Conclusion
DM, heart failure
HEART FAILURE, LVH, TYPE 2 DIABETES
In conclusion, we have used cell studies to provide evidence that the well-tolerated type 2 diabetes drug metformin inhibits mTOR signaling by a different mechanism than rapamycin, through suppressing BCAA and glutamine uptake. The inhibitory effect of metformin is mediated, at least in part, by suppression of amino acid transporters. Amino acid supplementation attenuates many cellular responses to metformin. We demonstrated that the effect of metformin on BCAA uptake is clinically significant, as in a large cohort of genotyped DM patients, metformin treatment attenuates the LVH risk genotype of KLF15, a transcriptional ‘master regulator’ of BCAA catabolism. Furthermore, we demonstrated a selective effect of metformin on BCAA and glutamine in a double-blind placebo-controlled trial of non-diabetic heart failure patients. We conclude that metformin modulates amino acids in cell models and in humans. Our findings support an unfolding strategy of investigating specific mechanisms to determine their utility in treating specific genotypes for metformin prescription 