Zanthoxylum alkylamides ameliorate protein metabolism in type 2 diabetes mellitus rats by regulating multiple signaling pathways.

Type 2 diabetes mellitus (T2DM) can easily induce insulin resistance (IR) in skeletal muscle, causing protein metabolism disorder and inflammation. The present study aimed to investigate whether Zanthoxylum alkylamides (ZA) could ameliorate T2DM through regulating protein metabolism disorder by using a rat model of T2DM. The predominant bioactive constituents found in ZA were hydroxyl-α-sanshool, hydroxyl-ß-sanshool and hydroxyl-γ-sanshool. The results showed that ZA improved a series of biochemical indices associated with protein metabolism and inflammation in T2DM rats. Our mechanistic finding indicated that ZA promoted protein anabolism in T2DM rats by up-regulating the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. ZA also promoted glucose transportation in skeletal muscle to ameliorate skeletal muscle IR and energy metabolism through regulating the AMP-activated protein kinase (AMPK) signaling pathway. Moreover, ZA inhibited protein degradation and improved protein catabolism disorder in T2DM rats by down-regulating the PI3K/Akt/forkhead box O (FoxO) signaling pathway, and ZA further ameliorated inflammation to inhibit protein catabolism via regulating the tumor necrosis factor α (TNF-α)/nuclear factor κB (NF-κB) pathway in the skeletal muscle of T2DM rats. Collectively, the ameliorating effect of ZA on protein metabolism disorder in T2DM rats was the common result of regulating multiple signaling pathways. ZA decreased skeletal muscle IR to promote protein anabolism and inhibit protein catabolism for improving protein metabolism disorder, thus ultimately ameliorating T2DM. In sum, our findings demonstrated that ZA treatment could effectively ameliorate T2DM through improving protein metabolism, providing a new treatment target for T2DM.