**3.5 RAGE, diabetes and COVID-19**

The severe acute respiratory syndrome coronavirus (SARS-CoV)-2 pandemic has affected millions of people globally in recent years [102]. Life threatening severe lung inflammation and infections of cardiovascular and central nervous systems as well as the gastrointestinal tract have been reported during SARS-CoV-2 infection [103].

Emerging evidence suggests that individuals with diabetes have poorer prognosis when infected with SARS-CoV-2. Given that the greatest basal expression of RAGE in the body is within the lungs, it is highly likely that RAGE mediated immune processes contribute to these poorer outcomes. In hyperglycemia priming of neutrophils may result in the uncontrolled formation of NETs and release of HMGB1 further increasing vascular permeability. RAGE levels were elevated in both rodent models and humans with acute lung injury and associated with inflammasome formation and IL-1β release [104–106] Whilst most recent SARS-CoV-2 studies focused on comorbidities associated with type 2 diabetes, a common theme of imbalanced immune responses, upregulation of RAGE ligands such as HMGB1 and S100 proteins, insulin resistance, hyperglycemia and release of pro-inflammatory cytokines is seen [107, 108]. Furthermore, several studies reported a significant increase in diabetic ketoacidosis (DKA) in recent onset T1DM during the pandemic [109–111]. These findings have important implications on future treatment and management of patients with dysglycaemia and severe respiratory conditions.
