Metformin suppresses leucine uptake in hepatocytes reversibly, by reducing the availability of functional SNAT2
In additional cell signalling studies we established that metformin but not rapamycin-dependent inhibition of mTOR could be attenuated by increasing leucine supplementation. The relevance of the reversibility of the metformin effect to cell outputs was first confirmed using a colony formation assay in soft agar [We found no evidence for metformin acting directly on amino acid transporters but the effect of metformin was not additive with the inhibitor BCH, which does suppress leucine uptake directly. Together, these findings suggest that both drugs suppress system L amino acid transport but that metformin acts indirectly. Consistent with this, we found that system A transporter SNAT2 was the most strongly downregulated transporter gene we studied, with the leucine antiporter LAT1 and Na