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

Kalender A; Selvaraj A; Thomas G; Kozma SC et al. · 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.

Tier D because it is mechanistic or in-vitro work (model: Mammalian cells (AMPK-null and TSC1/2-null)), not a whole-organism health-outcome study; tier describes study design, not quality -- this is often exactly where causal biology gets established.

At a glance

Evidence tier	D Mechanistic / in vitro / review
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

Target	Metformin -> Rag GTPases -> mTORC1 (AMPK-independent)
Model	Mammalian cells
Effect	Metformin inhibits mTORC1 without AMPK or TSC1/2, in a Rag GTPase-dependent manner

Abstract

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 →

Cite this record

Barton, O. (2026). Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner — evidence-graded record KAL2010. In Oliver's mTOR Atlas. https://mtor-atlas.org/study/KAL2010/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_KAL2010,
  author       = {Barton, Oliver},
  title        = {{Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner} --- evidence-graded record KAL2010},
  howpublished = {Oliver's mTOR Atlas},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/KAL2010/},
  note         = {Dataset DOI: 10.5281/zenodo.22059963}
}

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