The Beneficial Effect of <i>Lycium barbarum</i> Polysaccharides on Insulin Resistance and Hepatic Glucose Production in Diabetes

<i>Lycium barbarum</i> polysaccharides (LBP) displays some antidiabetic effects, but the mechanism is partial disclosure of its preventive activities related to insulin signaling and hepatic glucose metabolism. This study investigates the beneficial effect of LBP on insulin resistance and hepatic glucose production (HGP) in 30 mM glucose induced insulin resistant HepG2 cells (IR-HepG2) and high fat diet/streptozotocin induced diabetic mice. Additionally, the subacute toxicity of 14-day-administration of LBP was assessed in C57BL/6 mice. The results showed that LBP effectively reverted the inhibition of protein kinase B (AKT) and glycogen synthase 3 (GSK3) phosphorylation and countered the elevation of reactive oxygen species (ROS) in IR-HepG2 triggered by 30 mM glucose. Furthermore, LBP prevented the decline of glucose transporter isoform 2 (GLUT2) level in the diabetic mice liver and restored reduced glucose consumption and uptake in IR-HepG2. LBP also prevented the decrease in glycogen synthase (GYS2) mRNA expression and the reduction of liver glycogen content in diabetes mellitus (DM) mice. Moreover, LBP downregulated the expressions of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) to inhibit gluconeogenesis, while upregulated the expressions of glucokinase (GK), phosphofructokinase 1 (PFK1) and pyruvate kinase (PK) to activate glycolysis via the AMP-activated protein kinase (AMPK) signaling pathway in DM mice. No observed toxicity was found in both HepG2 cells and C57BL/6 mice under the tested conditions and doses. These findings suggest that LBP improves insulin sensitivity in high glucose induced IR-HepG2 and reduces HGP by regulating glucose uptake, glycogen synthesis and gluconeogenic/glycolytic flux. It may serve as a potential therapeutic approach for diabetes treatment.