Pathway link MTORC2-INSULINRES
mTORC2 Insulin resistance
mTORC2 inhibits Insulin resistance.
Losing mTORC2 disconnects Akt from insulin signalling and can cause blood-sugar problems – a separate effect from any lifespan benefit.
The conditions it holds under
In mice, intermittent dosing largely spared glucose tolerance while keeping mTORC1 inhibition (ARR2015); not tested against this endpoint in humans.
- Time it takes
- long exposure (days to weeks)
- Step
- indirect (through steps not drawn here)
- Measured in
- mouse
- Reaches people?
- plausible in people, not shown directly
- How settled
- emerging, few independent studies
Studies behind it
| Year | Evidence | Study |
|---|---|---|
| 2012 | A | Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevityLAM2012 Chronic rapamycin (about 2 mg/kg a day, close to the lifespan-extending dose) made mice glucose intolerant and insulin resistant. A clamp test placed the problem in the liver, which kept making glucose, while muscle and fat took up glucose normally. Removing mTORC1 from the liver did not cause this. Rapamycin did break up mTORC2 (it separated mTOR from Rictor) in liver, fat and muscle, and deleting Rictor in the liver alone reproduced the glucose problem. In the genetic part, female mice with one working copy each of mTOR and mLST8 had about 50% less mTORC1 signalling in the liver, normal mTORC2 signalling and normal glucose tolerance, and lived 14.4% longer on average (p = 0.046). Males did not. Boundary: mouse drug and genetics work, not people, and the lifespan gain is female-only. It supports separating the two effects, but the paper does not test a drug that blocks mTORC1 without touching mTORC2. |
| 2015 | A | Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune systemARR2015 Mice given rapamycin every day (2 mg/kg) developed glucose intolerance (the glucose curve was about 71% higher), raised fasting glucose and insulin, and their pancreatic islets released less insulin. The same dose given once every 5 days did not impair glucose tolerance or insulin tolerance, and fasting glucose and insulin stayed normal. Dosing every 3 days was already too frequent. Pyruvate tolerance, a liver measure, was still impaired, about half as much as with daily dosing. The drug is cleared within about a week (blood half-life roughly 15 hours), so mTORC1 was not blocked continuously. The immune effect got smaller but did not disappear (regulatory T cells fell about 25% versus about 60% on daily dosing), and testis weight still dropped by about 60% versus 75 to 80%. Everolimus and temsirolimus blocked mTORC1 as well as rapamycin but disturbed glucose tolerance less. Boundary: young male mice treated for 2 to 8 weeks, side effects only. No lifespan or benefit was measured, so this shows that harm can be reduced, not that the benefit is kept (see ARR2016 and BIT2016). |
Points the other way
No study in the Atlas contradicts this link. That means none in this curated set, not none in the literature.
Who has checked this
- Checked by
- No researcher outside the project has checked this link yet.
- Curator sign-off
- Not signed off yet. This link was drafted with AI help and has not been reviewed link by link; treat it as a proposal until it is.
- Curated by
- Oliver Barton, with AI help for drafting; see how links are checked.
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