ARL15 is a small GTPase member of the RAS superfamily 1 that regulates magnesium homeostasis and metabolic processes. Primary function: ARL15 serves as a GTP-binding protein that modulates divalent cation transport by inhibiting CNNM2-mediated magnesium efflux and TRPM7-mediated magnesium influx 2, while also regulating TRPM6-mediated magnesium currents in human kidney cells 3. Mechanism: The protein undergoes palmitoylation-dependent translocation within the Golgi apparatus during adipogenesis and interacts with trafficking regulators including ARL6IP5 4. ARL15 overexpression enhances insulin signaling through the IR/IRS1/AKT/eNOS pathway and reduces oxidative stress in endothelial cells exposed to high glucose 5. Disease relevance: Genetic variants in ARL15 are significantly associated with reduced circulating adiponectin levels, increased type 2 diabetes risk, coronary heart disease, lipid metabolism disorders, rheumatoid arthritis, and periodontitis 6718. Loss-of-function mutations are found in lipodystrophy patients 4. Clinical significance: ARL15 represents an emerging therapeutic target for metabolic and immune-related disorders, with its variants modifying the association between magnesium deficiency and insulin resistance 31.