Insulin resistance
Metabolic side effect of chronic mTOR inhibition. In mice, mTORC2 disruption is a major contributor (LAM2012). In humans the relative contributions are not resolved: mTORC2 loss, S6K1-IRS-1 feedback relief (HAR2004, SHA2004) and direct beta-cell effects are all plausible, and no study has apportioned them.
The body responding less well to insulin.
In mice, mTORC2 disruption is a major contributor (LAM2012); in humans the relative contributions of mTORC2 loss, S6K1–IRS-1 feedback and direct β-cell effects are unresolved.
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| H | Human study | 1 |
| A | Animal model | 1 |
| RT | Registered trial, no results yet | 1 |
| R | Review — secondary literature, not a new result | 1 |
Studies
| Year | Evidence | Study |
|---|---|---|
| 2013 | H | High-dose resveratrol supplementation in obese men: an investigator-initiated, randomized, placebo-controlled clinical trial of substrate metabolism, insulin sensitivity, and body composition POU2013 4 weeks of high-dose resveratrol had no effect on insulin sensitivity, blood pressure, or body composition - directly contradicting the promising rodent data that drove the original hype. |
| 2012 | A | Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity LAM2012 In mice, chronic rapamycin also disrupts mTORC2, causing insulin resistance; lifespan extension can be uncoupled from this side effect. |
| 2016 | R | The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging KEN2016 A Cell Metabolism review framing mTOR as the 'grand conductor' that coordinates whole-body metabolism, tissue by tissue. Especially valuable for its clear-eyed section on WHY rapamycin causes metabolic side effects (the mTORC2 problem) - which is the main barrier to using it against aging. Pairs perfectly with Lamming's own 2012 mechanism paper. |
| RT | Everolimus Aging Study (EVERLAST): Clinical Evaluation of mTORC1 Inhibition for Geroprotection NCT05835999 Currently active phase 2 trial (NCT05835999) directly testing this Atlas's open dosing hypothesis: whether daily low-dose (0.5mg) versus weekly (5mg) everolimus can improve aging biomarkers and insulin resistance in humans without the metabolic penalty seen with continuous higher-dose rapalog use. No results yet - status ACTIVE_NOT_RECRUITING. |