Abstract: This study aimed to evaluate the effects of mussel polysaccharides on glucose metabolism in insulin resistance HepG2 cells. Using the mussel polysaccharide (MP) as the research material, the CCK8 method was used to detect the proliferation of HepG2 cells, and different concentrations of insulin were screened to construct a cellular insulin resistance model to detect the effect of mussel polysaccharide on glucose consumption of insulin-resistant HepG2 cells. The results showed that when the insulin concentration was 10⁻⁶ mol/L, the glucose content of HepG2 cells was the highest and the ability to consume glucose was the weakest, and it was the best concentration for constructing the insulin resistance model. MP (100-1000 μg/mL) were non-toxic to HepG2 cells, could promote cell proliferation. Compared with IR-HepG2 cells, 200, 400 and 600 μg/mL of MP significantly elevated glycogen content by 17.20%, 22.95% and 32.50%, respectively. Meanwhile, high-dose MP significantly up-regulated the relative gene expression of PI3K and GLUT2, decreased the expression of GSK-3β. It provides an experimental basis for the subsequent hypoglycemia of MP, and also helps to promote the exploitation and potential application of MP.