Suppression of ITPK1 and IPMK activities impairs mTORC1 signaling in pancreatic β-cells and implicates IP ₅ in stabilizing activated mTORC1

mTORC1 is a central metabolic regulator whose chronic activation contributes to metabolic disease, yet mechanisms that sustain mTORC1 activity after its activation are poorly understood. We show that enzymes controlling inositol phosphate metabolism regulate the stability of mTORC1 signaling in pancreatic β-cells by maintaining cellular levels of inositol pentakisphosphate (IP ₅ ). Reducing IP ₅ impairs basal and sustained mTORC1 signaling without affecting upstream growth factor or energy-sensing pathways, revealing a mechanism that controls signal duration rather than activation. These findings identify IP ₅ as a metabolic regulator of mTORC1 and suggest that targeting inositol phosphate metabolism may provide a strategy to modulate mTORC1 activity in metabolic disease.