Amino acid homeostasis is a target of metformin therapy.

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

Journal: Molecular metabolism 2023;74():101750

PMID: 37302544

Free Full Text on Elsevier Science View on PubMed

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.

Address: Division of Cellular and Systems Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, DD1 9SY, UK.; Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, DD1 9SY, UK.; Division of Cellular and Systems Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, DD1 9SY, UK; Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, RILD Building, Exeter, EX2 5DW, UK.; Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, RILD Building, Exeter, EX2 5DW, UK.; Division of Cellular and Systems Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, DD1 9SY, UK; Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, DD1 9SY, UK.; Public Health and Epidemiology Department, Dasman Diabetes Institute, Kuwait City, Kuwait.; Division of Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, DD1 9SY, UK.; Centre for Advanced Scientific Technologies, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, 2200, Denmark.; Université Paris Cité, CNRS, Inserm, Institut Cochin, Paris, 75014, France.; Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, DD1 9SY, UK. Electronic address: [email protected].; Division of Cellular and Systems Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, DD1 9SY, UK. Electronic address: [email protected].

DOI: 10.1016/j.molmet.2023.101750

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MeSH Terms: Humans, Metformin, Amino Acids, Branched-Chain, Amino Acids, Glucose, Homeostasis