Amino acid homeostasis is a target of metformin therapy
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 a...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-08-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877823000844 |
| _version_ | 1827900150845014016 |
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| author | 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 Kei Sakamoto Benoit Viollet Marc Foretz Chim C. Lang Graham Rena |
| author_facet | 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 Kei Sakamoto Benoit Viollet Marc Foretz Chim C. Lang Graham Rena |
| author_sort | Calum Forteath |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T23:27:08Z |
| format | Article |
| id | doaj.art-6034f1d72e63418cb69e689338644a8d |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-03-12T23:27:08Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-6034f1d72e63418cb69e689338644a8d2023-07-16T04:18:28ZengElsevierMolecular Metabolism2212-87782023-08-0174101750Amino acid homeostasis is a target of metformin therapyCalum Forteath0Ify Mordi1Raid Nisr2Erika J. Gutierrez-Lara3Noor Alqurashi4Iain R. Phair5Amy R. Cameron6Craig Beall7Ibrahim Bahr8Mohapradeep Mohan9Aaron K.F. Wong10Adel Dihoum11Anwar Mohammad12Colin N.A. Palmer13Douglas Lamont14Kei Sakamoto15Benoit Viollet16Marc Foretz17Chim C. Lang18Graham Rena19Division of Cellular and Systems Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, DD1 9SY, UKDivision of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, DD1 9SY, UKDivision of Cellular and Systems Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, DD1 9SY, UKDivision of Cellular and Systems Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, DD1 9SY, UKDivision of Cellular and Systems Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, DD1 9SY, UKDivision of Cellular and Systems Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, DD1 9SY, UKDivision 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, UKDepartment of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, RILD Building, Exeter, EX2 5DW, UKDivision of Cellular and Systems Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, DD1 9SY, UKDivision of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, DD1 9SY, UKDivision of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, DD1 9SY, UKDivision 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, UKPublic Health and Epidemiology Department, Dasman Diabetes Institute, Kuwait City, KuwaitDivision of Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, DD1 9SY, UKCentre for Advanced Scientific Technologies, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UKNovo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, 2200, DenmarkUniversité Paris Cité, CNRS, Inserm, Institut Cochin, Paris, 75014, FranceUniversité Paris Cité, CNRS, Inserm, Institut Cochin, Paris, 75014, FranceDivision of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, DD1 9SY, UK; Corresponding author. Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, UK. DD1 9SY.Division of Cellular and Systems Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, DD1 9SY, UK; Corresponding author. Division of Cellular and Systems Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, UK. DD1 9SY.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.http://www.sciencedirect.com/science/article/pii/S2212877823000844MetforminBranched chain amino acidsmTORSNAT2GlutamineRapamycin |
| spellingShingle | 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 Kei Sakamoto Benoit Viollet Marc Foretz Chim C. Lang Graham Rena Amino acid homeostasis is a target of metformin therapy Molecular Metabolism Metformin Branched chain amino acids mTOR SNAT2 Glutamine Rapamycin |
| title | Amino acid homeostasis is a target of metformin therapy |
| title_full | Amino acid homeostasis is a target of metformin therapy |
| title_fullStr | Amino acid homeostasis is a target of metformin therapy |
| title_full_unstemmed | Amino acid homeostasis is a target of metformin therapy |
| title_short | Amino acid homeostasis is a target of metformin therapy |
| title_sort | amino acid homeostasis is a target of metformin therapy |
| topic | Metformin Branched chain amino acids mTOR SNAT2 Glutamine Rapamycin |
| url | http://www.sciencedirect.com/science/article/pii/S2212877823000844 |
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