Hyperglycemia associated brain dysfunction: rodent models for studying diabetic cognitive deficits

Diabetes and chronic hyperglycemia exert a profound impact on the central nervous system, significantly increasing the risk of cognitive impairment and neurodegenerative disease. This neurological decline is driven by a complex interplay of molecular and cellular mechanisms, including dysregulated insulin signaling, impaired cerebral glucose metabolism, excitotoxic glutamate accumulation, oxidative stress, and neuroinflammation. Collectively, these metabolic stressors compromise synaptic integrity and plasticity, promoting pathological hallmarks such as amyloid-beta accumulation, tau hyperphosphorylation, and neuronal atrophy. Structural and functional abnormalities are particularly prevalent in the hippocampus and prefrontal cortex, regions essential for learning and memory. Researchers utilize a diverse array of rodent model systems, including chemically induced, diet-induced, genetic, and autoimmune models, to study specific disease facets. No single model, however, perfectly replicates the complexity of human diabetes; instead, models vary in their face, construct, and predictive validity. While some systems offer high translational relevance, others provide superior mechanistic clarity. Consequently, the strategic selection of animal models is crucial for accurately characterizing diabetes-associated neurological dysfunction and facilitating the translation of preclinical findings into effective human clinical interventions. In this review we discuss the major diabetic rodent models and synthesize the current evidence linking diabetes and hyperglycemia to neurological dysfunction in the context of the rodent model(s) best suited for investigating specific impairments. Understanding how metabolic disease influences neuronal and molecular pathways that are critical for cognition and being able to study them in a translational model is essential for identifying early therapeutic targets and reducing the growing neurological burden of diabetes.