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Updated: Sep 24, 2025

Extracellular Glucose Depletion as an Indirect Measure of Glucose Uptake in Cells and Tissues Ex Vivo
Published on: April 6, 2022
A glucose-like metabolite deficient in diabetes inhibits cellular entry of SARS-CoV-2
Liangqin Tong1,2,3, Xiaoping Xiao1,2,3, Min Li4
1Tsinghua-Peking Joint Center for Life Sciences, School of Medicine, Tsinghua University, Beijing, China.
Abstract:
The severity and mortality of COVID-19 are associated with pre-existing medical comorbidities such as diabetes mellitus. However, the underlying causes for increased susceptibility to viral infection in patients with diabetes is not fully understood. Here we identify several small-molecule metabolites from human blood with effective antiviral activity against SARS-CoV-2, one of which, 1,5-anhydro-D-glucitol (1,5-AG), is associated with diabetes mellitus. The serum 1,5-AG level is significantly lower in patients with diabetes. In vitro, the level of SARS-CoV-2 replication is higher in the presence of serum from patients with diabetes than from healthy individuals and this is counteracted by supplementation of 1,5-AG to the serum from patients. Diabetic (db/db) mice undergo SARS-CoV-2 infection accompanied by much higher viral loads and more severe respiratory tissue damage when compared to wild-type mice. Sustained supplementation of 1,5-AG in diabetic mice reduces SARS-CoV-2 loads and disease severity to similar levels in nondiabetic mice. Mechanistically, 1,5-AG directly binds the S2 subunit of the SARS-CoV-2 spike protein, thereby interrupting spike-mediated virus-host membrane fusion. Our results reveal a mechanism that contributes to COVID-19 pathogenesis in the diabetic population and suggest that 1,5-AG supplementation may be beneficial to diabetic patients against severe COVID-19.
Insights
Low levels of 1,5-anhydro-D-glucitol (1,5-AG) in diabetes increase SARS-CoV-2 replication. Supplementing 1,5-AG in diabetic individuals may reduce COVID-19 severity by blocking viral entry.
Area of Science:
- Virology
- Metabolomics
- Immunology
Background:
- COVID-19 severity and mortality are linked to comorbidities like diabetes mellitus.
- The mechanisms behind increased viral susceptibility in diabetic patients remain unclear.
Purpose of the Study:
- To identify small-molecule metabolites with antiviral activity against SARS-CoV-2.
- To investigate the role of 1,5-anhydro-D-glucitol (1,5-AG) in COVID-19 pathogenesis in diabetic individuals.
Main Methods:
- Screening of human blood metabolites for antiviral properties against SARS-CoV-2.
- In vitro experiments using serum from diabetic and healthy individuals, with and without 1,5-AG supplementation.
- In vivo studies using diabetic (db/db) and wild-type mice infected with SARS-CoV-2, with and without 1,5-AG supplementation.
- Mechanistic studies involving direct binding assays of 1,5-AG to the SARS-CoV-2 spike protein.
Main Results:
- 1,5-anhydro-D-glucitol (1,5-AG) demonstrated effective antiviral activity against SARS-CoV-2.
- Serum 1,5-AG levels were significantly lower in diabetic patients.
- SARS-CoV-2 replication was higher in serum from diabetic patients, an effect reversed by 1,5-AG supplementation.
- Diabetic mice exhibited higher viral loads and lung damage; 1,5-AG supplementation mitigated these effects.
- 1,5-AG was found to directly bind the S2 subunit of the SARS-CoV-2 spike protein, inhibiting membrane fusion.
Conclusions:
- Reduced 1,5-AG levels in diabetes contribute to increased SARS-CoV-2 susceptibility and severity.
- 1,5-AG inhibits SARS-CoV-2 by blocking virus-host membrane fusion.
- 1,5-AG supplementation presents a potential therapeutic strategy for managing severe COVID-19 in diabetic patients.
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