Insulin
Pancreatic peptide hormone; the growth-factor input that reaches mTORC1 through the insulin receptor, IRS proteins, PI3K and Akt. Added 2026-10-10 after an audit found the Atlas modelled a single 'Growth hormone / IGF-1 axis' input whose edge text described insulin docking on its receptor, while insulin itself had no node and growth hormone does not use that receptor.
The after-a-meal hormone. The hormone the pancreas releases after a meal. It is one of the two main 'go' signals mTORC1 listens to: it lands on its own receptor and the message travels inward through IRS proteins, PI3K and Akt. The other kind of signal is the nutrients themselves.
Distinct from the GH/IGF-1 node: insulin binds InsR directly, while GH acts through GHR-JAK2-STAT5b and reaches this arm largely by inducing hepatic IGF-1. The AKT pathway multiplexes the temporal pattern of the insulin signal, so amplitude and time course are not interchangeable.
TL;DR. Insulin appears in 6 curated studies in Oliver's mTOR Atlas: 6 at the molecular level (cells, biochemistry, structure). No study in people is recorded for it in the Atlas yet. It has 1 interaction in the curated pathway model.
In the pathway model
| Interaction | Mechanism | Evidence | Studies |
|---|---|---|---|
| Insulin activates PI3K mechanism: signal-relay · this link in full · on the map table | Insulin lands on its own receptor on the cell surface. The message is passed inward by IRS proteins to PI3K, which builds a signalling lipid, and that is the beginning of the route to mTORC1. This is also the step that breaks when the pathway is overactive for too long. Insulin binds the insulin receptor, which phosphorylates IRS proteins; those recruit PI3K, which makes PIP3 and so starts the arm that reaches mTORC1 through Akt. The step is also where the pathway's best-known feedback lands: S6K1 depletes IRS1/2 and the cell goes deaf to insulin (SHA2004). Insulin binds the insulin receptor, which phosphorylates IRS proteins; those recruit PI3K, which makes PIP3 and so starts the arm that reaches mTORC1 through Akt. The step is also where the pathway's best-known feedback lands: S6K1 depletes IRS1/2 and the cell goes deaf to insulin (SHA2004). Holds under: Insulin and IGF-1 share this receptor arm; growth hormone does not, and is kept separate for that reason. The amplitude and the time pattern of the insulin signal are not interchangeable: KUB2012 shows the AKT pathway multiplexes insulin's temporal pattern, so a single arrow understates what the cell reads. Cell and genetic work, plus human physiology for the insulin-resistance end of it. plausible in people, not shown directly · settled in the literature | M | HAR2004, GAR2003, SAU2003, SAN2007, SHA2004 |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| M | Molecular — cells, biochemistry, structure | 6 |
No direct human evidence in the Atlas for this entity yet — everything below rests on animal or molecular work.
Studies
| Year | Evidence | Study |
|---|---|---|
| 2012 | M | Temporal coding of insulin action through multiplexing of the AKT pathway KUB2012 The same pathway can carry different messages in the shape of its signal over time. A short insulin pulse produced transient AKT phosphorylation and a sustained dose produced sustained AKT phosphorylation. S6K read only the transient part, G6Pase only the sustained part and GSK3-beta both. Which output responds depends on the pattern, not just the amount - the clearest cell-level case in the atlas that timing carries information in this pathway. |
| 2007 | M | PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase SAN2007 Identified PRAS40 as the missing insulin-controlled brake INSIDE mTORC1. When insulin is absent PRAS40 clamps the complex shut; insulin makes Akt phosphorylate PRAS40, releasing the brake so Rheb can fully switch mTORC1 on. Explained how hormone signals set the exact strength of mTORC1 activity. |
| 2004 | M | The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins HAR2004 One of two 2004 papers that placed mTORC1's main negative feedback loop downstream of TSC-Rheb-S6K1 (rapamycin-sensitive IRS-1 degradation had been reported earlier, Haruta 2000). When mTORC1/S6K1 activity is left switched on, S6K1 phosphorylates IRS-1 and represses its expression, so the insulin receptor can no longer signal to PI3K. This is the textbook explanation for why blocking mTORC1 paradoxically raises Akt activity, and it contributes to insulin resistance when mTORC1 is chronically overactive (for example with TSC loss or nutrient excess). The insulin resistance seen with chronic rapamycin is instead attributed mainly to mTORC2 disruption (LAM2012). |
| 2004 | M | Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies SHA2004 The companion paper to Harrington 2004, published two months later. In cultured mammalian cells, constitutive Rheb/mTOR/S6K activity depletes IRS1 and IRS2, producing cellular insulin resistance and impaired survival signalling. Together the two papers establish the S6K1 -> IRS negative feedback arm. |
| 2003 | M | Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2 GAR2003 Insulin activates Rheb-GTP, inhibited by TSC1/2, positioning Rheb as the direct upstream activator of TOR. |
| 2003 | M | Rheb promotes cell growth as a component of the insulin/TOR signalling network SAU2003 Rheb promotes cell growth as a component of the insulin/TOR network in Drosophila. |
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