Rapamycin, an inhibitor of mTORC1, extends lifespan in various organisms but causes insulin resistance and glucose intolerance. This study shows that rapamycin disrupts mTORC2 in vivo, which is essential for insulin-mediated suppression of hepatic gluconeogenesis. mTORC2 disruption is a key mediator of rapamycin's effects on glucose homeostasis, while mTORC1 inhibition independently extends lifespan. Female mice with reduced mTORC1 activity and normal glucose tolerance and insulin sensitivity exhibit increased lifespan, indicating that mTORC2 disruption is responsible for the adverse effects of rapamycin on glucose homeostasis. Rapamycin also disrupts mTORC2 in multiple tissues, leading to hepatic insulin resistance and impaired glucose tolerance. However, mTORC2 disruption in the liver is sufficient to impair hepatic insulin sensitivity, contributing to rapamycin-induced glucose intolerance. The study also shows that mTORC2 disruption can be uncoupled from longevity, as female mice with reduced mTORC1 and mLST8 activity exhibit increased lifespan without changes in glucose tolerance. These findings suggest that mTORC2 disruption profoundly affects metabolism and may be relevant to the pathogenesis of type 2 diabetes and the metabolic syndrome. Rapamycin's effects on longevity and glucose homeostasis can be uncoupled, indicating that mTORC1 inhibition may provide many of the benefits of rapamycin on health and longevity while avoiding its side effects.Rapamycin, an inhibitor of mTORC1, extends lifespan in various organisms but causes insulin resistance and glucose intolerance. This study shows that rapamycin disrupts mTORC2 in vivo, which is essential for insulin-mediated suppression of hepatic gluconeogenesis. mTORC2 disruption is a key mediator of rapamycin's effects on glucose homeostasis, while mTORC1 inhibition independently extends lifespan. Female mice with reduced mTORC1 activity and normal glucose tolerance and insulin sensitivity exhibit increased lifespan, indicating that mTORC2 disruption is responsible for the adverse effects of rapamycin on glucose homeostasis. Rapamycin also disrupts mTORC2 in multiple tissues, leading to hepatic insulin resistance and impaired glucose tolerance. However, mTORC2 disruption in the liver is sufficient to impair hepatic insulin sensitivity, contributing to rapamycin-induced glucose intolerance. The study also shows that mTORC2 disruption can be uncoupled from longevity, as female mice with reduced mTORC1 and mLST8 activity exhibit increased lifespan without changes in glucose tolerance. These findings suggest that mTORC2 disruption profoundly affects metabolism and may be relevant to the pathogenesis of type 2 diabetes and the metabolic syndrome. Rapamycin's effects on longevity and glucose homeostasis can be uncoupled, indicating that mTORC1 inhibition may provide many of the benefits of rapamycin on health and longevity while avoiding its side effects.