According to our study, although there were no significant differences found in the protein expression in the phosphorylation of AKT protein between HE mice and control mice, inhibited IRS-1/PI3K/AKT pathway and GLUT4 protein content were observed in the skeletal muscles of the HFD mice, and aerobic exercise reversed the inactivation of the pathway. This evidence concerns the gene IRS1 and hereditary elliptocytosis.