Elevated Blood Glucose Levels as a Primary Risk Factor for the Severity of COVID-19
Authors: Logette Emmanuelle , Lorin Charlotte , Favreau Cyrille , Oshurko Eugenia , Coggan Jay S. , Casalegno Francesco , Sy Mohameth François , Monney Caitlin , Bertschy Marine , Delattre Emilie , Fonta Pierre-Alexandre , Krepl Jan , Schmidt Stanislav , Keller Daniel , Kerrien Samuel , Scantamburlo Enrico , Kaufmann Anna-Kristin , Markram Henry 
Published: May 2021

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

Patients with severe COVID-19 commonly present with elevated blood glucose levels.

Elevated blood glucose impacts numerous biochemical pathways that can facilitate many steps of the SARS-CoV-2 infection.

Elevated blood glucose increases glucose in the pulmonary airway surface liquid (ASL), which breaks down the primary innate antiviral defenses of the lungs and facilitates viral infection and replication.

Elevated blood glucose causes dysregulations of the immune response that facilitates the cytokine storm and acute respiratory distress syndrome (ARDS).

Elevated glucose levels act synergistically with SARS-CoV-2-dependent inactivation of angiotensin-converting enzyme 2 (ACE2) to escalate the disease to multi-organ failure and thrombotic events.