# Main Protease From SARS‐CoV‐2 Dysregulates Glucose Handling in the C2C12 Cell Line In Vitro: A Mechanistic Study

## TL;DR

This study shows that a key protein from SARS-CoV-2 disrupts glucose handling in muscle cells, potentially explaining why some people develop diabetes after infection.

## Contribution

The study reveals a novel mechanism by which SARS-CoV-2 Main protease affects glucose metabolism in skeletal muscle cells.

## Key findings

- SARS-CoV-2 Mpro impairs baseline and insulin-stimulated glucose uptake in C2C12 cells.
- Mpro compromises GLUT4 translocation and expression, suggesting insulin resistance.
- Mpro increases lipid peroxidation and alters IL-6 levels, indicating metabolic stress.

## Abstract

There is evidence demonstrating the risk of developing diabetes mellitus because of SARS‐CoV‐2 infection. Therefore, further research is needed to determine pathological mechanisms at which SARS‐CoV‐2 induces diabetes mellitus. This study therefore aims to understand the effect of SARS‐CoV‐2 Main protease (Mpro) on glucose uptake and GLUT‐4 translocation as well as AKT, GLUT‐4, and IL‐6 expression in skeletal muscle (C2C12).

In this study, C2C12 cell preparations were exposed to different concentrations of Mpro (2.5, 5, 10, 20, 40, 80, and 160 nmol/mL) for 24 h to evaluate cytotoxicity and glucose uptake. For further assays, only the higher concentrations (40, 80, and 160 nmol/mL) were used. The impact of Mpro on cell viability, glucose uptake, AKT, GLUT‐4 and IL‐6 expression, GLUT‐4 translocation as well as lipid peroxidation were analyzed.

Following 24 h of treatment with SARS‐CoV‐2 Mpro, C2C12 cells were viable. The baseline and insulin‐stimulated glucose uptake were impaired in the C2C12 cell line. Mpro also compromised GLUT4 translocation and expression in the C2C12 cell line compared to the control. Baseline and Insulin‐stimulated AKT were not significantly altered in the presence of Mpro. Intracellular and extracellular IL‐6 levels were also affected by Mpro. An increase in MDA levels, a marker for lipid peroxidation, was observed.

The observations suggest that the SARS‐CoV‐2 Mpro may be inducing an insulin‐resistant state and dysregulation of glucose metabolism. Further studies are warranted to fully elucidate the mechanisms underlying the development of new‐onset diabetes mellitus in patients with a history of COVID‐19.