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Review
. 2024 Aug 2;16(8):1243.
doi: 10.3390/v16081243.

Potential Effects of Hyperglycemia on SARS-CoV-2 Entry Mechanisms in Pancreatic Beta Cells

Tara M Michaels  1 , M Faadiel Essop  2 , Danzil E Joseph  1
Affiliations
Review

Potential Effects of Hyperglycemia on SARS-CoV-2 Entry Mechanisms in Pancreatic Beta Cells

Tara M Michaels et al. Viruses. .

Abstract

The COVID-19 pandemic has revealed a bidirectional relationship between SARS-CoV-2 infection and diabetes mellitus. Existing evidence strongly suggests hyperglycemia as an independent risk factor for severe COVID-19, resulting in increased morbidity and mortality. Conversely, recent studies have reported new-onset diabetes following SARS-CoV-2 infection, hinting at a potential direct viral attack on pancreatic beta cells. In this review, we explore how hyperglycemia, a hallmark of diabetes, might influence SARS-CoV-2 entry and accessory proteins in pancreatic β-cells. We examine how the virus may enter and manipulate such cells, focusing on the role of the spike protein and its interaction with host receptors. Additionally, we analyze potential effects on endosomal processing and accessory proteins involved in viral infection. Our analysis suggests a complex interplay between hyperglycemia and SARS-CoV-2 in pancreatic β-cells. Understanding these mechanisms may help unlock urgent therapeutic strategies to mitigate the detrimental effects of COVID-19 in diabetic patients and unveil if the virus itself can trigger diabetes onset.

Keywords: COVID-19; SARS-CoV-2; endosomal entry; hyperglycemia; membrane fusion; new-onset diabetes; pancreatic β-cells.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
The general structure of a CoV. The S-protein of an HCoV, containing the RBD, mediates membrane fusion by binding to various cellular receptors. Adapted from “Coronavirus Structure and Protein Visualization”, by Biorender.com (2024). Retrieved from https://app.biorender.com/biorender-templates (accessed on 24 May 2024).
Figure 2
Figure 2
The expanded entry pathways of SARS-CoV-2. The S-protein of SARS-CoV-2 binds to its primary receptor, ACE2, or potentially to Basigin (step 1), which induces conformational changes in the S1 subunit and exposes the S2 site for cleavage. The S-protein can bind to NRP1 and DPP4, enabling membrane fusion. Depending on the entry pathway taken by SARS-CoV-2, the S2 site is cleaved by either TMPRSS2 or ADAM 10/17 (membrane fusion entry, part A) or Cathepsins B/L (receptor-mediated endosomal entry, part B). In the presence of proteases on the plasma membrane, S-protein cleavage occurs at the cell surface (part A, step 2). With endosomal entry, the S-protein-receptor complex is internalized via clathrin-mediated endocytosis (part B, step 2) into endolysosomes, where the S2 site is cleaved by Cathepsins B/L (part B, step 4). Before this, the cleavage via cathepsins requires an acidic environment for its activity; therefore, endosomal acidification occurs (part B, step 3). Fusion between the virus and host cellular membranes forms a fusion pore where viral RNA is released into the host cytoplasm for viral uncoating and replication. Adapted from Jackson et al. [79]. Created in BioRender.com.
See this image and copyright information in PMC

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