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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibits increased mortality and morbidity in elderly individuals, especially in those with comorbidities, such as diabetes mellitus (DM) [1]. Previously, DM was identified as an independent factor predisposing to poor outcomes in patients infected by other coronaviruses, such as severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) [2] and Middle East respiratory syndrome coronavirus (MERS-CoV) [3]. Moreover, during the SARS-CoV-1 outbreak, acute DM was commonly observed in individuals with no history of DM or glucocorticoid use, and was an independent predictor of mortality [2].

Interestingly, DM may also be associated with severe coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2. Of note, “new-onset” hyperglycaemia and acute metabolic decompensation of pre-existing DM are now emerging as a complication of COVID-19, especially among hospitalised patients. Impressively, this “new-onset” hyperglycaemia is not associated with any other risk factors, notably obesity, prediabetes, DM, or corticosteroid administration. These findings point to a bidirectional relationship between DM and COVID-19 [4].

First, some patient cases have illustrated that COVID-19 may accelerate diabetic ketoacidosis (DKA) in subjects with new-onset or pre-existing DM [5]. Early recognition of DKA symptoms is required to improve the prognosis of COVID-19-related DKA [5].

Moreover, it is known that SARS-CoV-2 may enter the pancreatic beta cells via the expression of angiotensin-converting enzyme 2 (ACE2) receptors [6]. It would be possible that the virus impairs pancreatic insulin secretion, thereby either aggravating DM or triggering new-onset DM [6]. A further underlying mechanism appears to be insulin resistance due to the high levels of interleukin-6 (IL-6) and tumour necrosis factor alpha (TNFα) in subjects with severe COVID-19 [7, 8].

Vice versa, this new-onset hyperglycaemia is linked to important perturbations. The latter include glycation of ACE2 receptors [9], excess cytokine release [10, 11], and a pro-thrombotic state via increased antithrombin III production [12], ultimately leading to a more sinister prognosis [10]. Indeed, a strong association of plasma glucose at admission with intubation and death has been demonstrated in DM [13]. Similarly, a correlation of plasma glucose on admission with radiographic evidence of acute respiratory distress syndrome (ARDS) irrespective of prior DM or no DM has been documented [14]. Perhaps, the latter is hardly surprising, given the established observation that new-onset hyperglycaemia may result from various clinical conditions, notably HIV and other viral infections [15, 16], organ transplantation [17], stroke [18] and myocardial infarction [19]. Of note, in such conditions new hyperglycaemia portends a very sinister prognosis.

In this context, there is accumulating evidence that hyperglycaemia at admission, both in DM subjects and in those with secondary hyperglycaemia, indicates a poor prognosis [20,21,22]. Importantly, newly diagnosed DM is linked to increased mortality, as compared with known DM and normal glucose levels in patients with COVID-19 [21]. In the light of these findings, several leading diabetologists have established a global registry of patients with COVID-19-related new DM to further investigate the intricacies and implications of these associations [23].

In conclusion, not only is DM associated with worse prognosis in COVID-19 but, vice versa, the latter may lead to new-onset DM, as well [5, 6]. Some mechanisms mediating this new hyperglycaemia have been implicated [6,7,8]. From a practical viewpoint, new hyperglycaemia is linked to unfavourable prognosis [20,21,22,23], perhaps even more than in pre-existing DM [21]. Hence, we need more knowledge [23], but we also need to deal with the emerging clinical implications, mastering the “fearful symmetry” [24] of these new conditions.