Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner

Kalender A, Selvaraj A, Kim SY, Gulati P, Brûlé S, Viollet B, Kemp BE, Bardeesy N, Dennis P, Schlager JJ, Marette A, …, Thomas G · 2010 · Cell Metabolism · Atlas ID KAL2010

What this study shows

Metformin inhibits mTORC1 even in cells lacking AMPK or TSC1/TSC2, and the effect requires the Rag GTPases instead. Together with Foretz 2010 this places a large part of metformin's action outside the AMPK axis it is usually credited to.

Abstract

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Dysfunctional mTORC1 signaling is associated with a number of human pathologies owing to its central role in controlling cell growth, proliferation, and metabolism. Regulation of mTORC1 is achieved by the integration of multiple inputs, including those of mitogens, nutrients, and energy. It is thought that agents that increase the cellular AMP/ATP ratio, such as the antidiabetic biguanides metformin and phenformin, inhibit mTORC1 through AMPK activation of TSC1/2-dependent or -independent mechanisms.

Read the full abstract on PubMed →

At a glance

Evidence type	M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: Mammalian cells (AMPK-null and TSC1/2-null)) rather than a whole-organism health-outcome study. That is often exactly where causal biology gets established -- the code says which system the finding was shown in, and nothing about how good the work is.
Study type	5 - Mechanistic / In Vitro
Model system	Mammalian cells (AMPK-null and TSC1/2-null)
Journal	Cell Metabolism
Year	2010
Peer reviewed	Yes
Record last updated	2026-07-29
Source	DOI 10.1016/j.cmet.2010.03.014 · PMID 20444419

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	Metformin and phenformin (biguanides)
Target	mTORC1 via Rag GTPases (AMPK- and TSC-independent)
Model	Mammalian cells (AMPK-null and TSC1/2-null); preclinical models
Effect	Biguanides inhibit mTORC1 without AMPK or TSC1/2; the effect requires the Rag GTPases

In the Atlas

Links in the pathway map

Supports Metformin inhibits mTORC1
Points the other way on Metformin activates AMPK

Cite this paper

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Kalender, A., Selvaraj, A., Kim, S. Y., Gulati, P., Brûlé, S., Viollet, B., Kemp, B. E., Bardeesy, N., Dennis, P., Schlager, J. J., Marette, A., Kozma, S. C., & Thomas, G. (2010). Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metabolism. https://doi.org/10.1016/j.cmet.2010.03.014

@article{KAL2010,
  author       = {Kalender, A. and Selvaraj, A. and Kim, S. Y. and Gulati, P. and Brûlé, S. and Viollet, B. and Kemp, B. E. and Bardeesy, N. and Dennis, P. and Schlager, J. J. and Marette, A. and Kozma, S. C. and Thomas, G.},
  title        = {{Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner}},
  journal      = {Cell Metabolism},
  year         = {2010},
  doi          = {10.1016/j.cmet.2010.03.014},
  note         = {PMID: 20444419},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper.

Barton, O. (2026). Oliver's mTOR Atlas (record KAL2010) [Data set]. https://mtor-atlas.org/study/KAL2010/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_KAL2010,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record KAL2010},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/KAL2010/},
  doi          = {10.5281/zenodo.22059963}
}

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