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

ABSTRACT Background 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). Methods 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. Results 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. Conclusions 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.