Neuroprotective and Cognitive Benefits of a Ketogenic Diet in a Type 2 Diabetes Rat Model

Diabetes mellitus is a widespread metabolic disease that also increases the risk of cognitive decline through mechanisms such as oxidative stress, inflammation, and vascular damage. Recently, the ketogenic diet has attracted attention as a nutritional approach that may improve glucose control and support cognitive health in diabetes. The present study evaluated the neuroprotective and behavioral effects of a ketogenic diet (KD) in a rat model of type 2 diabetes mellitus (T2DM). Adult male Wistar rats were assigned to four groups (n = 7 each): control (normal diet), KD, diabetic (high-fat diet + nicotinamide (60 mg/kg, ip) / streptozotocin (50 mg/kg, i.p)), and diabetic + KD. After eight weeks, we assessed anxiety-like and memory behaviors via the hole-board, elevated plus maze, and object recognition tests. Oxidative stress markers (malondialdehyde, MDA; glutathione, GSH) and neuroinflammatory mediators (S100β, TNF-α, IL-6) were quantified. Histopathological and immunohistochemical analyses of CA1, CA3, and dentate gyrus regions evaluated neuronal integrity and oxidative DNA damage (8-OHdG) and neurotrophic factor BDNF. KD alone induced ketosis and modest anxiety-like behaviors but preserved recognition memory. In diabetic rats, KD significantly reduced hyperglycemia and insulin (p < 0.001-0.01), ameliorated oxidative damage (p < 0.01), and partially normalized S100β, TNF-α, IL-6, and BDNF levels (p < 0.05). Behaviorally, KD attenuated diabetes-induced anxiety and improved cognitive difference score (p < 0.05). Histologically, KD mitigated diabetes-associated neuronal degeneration and reduced 8-OHdG immunopositivity. These findings indicate that KD confers neuroprotective benefits under diabetic conditions by modulating glycemic control, oxidative stress, inflammation, and neurotrophic support in the brain.