Amino acid homeostasis is a target of metformin therapy

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  • Calum Forteath
  • Ify Mordi
  • Raid Nisr
  • Erika J. Gutierrez-Lara
  • Noor Alqurashi
  • Iain R. Phair
  • Amy R. Cameron
  • Craig Beall
  • Ibrahim Bahr
  • Mohapradeep Mohan
  • Aaron K.F. Wong
  • Adel Dihoum
  • Anwar Mohammad
  • Colin N.A. Palmer
  • Douglas Lamont
  • Sakamoto, Kei
  • Benoit Viollet
  • Marc Foretz
  • Chim C. Lang
  • Graham Rena

Objective: Unexplained changes in regulation of branched chain amino acids (BCAA) during diabetes therapy with metformin have been known for years. Here we have investigated mechanisms underlying this effect. Methods: We used cellular approaches, including single gene/protein measurements, as well as systems-level proteomics. Findings were then cross-validated with electronic health records and other data from human material. Results: In cell studies, we observed diminished uptake/incorporation of amino acids following metformin treatment of liver cells and cardiac myocytes. Supplementation of media with amino acids attenuated known effects of the drug, including on glucose production, providing a possible explanation for discrepancies between effective doses in vivo and in vitro observed in most studies. Data-Independent Acquisition proteomics identified that SNAT2, which mediates tertiary control of BCAA uptake, was the most strongly suppressed amino acid transporter in liver cells following metformin treatment. Other transporters were affected to a lesser extent. In humans, metformin attenuated increased risk of left ventricular hypertrophy due to the AA allele of KLF15, which is an inducer of BCAA catabolism. In plasma from a double-blind placebo-controlled trial in nondiabetic heart failure (trial registration: NCT00473876), metformin caused selective accumulation of plasma BCAA and glutamine, consistent with the effects in cells. Conclusions: Metformin restricts tertiary control of BCAA cellular uptake. We conclude that modulation of amino acid homeostasis contributes to therapeutic actions of the drug.

Original languageEnglish
Article number101750
JournalMolecular Metabolism
Number of pages16
Publication statusPublished - 2023

Bibliographical note

Publisher Copyright:
© 2023 The Authors

    Research areas

  • AMPK, Branched chain amino acids, Glutamine, Metformin, mTOR, Rapamycin, SNAT2

ID: 360606673