Figure 2.

T2DM and CVD: AMPK–SIRT1 signaling cascade. AMPK, the main mediator of CR action, synergically acts with SIRT1. AMPK actives SIRT1, increasing NAD⁽⁺⁾levels, while SIRT1 promotes AMPK activity by Liver Kinase B1 (LKB1). AMPK/SIRT1 regulating the eNOS/NOX ratio increases NO bioavailability and mitigates endothelial dysfunction. Moreover, AMPK and SIRT1 activated PGC-1α, which is the primary factor involved in mitochondrial biogenesis. Then, AMPK/SIRT1/PGC-1α activation counteracts oxidative condition. PPARs are other common targets of SIRT1/AMPK: PPARα activation is related to inflammation, PPARγ, interacting with PGC-1α, improves adipose tissue plasticity and adipose browning tissue. Finally, PPARδ upregulation improves glucose metabolism in skeletal muscle.