Type 2 diabetes mellitus (T2DM) is a chronic
metabolic disease characterized by
hyperglycemia. The fruits of Zanthoxylum bungeanum Maxim. is a common spice and herbal medicine in China, and hydroxy-α-
sanshool (HAS) is the most abundant
amide in Z. bungeanum and reported to have significant
hypoglycemic effects. The purpose of this study was to evaluate the ameliorative effects of HAS on T2DM and the potential mechanisms responsible for those effects. An acute toxicity test revealed the median lethal dose (LD50) of HAS is 73 mg/kg. C57BL/6 J mice were fed a high-fat diet and given an
intraperitoneal injection of
streptozotocin (STZ) to induce T2DM in mice to evaluate the
hypoglycemic effects of HAS. The results showed that HAS significantly reduced fasting
blood glucose, reduced pathological changes in the liver and pancreas, and increased
liver glycogen content. In addition,
glucosamine (GlcN)-induced HepG2 cells were used to establish an
insulin resistance cell model and explore the molecular mechanisms of HAS activity. The results demonstrated that HAS significantly increases
glucose uptake and
glycogen synthesis in HepG2 cells and activates the PI3K/Akt pathway in GlcN-induced cells, as well as increases GSK-3β phosphorylation, suppresses phosphorylation of
glycogen synthase (GS) and increases
glycogen synthesis in liver cells. Furthermore, these effects of HAS were blocked by the PI3K inhibitor
LY294002. The results of our study suggest that HAS reduces hepatic
insulin resistance and increases
hepatic glycogen synthesis by activating the PI3K/Akt/GSK-3β/GS signaling pathway.