Figure 11. Proposed model of hyperglycemia's protumorigenic effects.

Under normal glucose levels or normoglycemia, glucose uptake and leptin/IGF1R signaling remain at relatively low basal levels. Under hyperglycemia, cells respond by increasing glucose uptake through GLUT receptors and this in turn activates metabolic pathways that not only respond to increased glucose levels but also have mitogenic effects on breast epithelial cells. Two key metabolic pathways that can have this effect include the leptin and IGF1R signaling pathways. Breast epithelial cells respond to increased glucose levels by increasing production of leptin and IGF1, which in turn increase the expression and activation of leptin and IGF1 receptors at the cell surface. Together, leptin and IGF1 act synergistically to enhance AKT/mTOR signaling leading to increased cell proliferation, in part, through modulation of PKC proteins and cell cycle-associated proteins.