key: cord-0990192-m84hom7h
authors: Maddaloni, Ernesto; Buzzetti, Raffaella
title: Covid‐19 and diabetes mellitus: unveiling the interaction of two pandemics
date: 2020-04-13
journal: Diabetes Metab Res Rev
DOI: 10.1002/dmrr.3321
sha: 4f39e3c2693381abb9ef1248a205025b59b11a14
doc_id: 990192
cord_uid: m84hom7h

A novel RNA betacoronavirus causing coronavirus disease 2019 (Covid‐19) has now been declared pandemic disease by WHO. Guo et al published the first report of biochemical features in patients with diabetes and the further risk that this disease can determine to the progression of Covid‐19. Among different cytokines found significantly higher in patients with diabetes compared to those without, Interleukin‐6 (IL‐6), which is already increased in conditions of chronic inflammation, may play a more deleterious role in Covid‐19 infection. Targeting the overexpression of Il‐6 effects with a monoclonal antibody against IL‐6 receptor or using Janus Kinase inhibitors may be particularly helpful for treatment of Covid‐19 pneumonia in diabetes.

ease 2019 . The disease has rapidly spread in several countries (114 with more than 120 000 confirmed cases when this article was written) and by March 11, 2020 , the Director-General of the World Health Organization, Tedros Adhanom Ghebreyesus, has declared Covid-19 a pandemic disease. The case fatality ratio of Covid-19 has been initially described in China to be about 1%-2%, 1 but higher percentages are being estimated in other countries, with Italy nowadays experiencing the highest numbers. 2 Differences among countries are unlikely due to viral changes, but more likely due to other reasons including different healthcare systems and actions taken to contain the outbreak (such as early or late lockdown), but also to differences in the prevalence and features of conditions that could interact with Covid-19 to worsen health outcomes, such as mean population age and comorbidities. Therefore, knowledge of the 6 Interleukin-6 (IL-6), among the different markers of inflammation (fibrinogen, C-reactive protein, D-dimer) that were found to be more elevated in Covid-19 cases with diabetes than in those without, deserves particular attention. IL-6 is a pleiotropic cytokine that mainly participates to acute phase inflammatory responses, but which is also significantly increased in conditions of chronic inflammation such as metabolic disorders and cardiovascular disease. The deleterious effects of overexpressed IL-6 signalling are tackled by tocilizumab, a monoclonal antibody against the IL-6 receptor approved for the treatment of some autoimmune disorders, such as giant cell arteritis or severe rheumatoid arthritis, and also successfully tested for other autoimmune disorders such as Graves orbitopathy. 7 Interestingly, preliminary observations suggest tocilizumab may significantly help the treatment of Covid-19 pneumonia, it is actually being used off-label in some Italian centres in patients with Covid-19 and it is currently being tested in an ad hoc randomized controlled trial. 8 If these observations will be confirmed, based on the data presented by Guo et al, 3 this drug may be particularly helpful in people with diabetes. As well, other drugs tackling the same pathway, such as drugs against IL6 itself (siltuximab) or Janus Kinase inhibitors (such as baricitinib, tofacitinib, upadacitinib), might be novel approaches to fight Covid-19, 9 especially in people with diabetes. However, fast and efficient trials are urged to give evidence based answers to all these unanswered questions. Noteworthy, the interaction between Covid-19 and diabetes could also be bi-directional, with SARS-CoV-2 potentially worsening preexisting diabetes or even predisposing to diabetes in nondiabetic subjects. Angiotensin Converting Enzyme 2 (ACE2) is the access door for SARS-CoV-2 to enter human cells 10 and ACE2 is widely expressed in the liver and in the endocrine pancreas, with a potential role in the development of insulin resistance and impaired insulin secretion. 11 Therefore, both hepatocytes and pancreatic betacells could be infected by SARS-CoV-2, worsening hyperglycaemia at least during the acute infection. In the long term, however, the infection of pancreatic beta cells could also trigger beta-cell autoimmunity in predisposed subjects. Should we also expect an increase in the incidence of autoimmune diabetes when Covid-19 pandemic will be solved? While the immediate consequences of Covid-19 pandemic represent the urgent problem we are called to solve as soon as possible, the long-term consequences of this infection should also be monitored in the immediate future.

In definitive, Covid-19 and diabetes represent two devastating pandemics with very different characteristics in terms of healthcare burden mainly because of different presentation (acute vs chronic) and transmission (communicable vs noncommunicable), but which may be much closer than previously thought.

Clinical characteristics of coronavirus disease 2019 in China

COVID-19 and Italy: what next? Lancet

Diabetes is a risk factor for the progression and prognosis of COVID-19

Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area

Diabetes and the severity of pandemic influenza a (H1N1) infection. Diabetes Care

COVID-19: consider cytokine storm syndromes and immunosuppression

Efficacy of tocilizumab in patients with moderate-to-severe corticosteroidresistant graves orbitopathy: a randomized clinical trial

Chinese Clinical Trial Registry, A multicenter, randomized controlled trial for the efficacy and safety of tocilizumab in the treatment of new coronavirus pneumonia (COVID-19)

Baricitinib as potential treatment for 2019-nCoV acute respiratory disease

Receptor recognition by novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS

The sweeter side of ACE2: physiological evidence for a role in diabetes

The authors declare no conflicts of interests related to this manuscript.

https://orcid.org/0000-0003-3844-9463Raffaella Buzzetti https://orcid.org/0000-0003-1490-6041