The glucose transport proteins (GLUT1 and GLUT4) facilitate glucose transport into insulin-sensitive cells. GLUT1 is insulin-independent and is widely distributed in different tissues. GLUT4 is insulin-dependent and is responsible for the majority of glucose transport into muscle and adipose cells in anabolic conditions. We suggest the hypothesis that insulin resistance is dependent on whether glucose is entering through GLUT1 or GLUT4 and on the two functional compartments of glucose 6-phosphate formation within the cell. Glucose entering the muscle cell through GLUT4 and phosphorylated by hexokinase II is mainly directed to glycogen synthesis and glycolysis. If glucose is entering through GLUT1 and phosphorylated by hexokinase I, the glucose 6-phosphate so formed is available for all metabolic pathways, including the hexosamine pathway. Hexosamines have a negative feedback effect on GLUT4, and reduced GLUT4 activity decreases insulin-mediated glucose uptake. Thus, insulin-independent glucose transport through GLUT1 can meet the basal needs of the muscle cell. If glucose entrance through GLUT1 and the activation of the hexosamine pathway is abundant, it can decrease the insulin-mediated glucose transport through GLUT4 leading to insulin resistance.