Strange it might sound, even overexpression of ACE2 would be counterproductive in COVID-19. SARS-CoV-2 utilizes ACE2 as a receptor for entry into the host pneumocytes [13]. Herein comes the confounding role of ACE inhibitors (ACEi) and angiotensin-receptor blockers (ARBs), drugs that are so widely used in DM. The expression of ACE2 is markedly increased in patients with DM (and hypertension) on ACEi or ARBs as an adaptive response to counteract the elevated levels of Ang-II and Ang-I. Thus, use of ACE2-stimulating drugs would facilitate the entry of SARS-CoV-2 into pneumocytes and consequently might result in more severe and fatal disease [14]. Amongst others, pioglitazone and liraglutide have also been shown to be associated with ACE2 upregulation in animal studies [14], [15]. Unfortunately, none of the studies have taken into account the baseline treatment. Furthermore, a recently concluded study showed that severe and critically ill patients with COVID-19 had a higher prevalence of hypokalemia that resulted from renal potassium wasting. This can be explained by downregulation of ACE2 following viral intrusion resulting in decreased degradation of angiotensin-II, increased aldosterone secretion and subsequent increased urinary potassium loss. Infact early normalization of serum potassium has been proposed to be a predictor of good prognosis in COVID-19 [16]. Thus, ACE2 overexpression, while facilitating entry of SARS-CoV-2, is unable to protect against lung injury as the enzyme gets degraded by the virus (see Fig. 1).
Fig. 1 Schematic diagram depicting interplay between SARS-CoV-2 and pneumocyte. SARS-CoV-2 gains entry into the pneumocyte using angiotensin-converting enzyme 2 (ACE2) as a receptor. ACE2 is upregulated with the prior use of angiotensin-converting enzyme inhibitors (ACEi)/angiotensin-receptor blockers (ARBs). Following entry into the pneumocyte, the virus replicates and ACE2 gets downregulated. As a result, there is reduced degradation of angiotensin-II which in turn leads to increased secretion of aldosterone and subsequent renal potassium wasting.