Diabetic encephalopathy (DE) is a severe complication of diabetes mellitus affecting the central nervous system (CNS), characterized by cognitive dysfunction. This review systematically explores how the interplay between brain insulin resistance (BIR) and neuroinflammation contributes to the pathogenesis of DE. BIR refers to the diminished responsiveness of the CNS to insulin signaling, resulting in the suppression of the PI3K/Akt and MAPK pathways, impaired glucose metabolism, and dysfunction across multiple neural cell types—including neurons, astrocytes, microglia, brain endothelial cells, and oligodendrocytes. These disturbances manifest as impaired energy metabolism, compromised synaptic plasticity, disruption of the blood–brain barrier, and reduced myelination. Importantly, BIR and neuroinflammation form a vicious cycle within these cells, mutually exacerbating each other and jointly driving the pathological progression of DE. Finally, we have compiled a list of currently available drugs that can improve BIR and suppress neuroinflammation, along with the latest progress in clinical trials, to provide new insights for the future of precision treatment for DE.

Ischemia–reperfusion injury (IRI) is a prevalent pathological process in clinical settings characterized by complex pathogenesis involving the interplay of oxidative stress, inflammation, mitochondrial dysfunction, and diverse cell death pathways. Fundamentally, IRI manifests as a complication arising from reperfusion therapies aimed at restoring blood flow following ischemia. Despite the existence of various therapeutic strategies, the development of effective interventions for IRI remains a significant challenge. Rutin, a low-molecular-weight flavonoid glycoside ubiquitously present in vegetables, fruits, and herbal medicines, exhibits promising therapeutic potential due to its pleiotropic biological activities, including antioxidant, anti-inflammatory, and cytoprotective effects against cell death. This review systematically elucidates the molecular mechanisms underlying the protective effects of rutin against IRI and synthesizes evidence from preclinical studies regarding its diverse modes of action. However, the clinical application of rutin is currently hampered by its relatively low bioavailability. Future research should prioritize the development of innovative pharmaceutical formulations to enhance its bioavailability, thereby fully unlocking its clinical translational value.