Chronic Inhibition of the mTORC1/S6K1 Pathway Increases Insulin-Induced PI3K Activity but Inhibits Akt2 and Glucose Transport Stimulation in 3T3-L1 Adipocytes
Bibliographic record
Abstract
The mammalian target of rapamycin complex 1 (mTORC)1 pathway has emerged as a critical signaling component in the modulation of insulin's metabolic action. This effect is triggered by a nutrient- and insulin-mediated negative feedback loop in which mTOR and S6 kinase (S6K)1 phosphorylate insulin receptor substrate (IRS)-1 on serine residues, which blunts phosphatidylinositol 3-kinase (PI3K) activation. Acute inhibition of mTORC1/S6K1 by rapamycin increases insulin signaling and glucose uptake in myocytes and adipocytes, but whether these effects can be maintained under chronic inhibition of mTORC1 or S6K1 remains unclear. Here, we analyzed the effect of chronic rapamycin inhibition or small interfering RNA-based down-regulation of specific elements of the mTORC1/S6K1 pathway on insulin signaling and glucose transport in adipocytes. Both chronic inhibition of mTORC1 by rapamycin or knockdown of either mTOR, raptor, or S6K1 reduced inhibitory serine phosphorylation of IRS-1, while increasing its insulin-stimulated tyrosine phosphorylation and associated PI3K activity. However, knockdown of either mTOR or raptor selectively blunted IRS-1 phosphorylation on Ser636/639, whereas only S6K1 knockdown was found to reduce phosphorylation of IRS-1 on Ser1101. Unexpectedly, insulin-induced activation of Akt2 and glucose transporter 4 expression were reduced after chronic disruption of the mTORC1/S6K1 pathway, impairing insulin-mediated glucose uptake despite increased PI3K activation. In conclusion, these data indicate that both mTORC1 and S6K1 are key elements of the negative feedback loop but inhibit insulin-induced PI3K activity through phosphorylation of specific serine residues in IRS-1. However, this study also shows that chronic inhibition of the mTORC1/S6K1 pathway uncouples IRS-1/PI3K signaling from insulin-induced glucose transport due to impaired activation of Akt2 and blunted glucose transporter 4 expression.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".