key: cord-0963041-2o8akp4i authors: Piarulli, Francesco; Lapolla, Annunziata title: COVID 19 and low-glucose levels : is there a link ? date: 2020-06-25 journal: Diabetes Res Clin Pract DOI: 10.1016/j.diabres.2020.108283 sha: c04b0da5eca92a1044e8f9b9557eef578894d702 doc_id: 963041 cord_uid: 2o8akp4i nan The COVID-19 pandemic is claiming many victims among those infected worldwide. Patients' prognosis depends primarily, but not exclusively on their viral load. The response of the host's immune system is partly responsible, either by default (in immunocompromised patients) or, paradoxically, by excess -when a destructive "cytokine storm" occurs in the lung as a result of an exaggerated mobilization of the host's immune cells. This cytokine storm seems to be the most serious prognostic factor because it aggravates the inflammatory, thrombophilic state, leading to a disseminated intravascular coagulation (DIC) -a situation difficult to control and potentially fatal. There is no clear scientific evidence as yet to indicate what triggers a cytokine storm. A highly contagious virus like influenza A, which causes annual flu epidemics all over the world, has been known to trigger such cytokine storms too, leading to inflammation, the need for hospitalization, and even death. The mechanisms behind such cytokine storms, that make some individuals suffer more from the flu than others, remain unclear, however. A study on influenza A virus infection in mice showed that glucose metabolism was a driving force behind the onset of the often fatal inflammatory response known as a cytokine storm. Mice treated with glucosamine produced significantly higher levels of inflammatory cytokines and chemokines than mice not given glucosamine. When researchers analyzed blood glucose levels in patients diagnosed with influenza A and healthy controls, they found that the hexosamine biosynthetic pathway, by means of which a 2 small portion of glucose is metabolized, plays an essential part in cytokine storms triggered by the influenza virus. These findings may partly explain why diabetics are at greater risk of serious complications and death from influenza and other infections. Preliminary data indicate that this appears to be the case for COVID-19 as well (1) It has been reported that hypoglycemic conditions induce an upregulation of the GLUT 3 glucose transporter in the plasma membrane of the monocyte-macrophage [5] , and that LPS amplifies GLUT 3 overexpression [6]. GLUT 3 upregulation is a self-regulating mechanism to ensure an adequate glucose supply to the cells, and thus protect monocytes against the harmful effects of low glucose levels, thus amplifying inflammatory cell activation in the presence of LPS. Wright et al. showed that acute hypoglycemia induced by hyperinsulinemic clamping led to an increase in CD40 expression (an inflammatory activation index) on monocytes in type 1 diabetic patients [7] . In vivo hypoglycemia may induce an increase in counter-regulatory hormonal adrenergic activity as well, resulting in further inflammatory stress [8] . 3 Hypoglycemia therefore, besides representing a risk factor of cardiovascular and total mortality (for all causes) in diabetic patients, could represent a trigger mechanism for the "cytokine storm" during COVID-19 disease [9] . In the light of these experimental data, we recommend pursuing optimal glycemic control, avoiding both hyper and hypoglycemia, to prevent or mitigateany cytokine storms, and thus improve the otherwise dismal prognosis for both diabetic and not diabetic patients admitted to semi-intensive or ICU with COVID-19. O-GlcNAc transferase promotes influenza A virus-induced cytokine storm by targeting interferon regulatory factor-5 Hyperglycemia-related mortality in critically ill patients varies with admission diagnosis Hypoglycemia and outcome in critically ill patients Low Glucose Concentrations Induce a Similar Inflammatory Response in Monocytes from Type 2 Diabetic Patients and Healthy Subjects Sustained hypoglycemia affects glucose transporter expression of human blood leukocytes The facilitative glucose transporter GLUT3: 20 years of distinction Effects of acute insulin-induced hypoglycemia on indices of inflammation: putative mechanism for aggravating vascular disease in diabetes Vascular disease and diabetes: is hypoglycaemia an aggravating factor? Action to Control Cardiovascular Risk in Diabetes Study Group Funding: The authors received no funding from an external source.