Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity

Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, Davis JG, Salmon AB, Richardson A, Ahima RS, Guertin DA, …, Baur JA · 2012 · Science · Atlas ID LAM2012

What this study shows

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.

Cited on mTOR drugs in development: RMC-5552, TOR-101, DL001, Everolimus

Abstract

ShowHide

Rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1), extends the life spans of yeast, flies, and mice. Calorie restriction, which increases life span and insulin sensitivity, is proposed to function by inhibition of mTORC1, yet paradoxically, chronic administration of rapamycin substantially impairs glucose tolerance and insulin action. We demonstrate that rapamycin disrupted a second mTOR complex, mTORC2, in vivo and that mTORC2 was required for the insulin-mediated suppression of hepatic gluconeogenesis.

Read the full abstract on PubMed →

At a glance

Evidence type	A Animal model Marked A because it is an animal intervention or observation study measuring an organismal outcome (model: Mouse (in vivo glucose and insulin tolerance)); the code names the system studied -- animal work can be rigorous and still not be human data.
Study type	4 - Animal Study
Model system	Mouse (in vivo glucose and insulin tolerance)
Journal	Science
Year	2012
Peer reviewed	Yes
Record last updated	2026-07-29
Source	DOI 10.1126/science.1215135 · PMID 22461615 · Free full text (PMC3324089)

Extracted findings

These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.

Intervention	Rapamycin (chronic)
Target	mTORC1 vs mTORC2
Model	Mouse
Effect	In mice, chronic rapamycin causes insulin resistance via disruption of mTORC2, uncoupled from its longevity effect

In the Atlas

Links in the pathway map

Supports mTORC1 inhibits Longevity
Supports mTORC2 inhibits Insulin resistance
Supports Rapamycin inhibits mTORC2

Open questions that cite this study

Cited as supporting evidence for the open question Sensor-selective geroprotection without the metabolic penalty.
Cited as supporting evidence for the open question Does mTORC1-selective dosing extend lifespan, and is rapamycin's glucose intolerance a cost at all?.
Cited as supporting evidence for the open question Brain-penetrant mTOR inhibition clears aggregates in models, but human dosing has not been shown to reach the brain — and mTORC2 is needed for memory in mice.

Learn the biology

Want to understand the biology behind this study? → Feedback Regulation

Cite this paper