- Title
- Examining the effects of small molecule tyrosine kinase inhibitors on glucose metabolism in skeletal muscle and liver cell lines in vitro
- Creator
- Mugiya, Takudzwa Cleophas
- Subject
- Diabetes
- Subject
- Blood glucose
- Subject
- Cancer
- Subject
- Insulin
- Subject
- Protein kinase B
- Subject
- Glucose transporters
- Date Issued
- 2025-04-02
- Date
- 2025-04-02
- Type
- Academic theses
- Type
- Master's theses
- Type
- text
- Identifier
- http://hdl.handle.net/10962/478829
- Identifier
- vital:78227
- Description
- Diabetes mellitus is rising due to aging, sedentary lifestyles, obesity, and unhealthy diets, posing a global health threat. Due to increase in prevalence together with shortfalls associated with current treatment options, there is still a necessity for a continuous search of new pharmacotherapies. Small molecule tyrosine kinase inhibitors are drugs, used in cancer chemotherapy and have been shown to affect glycaemic control and metabolism variably. Studies have shown that tyrosine kinase inhibitors can alter glycaemic control and glucose metabolism, with some demonstrating hypoglycaemic activities whilst others showing hyperglycaemic properties. The mechanism by which tyrosine kinase inhibitors cause glycaemic dysregulation is not well understood, therefore, the clinical significance of these chemotherapeutic agents on glucose handling is also poorly documented. Aims and objectives: This study aims to elucidate how small molecule tyrosine kinase inhibitors affect glucose metabolism in C2C12 and HepG2 cells in vitro, including their impact on glucose uptake, AKT, GLUT-4, and IL-6 expression, GLUT-4 translocation, and alpha-amylase and alpha-glucosidase activity. Methods: In this study, C2C12 and HepG2 cells were seeded in well plates and the initial media glucose concentration was recorded. Cells were then treated with small molecule tyrosine kinase inhibitors; imatinib, dasatinib, axitinib, and erlotinib for 24 hours. Thereafter, the effect of the test drugs was assessed on cell viability, glucose uptake, expression of AKT GLUT-4 and IL-6, and translocation of GLUT-4. Furthermore, effects of the drugs were assessed on the activities of alpha amylase and glucosidase using calometric assays. Results and Discussion: Cells treated with small molecule tyrosine kinase inhibitors were viable after 24 hours. 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. Small molecule tyrosine kinase inhibitors demonstrated an increase in GLUT4 translocation in the absence of insulin. GLUT4 expression was comparable in cells treated with small molecule tyrosine kinase inhibitors and the control. Small molecule tyrosine kinase inhibitors showed an increase in AKT expression. C2C12 cells treated with small molecule tyrosine kinase inhibitors were observed to have elevated IL-6 expression compared to the control. The HepG2 cells treated with erlotinib and imatinib demonstrated elevated glucose uptake while cells treated with axitinib and dasatinib were observed to have a lower glucose uptake. Treatment with dasatinib led to a decrease in Akt expression as concentration increased. Small molecule tyrosine kinase inhibitors demonstrated inhibition of alpha-amylase, while only dasatinib and axitinib showed inhibition of alpha-glucosidase. Conclusion: The results show that small molecule tyrosine kinase inhibitors impact glucose metabolism in C2C12 and HepG2 cells via their effect on GLUT-4 translocation and expression and AKT expression. Dasatinib showed promising potential with regard to antidiabetic capabilities. Further research is needed to better understand these mechanisms' effects on metabolic homeostasis and inform future therapeutic strategies.
- Description
- Thesis (MSc (Pharm)) -- Faculty of Pharmacy, Pharmacy, 2025
- Format
- computer
- Format
- online resource
- Format
- application/pdf
- Format
- 1 online resource (110 pages)
- Format
- Publisher
- Rhodes University
- Publisher
- Faculty of Pharmacy, Pharmacy
- Language
- English
- Rights
- Mugiya, Takudzwa Cleophas
- Rights
- Use of this resource is governed by the terms and conditions of the Creative Commons "Attribution-NonCommercial-ShareAlike" License (http://creativecommons.org/licenses/by-nc-sa/2.0/)
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | SOURCE1 | MUGIYA-MSC-TR25-25.pdf | 2 MB | Adobe Acrobat PDF | View Details Download |