# Small-Molecule Tyrosine Kinase Inhibitors Modulate Glucose Handling in C2C12 Cell Line In Vitro: A Mechanistic Study

## TL;DR

This study shows how certain cancer drugs affect glucose metabolism in muscle cells, with some showing potential for diabetes treatment.

## Contribution

The study reveals that SMTKIs modulate glucose handling in C2C12 cells through GLUT4 translocation and AKT expression.

## Key findings

- Imatinib increased glucose uptake in a concentration-dependent manner in C2C12 cells.
- SMTKIs increased GLUT4 translocation in the absence of insulin and elevated IL-6 expression.
- Dasatinib shows potential antidiabetic properties due to its effects on glucose metabolism.

## Abstract

Background: Small-molecule tyrosine kinase inhibitors (SMTKIs), widely used in cancer chemotherapy, have been reported to variably affect glycaemic control and metabolism, with some agents demonstrating hypoglycaemic effects while others show hyperglycaemic properties. This study aims to elucidate how small-molecule tyrosine kinase inhibitors affect glucose metabolism in C2C12 cells in vitro. Specifically, this study investigated their impact on glucose uptake, AKT expression, GLUT4 expression and translocation, and IL-6 expression. Methods: In this study, skeletal muscle (C2C12) preparations were separately treated with small-molecule tyrosine kinase inhibitors; imatinib, dasatinib, axitinib, and erlotinib for 24 h. Thereafter, the effect of the test drugs was assessed on cell viability using the MTT assay, while glucose uptake was determined by measuring residual glucose concentrations in the culture medium with a glucometer. The expression of AKT, GLUT4, and IL-6 and translocation of GLUT4 were evaluated using ELISA. Furthermore, the effect of the drugs was assessed on insulin-stimulated AKT phosphorylation and GLUT4 translocation. Imatinib, dasatinib, axitinib, and erlotinib were selected due to their effect of glucose metabolism, highlighted in the literature. Results and Discussion: C2C12 cells treated with SMTKIs were viable after 24 h. A concentration-dependent increase in glucose uptake in C2C12 cells treated with imatinib was observed as the concentration of imatinib increased. Axitinib, dasatinib, and erlotinib demonstrated glucose uptake levels comparable to the control across all concentrations. SMTKIs demonstrated an increase in GLUT4 translocation in the absence of insulin. GLUT4 expression was unchanged in cells treated with small-molecule tyrosine kinase inhibitors compared to the control. Small-molecule tyrosine kinase inhibitors showed an increase in AKT expression. C2C12 cells treated with SMTKI were observed to have elevated IL-6 expression compared to the control. Conclusions: The results show that SMTKIs, in particular dasatinib, impact glucose metabolism in C2C12 cells via their effect on GLUT4 translocation and expression and AKT expression. Dasatinib shows promising potential with regard to antidiabetic capabilities. Further research is needed to better understand SMKI effects on metabolic homeostasis, which can perhaps inform future therapeutic strategies.