JDC Gems

2. The enigma of COVID-19, diabetes mellitus and ACE2

      The novel coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has scourged the world since its outbreak in December 2019 at Wuhan, China resulting in the WHO declaring it as a pandemic. The disease has also infiltrated the Indian masses and is spreading fast. Although the overall mortality rate of COVID-19 is low, patients with comorbidities are more likely to have severe disease and subsequent mortality. Many of the available studies showed diabetes as a distinctive comorbidity associated with more severe disease, acute respiratory distress syndrome and increased mortality. Further, in the largest series reported by the Chinese Center for Disease Control and Prevention comprising of 72,314 cases of COVID-19, patients with diabetes had higher mortality (7.3% in diabetes vs. 2.3% overall).

      With the available studies it can be stated that patients with diabetes are more likely to be older than those without diabetes and advancing age has consistently been shown to be associated with poor prognosis in COVID-19. A series of explanations can be put forward for the apparent association between pre-existing diabetes and COVID-19 severity. First and the foremost is the innate immunity, the primary mode of defense against SARS-CoV-2, is inevitably compromised in patients with uncontrolled DM thereby allowing unhindered proliferation of the pathogen within the host. Even short-term hyperglycemia has been shown to transiently statue the innate immune system.

      The role of angiotensin-converting enzyme 2 (ACE2) in the association between diabetes and COVID-19 is possible. ACE2 is a type 1 integral membrane glycoprotein that is expressed in the epithelial cells of the lungs, kidney, intestine and blood vessels. In normal physiology, ACE2 breaks down angiotensin-II and to a lesser extent, angiotensin-I to smaller peptides, angiotensin (1–7) and angiotensin (1–9), respectively which plays major roles in anti-inflammatory and anti-oxidant protection of the lungs against ARDS. The important fact here to be stressed with respect to patients with diabetes is that ACE2 expression is reduced in patients with diabetes possibly due to glycosylation; this might explain the increased predisposition to severe lung injury and ARDS with COVID-19 and the high risk associated with COVID-19 in uncontrolled diabetes condition.

      Even over expression of ACE2 would be counterproductive in COVID-19. SARS-CoV-2 utilizes ACE2 as a receptor for entry into the host pneumocytes. Here is 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. But as it was not supported by any clinical evidence this point can be ignored and all the International medical organizations recommends the continuing use of ACE2 inhibitors by patients who are taking as part of regular medication.

      Whatever be the underlying etiology, people with uncontrolled diabetes are definitely at an increased risk of severe and fatal COVID19 disease. Hence it is advisable that individuals having underlying diabetes take extra precautions not to contract the virus. Social distancing, strict hand and respiratory hygiene are the need of the hour. People with diabetes should ensure good glucose control as improvement in glycemia does boost host immune response.

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