Understanding diabetic encephalopathy: a model-based approach to explore cognitive and motor impairments through glutamatergic dysregulation.

BACKGROUND

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder marked by persistent hyperglycemia that adversely affects multiple organ systems, including the central nervous system (CNS). Diabetic encephalopathy (DE), a serious neurological complication of T2DM, manifests as cognitive decline, motor dysfunction, and neurochemical imbalances. However, the lack of suitable animal models has hindered deeper insights into its pathogenesis. This study aimed to develop and validate a T2DM-induced DE model using nicotinamide (NA) and streptozotocin (STZ) to replicate chronic hyperglycemia and assess associated neurobehavioral and biochemical alterations.

METHODS AND RESULTS

Adult male Wistar rats were administered NA (120 mg/kg) followed by STZ (60 mg/kg) to induce T2DM. The model replicated key features of DE, including hyperglycemia, cognitive and motor impairments and neurochemical disruptions. Elevated HbA1c, insulin, AST, ALT, urea and uric acid levels, along with reduced AChE activity, highlighted metabolic and neurological effects. Behavioral tests, such as the Morris water maze and rotarod, confirmed impairments, while biochemical analyses emphasized glutamatergic dysregulation in the glucose-glutamate-NMDAR-cGMP pathway, affecting learning and memory processes like long-term potentiation (LTP) and depression (LTD).

CONCLUSIONS

This study presents a reliable T2DM-induced DE model that closely mimics clinical features of the disease, without relying on Alzheimer's-like pathology. The model highlights key roles of glutamatergic dysregulation, oxidative stress, and metabolic disturbances in DE progression. The findings align with evidence linking oxidative stress, neuroinflammation and impaired insulin signalling to DE progression. Recovery in the positive control group emphasizes the therapeutic potential of targeting these pathways.