The Dual Role of Metformin: Repurposing an Antidiabetic Drug for Cancer Therapy

Maintaining glucose homeostasis is vital for normal physiological function, and any disturbance in this balance is associated with the development of degenerative and chronic diseases, like Type 2 Diabetes (T2D) and certain types of cancer, where altered glucose metabolism plays a central role. Epidemiological evidence indicates a positive association between diabetes and an increased risk of developing certain types of cancer. Such a correlation may be driven by shared risk factors, namely obesity, inflammation, and insulin resistance. The observed association between diabetes and an increased risk of certain cancers, along with the rising incidence of both diseases, has in recent years raised interest in treatments that may target both conditions. Among them, the biguanide metformin, the first-line drug prescribed for T2D, has attracted significant attention as a repurposed drug due to its potential role in cancer treatment. Metformin is a glucose-lowering drug that reduces hepatic glucose production and improves insulin sensitivity, promoting glucose uptake by the skeletal muscle, contributing to better glycemic control in individuals with T2D and prediabetic syndromes. However, beyond its metabolic effects, metformin also influences key signaling pathways involved in cell growth and survival, such as the AMP-activated protein kinase (AMPK)/mTOR axis, raising interest in its potential application as an anticancer agent. Furthermore, metformin inhibits mitochondrial complex I, disrupting cellular energy production, which is essential for cancer proliferation. This review aims to explore and clarify the multifunctional role of metformin in both T2D and cancer, focusing on the metabolic alterations observed in these diseases. It highlights how glucose metabolism dysregulation contributes to disease progression in both contexts and explores the molecular targets of metformin in each condition and its potential for dual therapeutic benefit. Finally, selected clinical trials concerning metformin use in cancer therapy, alone or in combination, will be presented, highlighting its potential to enhance treatment response, reduce resistance, and improve overall patient outcomes.