key: cord-0799158-b85mirzl authors: Papachristou, Stella; Stamatiou, Iliana; Stoian, Anca P.; Papanas, Nikolaos title: New-Onset Diabetes in COVID-19: Time to Frame Its Fearful Symmetry date: 2020-12-26 journal: Diabetes Ther DOI: 10.1007/s13300-020-00988-7 sha: a4e5091f4f9c3764a0a8b0f67507e631b68558d0 doc_id: 799158 cord_uid: b85mirzl There is increasing evidence that coronavirus disease 2019 (COVID-19) may lead to new-onset diabetes mellitus (DM). This may occur even in patients without predisposing factors for impaired glucose metabolism. Both impaired pancreatic insulin secretion and insulin resistance have been implicated as underlying mechanisms. Importantly, new-onset hyperglycaemia is associated with worse prognosis in patients with COVID-19. Indeed, its prognosis may be even more sinister than in patients with pre-existing DM. More research data and knowledge are currently being collected to improve our insights into this constellation and to guide therapies in clinical reality. 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 (TNFa) 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. Funding. No funding or sponsorship was received for this study or publication of this article. Authorship. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. Disclosures. Nikolaos Papanas has been an advisory board member of AstraZeneca, Boehringer Ingelheim, MSD, Novo Nordisk, Pfizer, Takeda and TrigoCare International; has participated in sponsored studies by AstraZeneca, Eli Lilly, GSK, MSD, Novo Nordisk, Novartis and Sanofi-Aventis; has received honoraria as a speaker for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Elpen, MSD, Mylan, Novo Nordisk, Pfizer, Sanofi-Aventis and Vianex; and attended conferences sponsored by TrigoCare International, Eli Lilly, Galenica, Novo Nordisk, Pfizer and Sanofi-Aventis. Anca Pantea Stoian has given talks, attended conferences, and participated in advisory boards, and clinical trials sponsored by various pharmaceutical companies and she is currently Vice President of the National Diabetes Commission, Ministry of Health, Romania. Stella Papachristou and Iliana Stamatiou have nothing to disclose. Compliance with Ethics Guidelines. This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors. Data Availability. Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. Commons Attribution-Non-Commercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creativecommons.org/licenses/by-nc/4.0/. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan Plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with SARS Risk factors for primary Middle East respiratory syndrome coronavirus illness in humans, Saudi Arabia Hyperglycemia without diabetes and new-onset diabetes are both associated with poorer outcomes in COVID-19 Diabetic ketoacidosis precipitated by COVID-19: a report of two cases and review of literature Covid-19 and diabetes mellitus: unveiling the interaction of two pandemics SARS-CoV-2 inflammatory syndrome. 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