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.

Nature Metabolism
|May 9, 2022
PubMed

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.

Related Concept Videos

Overview of Carbohydrate Metabolism01:19

Overview of Carbohydrate Metabolism

Carbohydrate metabolism is a fundamental biochemical process that ensures a constant supply of energy to living cells. The most important carbohydrate is glucose, which can be broken down via glycolysis to enter into the Krebs cycle and eventually lead to the production of ATP through oxidative phosphorylation.
Glucose transport into cells is facilitated by a family of transport proteins called GLUT (Glucose Transporters). GLUT4 is the primary glucose transporter for insulin-stimulated glucose...
2.0K
Glucose Transporters01:27

Glucose Transporters

Glucose transporters facilitate the transport of glucose across the cell membrane. In addition to glucose, some glucose transporters can also aid the movement of other hexoses such as fructose, mannose, and galactose.
Facilitated diffusion-glucose transporters (GLUTs) are encoded by the solute-linked carrier (SLC) family 2, subfamily A gene family, or SLC2A. The 14 GLUT protein members are distributed into three classes:
24.4K
Glucose Absorption Into the Small Intestine01:26

Glucose Absorption Into the Small Intestine

Complex carbohydrates consumed cannot be absorbed into the small intestine in their original form. First, they must be hydrolyzed to a monosaccharide form such as glucose or galactose. These monosaccharides are then transported across the intestinal membrane and into the blood via transcellular transport. The intestinal epithelial cells allow the movement of these monosaccharides with a defined 'entry' through membrane transporter proteins present on their apical membrane and...
32.6K
Glucose Homeostasis: Pancreatic Islets and Insulin Secretion01:27

Glucose Homeostasis: Pancreatic Islets and Insulin Secretion

The pancreatic islets comprising only 1%-2% of the volume are highly vascularized and innervated mini-organs. They contain five endocrine cell types, including β cells that secrete insulin, which is synthesized as a single polypeptide chain, preproinsulin, processed to proinsulin, and finally to insulin and C-peptide. This process is complex and regulated, involving the Golgi complex, the endoplasmic reticulum, and the secretory granules of the β cell.
Insulin and C-peptide are...
1.5K
Hormones Regulating Blood Glucose01:16

Hormones Regulating Blood Glucose

Insulin is released by beta cells of the pancreas when blood glucose levels are high. It facilitates glucose absorption and utilization in insulin-dependent cells with insulin receptors on their plasma membranes. Insulin promotes glucose uptake by increasing the number of glucose transport proteins in the cell membrane, allowing glucose to enter the cell. As a result, glucose utilization and ATP production are enhanced.
In addition to accelerating glucose uptake and utilization, insulin has...
4.2K
Glucagon-like Receptor Agonists01:24

Glucagon-like Receptor Agonists

Incretins include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which stimulate insulin secretion post-meals. In type 2 diabetes, GIP's efficacy is reduced, making GLP-1 a viable drug target. GIP originates from preproGIP.
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by...
447