Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system
What this study shows
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).
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); 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 |
| Journal | Aging cell |
| Year | 2015 |
| Peer reviewed | Yes |
| Record last updated | 2026-07-29 |
| Source | DOI 10.1111/acel.12405 · PMID 26463117 · Free full text (PMC4717280) |
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 – alternative/intermittent dosing regimens |
| Target | mTORC1 (vs mTORC2) |
| Model | Mouse |
| Effect | Intermittent regimens and rapalogs inhibit mTORC1 while largely sparing glucose tolerance and immune function; no survival endpoint was measured |
| Dose | 2 mg/kg rapamycin administered daily (1x/day), weekly (1x/7 days), once every three days (1x/3 days), or once every five days (1x/5 days) to 9-week-old male C57BL/6J mice for 2-8 weeks. |
| Sample size | 9-11 male C57BL/6J mice per treatment group for glucose tolerance tests; 3-6 mice per group for blood rapamycin concentration; 4-9 mice per group for insulin/HOMA2 measurements; 6 mice per treatment for islet analysis. |
| Effect size | Daily rapamycin treatment significantly impaired glucose tolerance (20–116% increase in blood glucose, 71% increase in AUC), while weekly (1x/7 days) or 1x/5 days rapamycin treatment did not impair glucose tolerance. Rapamycin 1x/3 days significantly impaired glucose tolerance. Daily rapamycin inhibited both mTORC1 (S6 S240/244) and mTORC2 (AKT S473) signaling, while weekly rapamycin only inhibited mTORC1. |
| Limitations | No lifespan or healthspan endpoint. Side-effect endpoints only; benefit retention is inferred, not tested. |
In the Atlas
Links in the pathway map
- Supports mTORC2 inhibits Insulin resistance
Open questions that cite this study
- 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 Rapamycin + AMPK-axis drugs (acarbose / metformin): a male-mouse survival signal from cross-cohort comparison, untested in humans.
Learn the biology
Want to understand the biology behind this study? → Challenge 02: Why rapamycin does not switch mTORC1 off
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