The study investigates the effects of rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1), on insulin resistance and glucose homeostasis. Rapamycin extends lifespan in various organisms, but chronic administration impairs glucose tolerance and insulin action. The researchers found that rapamycin disrupts mTORC2, a second mTOR complex, in vivo, and that mTORC2 is essential for insulin-mediated suppression of hepatic gluconeogenesis. They also showed that decreased mTORC1 signaling, independent of changes in glucose homeostasis, can extend lifespan in female mice heterozygous for both mTOR and mLST8. This suggests that mTORC2 disruption is a key mediator of rapamycin's effects in vivo. Additionally, they demonstrated that disrupting mTORC2 in the liver impairs hepatic insulin sensitivity and glucose homeostasis, while disrupting mTORC1 signaling does not affect these processes. Finally, they found that selectively impairing mTORC1 signaling in female mice without affecting mTORC2 signaling increases lifespan without altering glucose tolerance or insulin sensitivity, indicating that the beneficial and detrimental effects of mTOR inhibition can be uncoupled.The study investigates the effects of rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1), on insulin resistance and glucose homeostasis. Rapamycin extends lifespan in various organisms, but chronic administration impairs glucose tolerance and insulin action. The researchers found that rapamycin disrupts mTORC2, a second mTOR complex, in vivo, and that mTORC2 is essential for insulin-mediated suppression of hepatic gluconeogenesis. They also showed that decreased mTORC1 signaling, independent of changes in glucose homeostasis, can extend lifespan in female mice heterozygous for both mTOR and mLST8. This suggests that mTORC2 disruption is a key mediator of rapamycin's effects in vivo. Additionally, they demonstrated that disrupting mTORC2 in the liver impairs hepatic insulin sensitivity and glucose homeostasis, while disrupting mTORC1 signaling does not affect these processes. Finally, they found that selectively impairing mTORC1 signaling in female mice without affecting mTORC2 signaling increases lifespan without altering glucose tolerance or insulin sensitivity, indicating that the beneficial and detrimental effects of mTOR inhibition can be uncoupled.