Impaired brain glucose metabolism has been singled out as an important contributor and possibly main trigger to the development of Alzheimer’s disease. Intracerebroventricular injections of streptozotocin (icv-STZ) precisely cause brain glucose hypometabolism without systemic diabetes and are a valuable tool for evaluating ensuing neurodegeneration. Here, a first-time comprehensive longitudinal study of brain glucose metabolism, functional connectivity and white matter microstructure was performed in icv-STZ rats using FDG-PET, resting-state fMRI and diffusion MRI, respectively. STZ rats displayed altered functional connectivity and white matter degeneration in brain regions typically involved in AD, in a temporal pattern of acute injury, transient recovery and chronic degeneration, which did not match the temporal pattern of glucose hypometabolism. This finding supports the hypothesis that a compensatory mechanism, possibly recruiting ketone bodies, can restore normal brain structure and function up to a certain level of pathological severity. This study further highlights the dynamics of how brain insulin resistance affects structure and function and identifies potent MRI-derived biomarkers to track neurodegeneration in human AD and diabetic populations.