Elevated Blood Glucose Levels as a Primary Risk Factor for the Severity of COVID-19

SARS-CoV-2 started spreading towards the end of 2019 causing COVID-19, a disease that reached pandemic proportions among the human population within months. The reasons for the spectrum of differences in the severity of the disease across the population, and in particular why the disease affects more severely the aging population and those with specific preconditions are unclear. We developed machine learning models to mine 240,000 scientific papers openly accessible in the CORD-19 database, and constructed knowledge graphs to synthesize the extracted information and navigate the collective knowledge in an attempt to search for a potential common underlying reason for disease severity. The literature repeatedly pointed to elevated blood glucose as a key facilitator in the progression of COVID-19. Indeed, when we retraced the steps of the SARS-CoV-2 infection we found evidence linking elevated glucose to each step of the life-cycle of the virus, progression of the disease, and presentation of symptoms. Specifically, elevations of glucose provide ideal conditions for the virus to evade and weaken the first level of the immune defense system in the lungs, gain access to deep alveolar cells, bind to the ACE2 receptor and enter the pulmonary cells, accelerate replication of the virus within cells increasing cell death and inducing an pulmonary inflammatory response, which overwhelms an already weakened innate immune system to trigger an avalanche of systemic infections, inflammation and cell damage, a cytokine storm and thrombotic events. We tested the feasibility of the hypothesis by analyzing data across papers, reconstructing atomistically the virus at the surface of the pulmonary airways, and performing quantitative computational modeling of the effects of glucose levels on the infection process. We conclude that elevation in glucose levels can facilitate the progression of the disease through multiple mechanisms and can explain much of the variance in disease severity seen across the population. The study proposes diagnostic recommendations, new areas of research and potential treatments, and cautions on treatment strategies and critical care conditions that induce elevations in blood glucose levels. Highlights ![Figure][1] ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by funding to the Blue Brain Project, a research center of the Ecole polytechnique federale de Lausanne (EPFL), from the Swiss government ETH Board of the Swiss Federal Institutes of Technology. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This work does not involve clinical trial nor patient data, and thus needed no IRB/oversight body. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The links to access the simulation codes used to generate the datasets presented in this study are provided in the related section of methods, and can be run using the instructions in the "README.md" files. All simulation codes will be publicly open sourced upon publication. * ACE2 : angiotensin-converting enzyme 2 AGEs : advanced glycation end products Ang II : angiotensin II ARDS : acute respiratory distress syndrome ASL : airway surface liquid BMI : body mass index CFR : case fatality rate CRD : carbohydrate recognition domain FPG : fasting plasma glucose GLUT : glucose transporter ICU : intensive care unit IFG : impaired fasting glucose IGT : impaired glucose tolerance KD : ketogenic diet OGTT : oral glucose tolerance test PPG : postprandial glucose ROS : reactive oxygen species [1]: pending:yes