I think Dudley Lamming is the key proponent (at least from my reading) of the idea that long-term, high dose, rapamycin tends to inhibit mTORC2 and thus cause the lipid and glucose disregulation.
Some references:
Here: Evidence that mTORC2 inhibition is detrimental, by Dudley Lamming
and
We have demonstrated that chronic, long-term administration of rapamycin results in inhibition of not only mTORC1, but also mTORC2, in vitro in cancer cell lines as well as in vivo in mice (Sarbassov et al ., 2006; Lamming et al ., 2012). Long-term rapamycin treatment results in glucose intolerance in humans, rats, and C57BL/6 mice as well as genetically heterogeneous HET3 mice (Houde et al ., 2010; Gyurus et al ., 2011; McCormack et al ., 2011; Lamming et al ., 2013). We found that this effect is mediated in part by decreased hepatic insulin sensitivity, an effect that can be reproduced by depletion of RICTOR, an essential protein component of mTORC2, in the whole body (Lamming et al ., 2012) or specifically in the liver (Hagiwara et al ., 2012; Lamming et al ., 2012; Yuan et al ., 2012). We have recently shown that Rictor deletion specifically in the liver has significant effects at both the mRNA and phosphoproteomic level that are distinct from those seen with acute rapamycin treatment (Lamming et al ., 2014).
https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12256
and
but there is some research that suggests a little mTORC2 inhibition may not be a bad thing: Ideas on Protocols for Testing Higher Rapamycin Doses - #13 by brandy111
I’m not at all familiar with the data behind blagosklonny’s comment regarding mTOR2 inhibition in humans.
But I did talk to Adam Salmon who is running the long-term marmoset rapamycin study at UT Southwestern in Texas and they are dosing at 1mg/kg (which does not raise blood/sirolimus levels anywhere near 100 to 500 ng/ml of rapamycin) and he said they definitely see mTORC2 inhibition. if this is true in primates, I suspect its also true in humans.
Also, see this paper by Dudley Lamming:
preprints202102.0491.v1-6.pdf (391.7 KB)
