Mechanism for the synergistic effect of rapamycin and resveratrol on hyperinsulinemia may involve the activation of protein kinase B

Dear Editor, We read with great interest Leontiev et al.'s paper entitled 'Resveratrol potentiates rapamycin to prevent hyperinsulinemia and obesity in male mice on high-fat diet' recently published in Cell Death & Disease.1 Their finding that rapamycin and resveratrol have a synergistic effect is important for treating insulin resistance. They showed that rapamycin inhibited mammalian target of rapamycin (mTOR) activity, while resveratrol inhibited S6 kinase (S6K). We think that these compounds may exert their effects through activating protein kinase B (Akt), a key regulator of insulin sensitivity. Both the inhibition of mTOR by rapamycin and of S6K by resveratrol could result in the activation of Akt due to the release of feedback inhibition on the insulin receptor substrates (IRS), which are stimulators of Akt.