Insulin resistance in skeletal muscle is a key feature in the pathogenesis of
type 2 diabetes (T2D) that often manifests early in its development.
Pharmaceutical and dietary strategies have targeted
insulin resistance to control T2D, and many natural products with excellent pharmacological properties are good candidates for the control or prevention of T2D.
Dihydromyricetin (DHM) is a natural
flavonol which provides a wide range of health benefits including anti-inflammatory and anti-
tumor effects. However, little information is available regarding the effects of DHM on skeletal muscle
insulin sensitivity as well as the underlying mechanisms. In the present study, we found that DHM activated
insulin signaling and increased
glucose uptake in skeletal muscle in vitro and in vivo. The expression of light chain 3, the degradation of sequestosome 1, and the formation of autophagosomes were also upregulated by DHM. DHM-induced
insulin sensitivity improvement was significantly abolished in the presence of
3-methyladenine,
bafilomycin A1, or Atg5
siRNA in C2C12 myotubes. Furthermore, DHM increased the levels of phosphorylated
AMP-activated protein kinase (AMPK),
peroxisome proliferator-activated receptor coactivator-1α (PGC-1α), and
Sirt3 in skeletal muscle in vitro and in vivo. Autophagy was inhibited in the presence of
Sirt3 siRNA in C2C12 myotubes and in skeletal muscles from
Sirt3-/- mice. Additionally, PGC-1α or AMPK
siRNA transfection attenuated DHM-induced
Sirt3 expression, thereby abrogating DHM-induced autophagy in C2C12 myotubes. In conclusion, DHM improved skeletal muscle
insulin sensitivity by partially inducing autophagy via activation of the AMPK-PGC-1α-Sirt3 signaling pathway.