Metformin Inhibits Hepatic mTORC1 Signaling via Dose-Dependent Mechanisms Involving AMPK and the TSC Complex

Howell JJ, Hellberg K, Turner M, Talbott G, Kolar MJ, Ross DS, Hoxhaj G, Saghatelian A, Shaw RJ, Manning BD · 2017 · Cell Metabolism · Atlas ID HOW2017

What this study shows

Pinned down HOW the diabetes drug metformin - a major longevity candidate - actually reaches mTOR. In the liver, metformin lowers cellular energy, and at low doses this shuts down mTORC1 specifically through AMPK and the TSC complex. Direct mechanistic bridge between a widely-used drug, energy sensing, and the mTOR pathway.

Abstract

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Metformin is the most widely prescribed drug for the treatment of type 2 diabetes. However, knowledge of the full effects of metformin on biochemical pathways and processes in its primary target tissue, the liver, is limited. One established effect of metformin is to decrease cellular energy levels. The AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) are key regulators of metabolism that are respectively activated and inhibited in acute response to cellular energy depletion.

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: Mouse liver + primary hepatocytes) 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	Mouse liver + primary hepatocytes
Journal	Cell Metabolism
Year	2017
Peer reviewed	Yes
Record last updated	2026-10-01
Source	DOI 10.1016/j.cmet.2016.12.009 · PMID 28089566 · Free full text (PMC5299044)

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 (dose-dependent)
Target	AMPK / TSC / Rag / mTORC1
Model	Mouse liver + primary hepatocytes
Effect	Metformin inhibits hepatic mTORC1 via dose-dependent AMPK- and TSC-complex-dependent mechanisms

In the Atlas

Open questions that cite this study

Cited as supporting evidence for the open question Rapamycin + AMPK-axis drugs (acarbose / metformin): a male-mouse survival signal from cross-cohort comparison, untested in humans.

Cite this paper

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Howell, J. J., Hellberg, K., Turner, M., Talbott, G., Kolar, M. J., Ross, D. S., Hoxhaj, G., Saghatelian, A., Shaw, R. J., & Manning, B. D. (2017). Metformin Inhibits Hepatic mTORC1 Signaling via Dose-Dependent Mechanisms Involving AMPK and the TSC Complex. Cell Metabolism. https://doi.org/10.1016/j.cmet.2016.12.009

@article{HOW2017,
  author       = {Howell, J. J. and Hellberg, K. and Turner, M. and Talbott, G. and Kolar, M. J. and Ross, D. S. and Hoxhaj, G. and Saghatelian, A. and Shaw, R. J. and Manning, B. D.},
  title        = {{Metformin Inhibits Hepatic mTORC1 Signaling via Dose-Dependent Mechanisms Involving AMPK and the TSC Complex}},
  journal      = {Cell Metabolism},
  year         = {2017},
  doi          = {10.1016/j.cmet.2016.12.009},
  note         = {PMID: 28089566},
}

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 HOW2017) [Data set]. https://mtor-atlas.org/study/HOW2017/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_HOW2017,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record HOW2017},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/HOW2017/},
  doi          = {10.5281/zenodo.22059963}
}

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