Proposed pathways for G6P metabolism in wild-type and G6pc3^−/− macrophages. Glucose transported into the cytoplasm by GLUT1 and GLUT3 is metabolized by hexokinase (HK) to G6P which can participate in glycolysis, hexose monophosphate shunt (HMS) pathway, glycogen synthesis, or be translocated into the lumen of the ER by the G6PT. In normal macrophages, G6P localized within the ER lumen can be hydrolyzed by G6Pase-β, and the resulting glucose transported back into the cytoplasm to reenter any of the previously mentioned cytoplasmic pathways. However, in G6pc3^−/− macrophages, which lack a functional G6Pase-β, ER-localized G6P cannot be recycled to the cytoplasm. Consequently, G6pc3^−/− macrophages exhibit reduced glucose uptake and impaired energy homeostasis, leading to impaired functionality. The GLUT1 and GLUT3 transporters, responsible for the transport of glucose in and out of the cell, is shown embedded in the plasma membrane. The G6PT transporter, responsible for the transport of G6P into the ER, and G6Pase-β, responsible for hydrolyzing G6P to glucose and phosphate, are shown embedded in the ER membrane.