Metformin resistance
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Mechanisms of Metformin Resistance in Disease Treatment
Metformin is widely used to improve insulin sensitivity in conditions like type 2 diabetes, prediabetes, obesity, and polycystic ovary syndrome. Its main action is to increase glucose uptake in tissues by promoting the expression and movement of the GLUT4 transporter to the cell surface, largely through the activation of the AMPK pathway and other insulin signaling mediators. However, the exact mechanisms and targets of metformin are still not fully understood, and resistance to metformin can develop in some patients, reducing its effectiveness 19.
Cellular and Molecular Pathways in Metformin Resistance
In cancer, especially breast cancer, long-term metformin treatment can lead to acquired resistance. This resistance is linked to changes in key signaling pathways. For example, in breast cancer cells, resistance is associated with the constant activation of the Akt/Snail1 pathway and suppression of the estrogen receptor, even though AMPK activity remains unchanged. This resistance can also lead to cross-resistance with other drugs like tamoxifen, making treatment more challenging . Similarly, in skin squamous cell carcinoma, resistance to therapies like photodynamic therapy is driven by metabolic reprogramming toward increased glycolysis. Metformin can help reverse this resistance by shifting metabolism back toward oxidative phosphorylation and inhibiting the AKT/mTOR pathway, suggesting its potential as an adjuvant therapy .
Role of MicroRNAs and Genetic Regulation
Metformin’s effects on insulin resistance and related diseases are also influenced by changes in microRNA (miR) expression. These small RNA molecules regulate gene expression and protein production. Metformin can alter miR levels through both AMPK-dependent and independent mechanisms, which may contribute to its therapeutic effects or, conversely, to resistance if these regulatory pathways are disrupted .
Environmental and Microbial Aspects of Metformin Resistance
Metformin’s impact extends beyond human cells. In the environment, metformin exposure can promote the development of antibiotic resistance in bacteria like Escherichia coli. This occurs through increased mutation rates and the upregulation of genes involved in drug efflux, making bacteria resistant to multiple antibiotics . In patients with type 2 diabetes, metformin can also increase the abundance of multidrug resistance genes in the gut microbiome, particularly in E. coli, raising concerns about the potential for increased antibiotic resistance in these individuals .
Overcoming Metformin Resistance and Enhancing Efficacy
Despite the challenges of resistance, metformin can sometimes restore the effectiveness of other treatments. For example, it has been shown to enhance the activity of tetracycline antibiotics against multidrug-resistant bacteria by increasing the accumulation of antibiotics inside bacterial cells and boosting immune responses . In metabolic diseases, metformin improves insulin sensitivity by activating AMPK, increasing GLUT4 activity, and regulating the purine nucleotide cycle, which helps maintain energy balance in cells 1910. In treatment-resistant bipolar depression, reversing insulin resistance with metformin has led to significant improvements in mood and functioning, suggesting a broader therapeutic potential .
Conclusion
Metformin resistance is a complex phenomenon involving changes in cellular signaling, gene regulation, and even environmental and microbial factors. While resistance can limit the effectiveness of metformin in treating metabolic diseases and cancer, understanding these mechanisms opens new avenues for overcoming resistance and improving patient outcomes. Continued research into the molecular and environmental factors influencing metformin resistance will be crucial for optimizing its use in clinical practice 12345678+2 MORE.
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