Amino acid homeostasis is a target of metformin therapy

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 - Nisr, 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 - 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., a grant PG/18/79/34106 from British Heart Foundation supporting I.P., and a studentship from The Cunningham Trust supporting L.L.. 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). Copyright: © 2023 The Authors. Published by Elsevier GmbH.

PY - 2023/8

Y1 - 2023/8

N2 - Unexplained changes in regulation of branched chain amino acids (BCAA) during diabetes therapy with metformin have been known for years. Here we demonstrate that metformin restricts tertiary control of BCAA cellular uptake, contributing towards therapeutic actions of the drug. In cell studies, we observed diminished uptake of amino acids following metformin treatment of a variety of cell types. Supplementation of media with amino acids attenuated metformin effects, providing an explanation for discrepancies between effective doses in vivo and in vitro observed in most studies. Data-Independent Acquisition proteomics demonstrated that SNAT2 was the most strongly suppressed amino acid transporter in liver cells following metformin treatment, although other transporters were affected. 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. We conclude that modulation of amino acid homeostasis contributes to therapeutic actions of metformin.

AB - Unexplained changes in regulation of branched chain amino acids (BCAA) during diabetes therapy with metformin have been known for years. Here we demonstrate that metformin restricts tertiary control of BCAA cellular uptake, contributing towards therapeutic actions of the drug. In cell studies, we observed diminished uptake of amino acids following metformin treatment of a variety of cell types. Supplementation of media with amino acids attenuated metformin effects, providing an explanation for discrepancies between effective doses in vivo and in vitro observed in most studies. Data-Independent Acquisition proteomics demonstrated that SNAT2 was the most strongly suppressed amino acid transporter in liver cells following metformin treatment, although other transporters were affected. 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. We conclude that modulation of amino acid homeostasis contributes to therapeutic actions of metformin.

KW - metformin

KW - branched chain amino acids

KW - mTOR

KW - SNAT2

KW - glutamine

KW - rapamycin

KW - AMPK

UR - https://www.scopus.com/pages/publications/85163929062

U2 - 10.1016/j.molmet.2023.101750

DO - 10.1016/j.molmet.2023.101750

M3 - Article

C2 - 37302544

SN - 2212-8778

VL - 74

JO - Molecular Metabolism

JF - Molecular Metabolism

M1 - 101750

ER -