cohort Study of Hospitalized Inner-City COVID-19 Patients

“…Some studies have shown that patients with type 2 diabetes (T2D) have an increased risk of morbidity and mortality in the setting of COVID-19 infection [ 5 , 6 , 7 ]. This is thought to be primarily mediated by the alteration of the immune system and renin-angiotensin-aldosterone systems, endothelial dysfunction, and oxidative stress due to chronic hyperglycemia [ 8 , 9 ]. In addition, recent evidence has highlighted not only that the severe systemic inflammation seen in COVID-19 patients causes stress-induced hyperglycemia, but also that SARS-CoV-2 can directly infect the pancreatic β-cells, resulting in β-cell dysfunction and insulin deficiency [ 9 , 10 ].…”