Advanced-glycation end-products axis: A contributor to the risk of severe illness from COVID-19 in diabetes patients

Abstract

Compelling pieces of evidence derived from both clinical and experimental research has demonstrated the crucial role of the receptor for advanced-glycation end-products (RAGE) in orchestrating a plethora of proinflammatory cellular responses leading to many of the complications and end-organ damages reported in patients with diabetes mellitus (DM). During the coronavirus disease 2019 (COVID-19) pandemic, many clinical reports have pointed out that DM increases the risk of COVID-19 complications, hospitalization requirements, as well as the overall severe acute respiratory syndrome coronavirus 2 case-fatality rate. In the present review, we intend to focus on how the basal activation state of the RAGE axis in common preexisting conditions in DM patients such as endothelial dysfunction and hyperglycemia-related prothrombotic phenotype, as well as the contribution of RAGE signaling in lung inflammation, may then lead to the increased mortality risk of COVID-19 in these patients. Additionally, the cross-talk between the RAGE axis with either another severe acute respiratory syndrome coronavirus 2 receptor molecule different of angiotensin-converting enzyme 2 or the renin-angiotensin system imbalance produced by viral infection, as well as the role of this multi-ligand receptor on the obesity-associated low-grade inflammation in the higher risk for severe illness reported in diabetes patients with COVID-19, are also discussed.

Keywords: Advanced glycation; Advanced-glycation end-products axis; Alarmins; COVID-19; Diabetes mellitus; Inflammation.

Figure 1

The chronic and low-grade inflammatory state preexisting in diabetes patients as well as in one of the most frequent co-morbidities observed in diabetes seems to be particularly exacerbated in coronavirus disease 2019 patients with diabetes. The receptor for advanced-glycation end-products axis hyper- activation, either by ligand-dependent or cognate-ligand independent mechanisms, is emerging as crucial contributor to this huge inflammatory response leading to acute respiratory distress syndrome, endotheliitis and thrombotic complications. ARDS: Acute respiratory distress syndrome; AT1R: Angiotensin II receptor type 1; COVID-19: Coronavirus disease 2019; RAGE: Receptor for advanced-glycation end-products; RAS: Renin-angiotensin system.