FOXO1 and Insulin resistance: In the liver, PI3K/Akt/mTOR represses FOXO1/PGC-1α to shift flux toward oxidation, while ANS rhythmicity prevents insulin resistance (Tsuneki et al., 2015; Liu et al., 2016), a circadian mechanism absent in metformin, as critiqued in the work of Kalsbeek et al. (2010) for hypothalamic clock dysregulation.