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 placebocontrolled
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.
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 placebocontrolled
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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 101750 |
| Tidsskrift | Molecular Metabolism |
| Vol/bind | 74 |
| Antal sider | 16 |
| ISSN | 2212-8778 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:G.R. acknowledges The Diabetes UK R.W. and J.M. Collins studentship, which supported C.F., a further grant 19/0006045 from Diabetes UK supporting R.N., Medical Research Council grant MR/K012924 supporting A.C. and a grant PG/18/79/34106 from British Heart Foundation supporting I.P. E.G.L. and G.R. acknowledge the Academy of Medical Sciences for award of a Newton Fellowship to E.G.L. N.A. and A.D. are supported by scholarships from their governments. C.C.L. acknowledges support from the British Heart Foundation (grant number PG/06/143/21897 and PG/14/4/30539). A.K.F.W acknowledges support from the British Heart Foundation (grant number PG/06/143/21897). M.M. acknowledges support from the British Heart Foundation (grant number PG/14/4/30539). A.C. received awards from the Anonymous Trust and Society for Endocrinology. A.M. and G.R. acknowledge a grant from the Dasman Diabetes Institute. I.M. is supported by an NHS Education for Scotland/Chief Scientist Office Postdoctoral Clinical Lectureship (PCL 17/07). C.B. is supported by a Diabetes UK RD Lawrence Fellowship (13/004647). We thank Professor Ewan Pearson for comments on the manuscript and Professor George Baillie (Glasgow) and members of his lab for advice on cardiac myocyte preparation.
Funding Information:
G.R. acknowledges The Diabetes UK R.W. and J.M. Collins studentship, which supported C.F., a further grant 19/0006045 from Diabetes UK supporting R.N., Medical Research Council grant MR/K012924 supporting A.C. and a grant PG/18/79/34106 from British Heart Foundation supporting I.P. E.G.L. and G.R. acknowledge the Academy of Medical Sciences for award of a Newton Fellowship to E.G.L. N.A. and A.D. are supported by scholarships from their governments. C.C.L. acknowledges support from the British Heart Foundation (grant number PG/06/143/21897 and PG/14/4/30539 ). A.K.F.W acknowledges support from the British Heart Foundation (grant number PG/06/143/21897 ). M.M. acknowledges support from the British Heart Foundation (grant number PG/14/4/30539 ). A.C. received awards from the Anonymous Trust and Society for Endocrinology. A.M. and G.R. acknowledge a grant from the Dasman Diabetes Institute. I.M. is supported by an NHS Education for Scotland/Chief Scientist Office Postdoctoral Clinical Lectureship ( PCL 17/07 ). C.B. is supported by a Diabetes UK RD Lawrence Fellowship ( 13/004647 ). We thank Professor Ewan Pearson for comments on the manuscript and Professor George Baillie (Glasgow) and members of his lab for advice on cardiac myocyte preparation.
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