Amino acid homeostasis is a target of metformin therapy

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

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

In: Molecular Metabolism, Vol. 74, 101750, 2023.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Forteath, C, Mordi, I, Nisr, R, Gutierrez-Lara, EJ, Alqurashi, N, Phair, IR, Cameron, AR, Beall, C, Bahr, I, Mohan, M, Wong, AKF, Dihoum, A, Mohammad, A, Palmer, CNA, Lamont, D, Sakamoto, K, Viollet, B, Foretz, M, Lang, CC & Rena, G 2023, 'Amino acid homeostasis is a target of metformin therapy', Molecular Metabolism, vol. 74, 101750. https://doi.org/10.1016/j.molmet.2023.101750

APA

Forteath, C., Mordi, I., Nisr, R., Gutierrez-Lara, E. J., Alqurashi, N., Phair, I. R., Cameron, A. R., Beall, C., Bahr, I., Mohan, M., Wong, A. K. F., Dihoum, A., Mohammad, A., Palmer, C. N. A., Lamont, D., Sakamoto, K., Viollet, B., Foretz, M., Lang, C. C., & Rena, G. (2023). Amino acid homeostasis is a target of metformin therapy. Molecular Metabolism, 74, [101750]. https://doi.org/10.1016/j.molmet.2023.101750

Vancouver

Forteath C, Mordi I, Nisr R, Gutierrez-Lara EJ, Alqurashi N, Phair IR et al. Amino acid homeostasis is a target of metformin therapy. Molecular Metabolism. 2023;74. 101750. https://doi.org/10.1016/j.molmet.2023.101750

Author

Forteath, Calum ; Mordi, Ify ; Nisr, Raid ; Gutierrez-Lara, Erika J. ; Alqurashi, Noor ; Phair, Iain R. ; Cameron, Amy R. ; Beall, Craig ; Bahr, Ibrahim ; Mohan, Mohapradeep ; Wong, Aaron K.F. ; Dihoum, Adel ; Mohammad, Anwar ; Palmer, Colin N.A. ; Lamont, Douglas ; Sakamoto, Kei ; Viollet, Benoit ; Foretz, Marc ; Lang, Chim C. ; Rena, Graham. / Amino acid homeostasis is a target of metformin therapy. In: Molecular Metabolism. 2023 ; Vol. 74.

Bibtex

@article{2cc1d075f5644ce6ac9e31edc39b5a1f,
title = "Amino acid homeostasis is a target of metformin therapy",
abstract = "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.",
keywords = "AMPK, Branched chain amino acids, Glutamine, Metformin, mTOR, Rapamycin, SNAT2",
author = "Calum Forteath and Ify Mordi and Raid Nisr and Gutierrez-Lara, {Erika J.} and Noor Alqurashi and Phair, {Iain R.} and Cameron, {Amy R.} and Craig Beall and Ibrahim Bahr and Mohapradeep Mohan and Wong, {Aaron K.F.} and Adel Dihoum and Anwar Mohammad and Palmer, {Colin N.A.} and Douglas Lamont and Kei Sakamoto and Benoit Viollet and Marc Foretz and Lang, {Chim C.} and Graham Rena",
note = "Publisher Copyright: {\textcopyright} 2023 The Authors",
year = "2023",
doi = "10.1016/j.molmet.2023.101750",
language = "English",
volume = "74",
journal = "Molecular Metabolism",
issn = "2212-8778",
publisher = "Elsevier",

}

RIS

TY - JOUR

T1 - Amino acid homeostasis is a target of metformin therapy

AU - Forteath, Calum

AU - Mordi, Ify

AU - Nisr, Raid

AU - Gutierrez-Lara, Erika J.

AU - Alqurashi, Noor

AU - Phair, Iain R.

AU - Cameron, Amy R.

AU - Beall, Craig

AU - Bahr, Ibrahim

AU - Mohan, Mohapradeep

AU - Wong, Aaron K.F.

AU - Dihoum, Adel

AU - Mohammad, Anwar

AU - Palmer, Colin N.A.

AU - Lamont, Douglas

AU - Sakamoto, Kei

AU - Viollet, Benoit

AU - Foretz, Marc

AU - Lang, Chim C.

AU - Rena, Graham

N1 - Publisher Copyright: © 2023 The Authors

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - AMPK

KW - Branched chain amino acids

KW - Glutamine

KW - Metformin

KW - mTOR

KW - Rapamycin

KW - SNAT2

U2 - 10.1016/j.molmet.2023.101750

DO - 10.1016/j.molmet.2023.101750

M3 - Journal article

C2 - 37302544

AN - SCOPUS:85163929062

VL - 74

JO - Molecular Metabolism

JF - Molecular Metabolism

SN - 2212-8778

M1 - 101750

ER -

ID: 360606673