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

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 (M^pro) 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 M^pro (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 M^pro 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 M^pro, C2C12 cells were viable. The baseline and insulin-stimulated glucose uptake were impaired in the C2C12 cell line. M^pro 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 M^pro. Intracellular and extracellular IL-6 levels were also affected by M^pro. An increase in MDA levels, a marker for lipid peroxidation, was observed.

The observations suggest that the SARS-CoV-2 M^pro 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.