Amino acid homeostasis is a target of metformin therapy

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.