Consistent with these observations, Kalender et al [57] reported that in mouse embryonic fibroblasts metformin, an anti-diabetic drug that decreases mitochondrial oxidative phosphorylation, inhibits mTORC1 via Rag GTPases rather than via AMPK activation, and similar AMPK-independent effects were reported for low concentrations of metformin in pancreatic cancer cells [46]. This evidence concerns the gene PRKAA1 and familial pancreatic carcinoma.