In cognitively normal patients, mild hyperglycemia selectively decreases 18F-Fluorodeoxyglucose (FDG) uptake in the posterior brain, reproducing Alzheimer disease pattern, hampering the diagnostic accuracy of this widely used tool. This phenomenon might involve either a heterogeneous response of glucose metabolism or a different sensitivity to hyperglycemia-related redox stress. Indeed, previous studies reported a close link between FDG uptake and activation of a specific pentose phosphate pathway (PPP), triggered by hexose-6P-dehydrogenase (H6PD) and contributing to fuel NADPH-dependent antioxidant responses in the endoplasmic reticulum (ER). To clarify this issue, dynamic positron emission tomography was performed in 40 BALB/c mice four weeks after administration of saline (n = 17) or 150 mg/kg streptozotocin (n = 23, STZ). Imaging data were compared with biochemical and histological indexes of glucose metabolism and redox balance. Cortical FDG uptake was homogeneous in controls, while it was selectively decreased in the posterior brain of STZ mice. This difference was independent of the activity of enzymes regulating glycolysis and cytosolic PPP, while it was paralleled by a decreased H6PD catalytic function and enhanced indexes of oxidative damage. Thus, the relative decrease in FDG uptake of the posterior brain reflects a lower activation of ER-PPP in response to hyperglycemia-related redox stress in these areas.