The downregulated PI3K, AKT, and GLUT2 mRNA levels indicate that HSHF feeding could induce hepatic insulin resistance, while E. prolifera polysaccharide and its Zn(II) complex significantly decreased insulin resistance and improved glucose transport, thereby showing hypoglycemic activity, in which the modulatory effect of Zn(II) on insulin signaling is possibly associated with phosphorylation of the insulin receptor IRS-2, activation of protein kinase B (Akt) signaling pathway, and increase of GLUT-2 expression and translocation. The gene discussed is IRS2; the disease is Insulin resistance.