Lactucin enhances glucose uptake and glycolysis in C2C12 myotubes by activating AMPK signaling pathway

Lactucin is a sesquiterpenoid from the well-known traditional Chinese medicine Cichorium intybus L. The antidiabetic effect of lactucin and its underlying mechanism remain unclear. Using fluorescence-labelled glucose analogue, we found that lactucin dose-dependently increased glucose uptake through upregulating expression and membrane translocation of GLUT4 in C2C12 myotubes. These effects were mediated by AMP-activated protein kinase (AMPK) activation, which was abolished by the co-treatment of Compound C or Ampkα1 silencing. Furthermore, lactucin induced a controlled suppression of mitochondrial function, as evidenced by decreased mitochondrial membrane potential and ATP levels, thereby mimicking cellular energy stress to activate AMPK. The metabolic reprogramming subsequently enhanced glycolysis and reduced intracellular lipid accumulation in C2C12 myotubes. Taken together, lactucin induces a controlled mitochondrial suppression and mimics exercise-like energy stress, which in turn enhances glucose uptake in C2C12 myotubes. We firstly uncover the metabolic reprogramming effect of lactucin, suggesting its potential as an antidiabetic agent.