This question is complex, but our weekly dosing protocols would seem to suggest we are mainly TOR1 inhibition. But in the renal transplant cohorts with reported lipids/CAD risk, they are under chronic dosing. Does this chronic dosing cross the mTOR2 threshold, or is still all TOR1?
From this mice study of chronic 2.24 mg/day (equivalent to 13 mg/day humans) they found 30% mTOR1 reduction, and NO mTOR2 reduction.
“Chronic rapamycin treatment inhibits mTORC1 but not mTORC2 in brains of C57BL/6J mice. Phosphorylation of Akt/PKB at Ser473, a target of mTORC2, was unaffected both in
whole brain lysates as well as in hippocampi. Taken together, these data indicate that
long-term oral treatment with rapamycin significantly inhibits mTORC1 but does not reduce mTORC2 activity in brain.”
So it seems it might take some massive doses to dysregulate mTOR2.
Rapamycin-mediated mTORC2 inhibition is determined by the relative expression of FK506-binding proteins (2015)
"Ten-week-old C57BL/6J mice were given intraperitoneal injections of 8 mg/kg (47 mg/day human equivalent) rapamycin every other day for 10 days. While rapamycin acutely and directly inhibits mTORC1, only chronic administration of rapamycin can inhibit mTORC2 in some, but not all, cell lines or tissues. The mechanism leading to cell specificity of mTORC2 inhibition by rapamycin is not understood and is especially important because many of the negative metabolic side effects of rapamycin, reported in mouse studies and human clinical trials, have been "attributed" recently to mTORC2 inhibition.
Role of mTOR in Glucose and Lipid Metabolism
“Relative to mTORC1, the upstream signals and downstream substrates of mTORC2 are less known. mTORC2 can be activated by the growth factors such as insulin and IGF, but insensitive to the nutrients. Activated mTORC2 phosphorylates AGC kinase family, including AKT, SGK, and PKCα, to regulate cellular survival and metabolism, as well as cytoskeletal remodeling. The most well characterized substrate of mTORC2 is AKT which is phosphorylated at the serine 473. AKT could further phosphorylate TSC2, the upstream inhibitor of mTORC1. Therefore, activation of mTORC2 inactivates mTORC1. Vice versa, mTORC1-S6K axis could also directly phosphorylate mSIN1, the core component of mTORC2 and inactivate it. Therefore, mTORC1 and mTORC2 form a feedback loop regulating the complex activity”
It appears mTOR2 is more acting on glucose pathways.
“Hepatic mTORC2 regulates glucose and lipid metabolism via AKT signaling. The role of hepatic mTORC2 has been examined in vivo using the mice lacking Rictor in liver. Deficient expression of mTORC2 in liver leads to defective insulin-stimulated AKT phosphorylation, resulting in constitutive gluconeogenesis”
So does elevated glucose signal mTOR2 dysregulation or still related to mTOR1?
For practical purposes, we can assume these two pathways are in play, but not sure how knowing is going to resolve clinically our concerns of elevation in lipids/glucose and CAD risk.
