Obesity is a growing global health crisis, exacerbating life-threatening conditions such as type 2 diabetes, cardiovascular diseases, and various cancers. Metabolic shifts in obese individuals often lead to insulin resistance, hyperglycemia, dyslipidemia, and chronic low-grade inflammation, creating a favorable environment for aggressive tumor development. A key characteristic of cancer cells is the reprogramming of energy metabolism, shifting from oxidative phosphorylation to aerobic glycolysis, known as the “Warburg effect.”
Aerobic glycolysis, while faster, is less efficient in ATP production compared to oxidative phosphorylation. To meet their energy demands, tumor cells increase glucose uptake through glucose transporters, particularly those of the GLUT/SLC2 family. Among these, GLUT12 was initially identified in the MCF7 breast cancer cell line. It is found in tissues like adipose tissue, skeletal muscle, and the small intestine, where insulin promotes its movement to the plasma membrane. Notably, overexpression of GLUT12 in mice has been shown to enhance overall insulin sensitivity, suggesting its role as a secondary insulin-responsive glucose transporter.
However, in obesity, GLUT12 expression is reduced and its responsiveness to insulin is impaired. Conversely, GLUT12 is found to be overexpressed in various human solid tumors, including breast, prostate, gastric, liver, and colon cancers. Factors like high glucose levels, insulin, and hypoxia can upregulate GLUT12 expression in both fat cells and tumor cells. Importantly, inhibiting GLUT12-mediated Warburg effect has been shown to suppress the proliferation, migration, and invasion of cancer cells, as well as the growth of xenografted tumors.
This review aims to provide an updated overview of the physiological role of GLUT12 and its involvement in both obesity and cancer. Understanding GLUT12’s function in these conditions may pave the way for considering this transporter as a potential therapeutic target in the fight against these diseases.
