Activation of the AMPK/Sirt1 pathway by a leucine–metformin combination increases insulin sensitivity in skeletal muscle, and stimulates glucose and lipid metabolism and increases life span in Caenorhabditis elegans

Background We have previously shown leucine (Leu) to activate Sirt1 by lowering its KM for NAD+, thereby amplifying the effects of other sirtuin activators and improving insulin sensitivity. Metformin (Met) converges on this pathway both indirectly (via AMPK) and by direct activation of Sirt1, and we recently found Leu to synergize with Met to improve insulin sensitivity and glycemic control while achieving ~ 80% dose-reduction in diet-induced obese mice. Accordingly, we sought here to define the mechanism of this interaction. Methods Muscle cells C2C12 and liver cells HepG2 were used to test the effect of Met–Leu on Sirt1 activation. Caenorhabditis elegans was used for glucose utilization and life span studies. Results Leu (0.5 mmol/L) + Met (50–100 μmol/L) synergistically activated Sirt1 (p Conclusion Thus, Leu and Met synergize to enable Sirt1 activation at low NAD+ concentrations (typical of energy replete states). Sirt1 and AMPK activations are required for Met–Leu's full action, which result in improvements in energy metabolism and insulin sensitivity.