Metabolic Dysfunction and Cognitive Decline in a Rat Model of Type 2 Diabetes

Background Diabetes Mellitus (DM) comprises a group of metabolic disorders. Type 2 DM (T2DM), strongly associated with obesity and dietary habits, represents a major global health challenge. Cognitive impairment is a recognized complication of poorly controlled DM; however, its underlying mechanisms remain incompletely understood. This study aimed to investigate T2DM-induced cognitive dysfunction using a rat model that closely mimics human T2DM. Methods Forty-eight male and female Sprague–Dawley rats were allocated into two groups: high-fat diet (HFD) group combined with low-dose streptozotocin (STZ) and a regular diet (RD) control group. The two groups further stratified into four groups according to sex. HFD rats received a diet rich in fat and fructose water for 21 weeks, followed by an intraperitoneal STZ injection (40 mg/kg). Body weight and metabolic parameters, including fasting blood glucose (FBG), fasting insulin (FI), and insulin resistance (HOMA2-IR), were assessed. Behavioral tests were performed after 15 weeks to evaluate cognitive and related functions. At the end of the experiment, hippocampal and serum levels of oxidative stress and neurodegeneration markers (Brain derived neurotrophic factor (BDNF), Neurotrophin-3 (NT-3), β-amyloid, Matrix metaloprotenase 9 (MMP9), Phosphorylated tau (P-tau) and Advanced glycation end products (AGEs) were analyzed. Results Results demonstrated that HFD significantly increased body weight ( p < 0.0001), FBG ( p < 0.0001), and insulin resistance ( p < 0.0001), accompanied by cognitive impairment as evidenced by behavioral testing (spatial learning and memory, p =0.0011). Biomarker analysis further supported the presence of hippocampal oxidative stress and neurodegenerative changes (BDNF, MMP9, P.tau, β-amyloid, p <0.05). Conclusion These findings highlight the detrimental impact of diet-induced metabolic dysfunction on cognitive health and provide insights into potential mechanisms linking T2DM and cognitive decline.