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

Praise Tatenda Nhau1, Mlindeli Gamede2, Andile Khathi3

  • 1Pharmacology Division, Faculty of Pharmacy, Rhodes University, Makhanda, South Africa.

Immunity, Inflammation and Disease
|February 27, 2026
PubMed
Abstract

Insights

SARS-CoV-2 infection may increase diabetes risk. The study found that the SARS-CoV-2 Main protease (Mpro) impairs glucose uptake and GLUT-4 translocation in skeletal muscle cells, suggesting a potential mechanism for COVID-19-induced diabetes.

Area of Science:

  • Virology
  • Endocrinology
  • Molecular Biology

Background:

  • Emerging evidence links SARS-CoV-2 infection to an increased risk of developing diabetes mellitus.
  • Understanding the precise pathological mechanisms is crucial for managing post-COVID-19 complications.
  • The SARS-CoV-2 Main protease (Mpro) is a key viral enzyme implicated in viral replication and pathogenesis.

Purpose of the Study:

  • To investigate the impact of SARS-CoV-2 Mpro on glucose uptake and GLUT-4 translocation in skeletal muscle cells (C2C12).
  • To analyze the effects of Mpro on AKT, GLUT-4, and IL-6 expression.
  • To assess Mpro's influence on lipid peroxidation markers.

Main Methods:

  • C2C12 myoblasts were treated with varying concentrations of purified SARS-CoV-2 Mpro for 24 hours.
  • Assays were performed to evaluate cell viability, glucose uptake, AKT and GLUT-4 expression, GLUT-4 translocation, IL-6 levels, and lipid peroxidation (MDA levels).
  • Concentrations used ranged from 2.5 to 160 nmol/mL, with higher concentrations (40, 80, 160 nmol/mL) selected for detailed analysis.

Main Results:

  • SARS-CoV-2 Mpro treatment did not affect C2C12 cell viability.
  • Both baseline and insulin-stimulated glucose uptake were significantly impaired by Mpro.
  • Mpro compromised GLUT-4 translocation and expression, while altering IL-6 levels and increasing lipid peroxidation markers (MDA). AKT expression remained largely unchanged.

Conclusions:

  • SARS-CoV-2 Mpro may induce an insulin-resistant state in skeletal muscle cells.
  • Dysregulation of glucose metabolism pathways, including impaired glucose uptake and GLUT-4 function, is a potential consequence of Mpro activity.
  • These findings highlight Mpro as a potential contributor to new-onset diabetes mellitus following COVID-19 infection, warranting further investigation.
Keywords:
GLUT 4MproSARS‐COV‐2diabetes mellitusinsulininsulin resistance

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