Linagliptin attenuates the adverse effects of a high-sugar diet on insulin sensitivity, hippocampal oxidative stress, and cognitive function in rats.

Abstract

INTRODUCTION: Diabetes mellitus (DM) is a global metabolic disorder, with type 2 diabetes mellitus (T2DM) being the most prevalent form. Recent research suggests that excessive sugar intake contributes to cognitive impairments, metabolic abnormalities, and neurodegenerative diseases through oxidative stress and inflammation. The hippocampus, crucial for memory and learning, is highly susceptible to oxidative damage. Linagliptin, a DPP-4 inhibitor, is known for its anti-diabetic properties, yet its potential neuroprotective effects remain unclear. This study investigates whether Linagliptin can mitigate hippocampal oxidative stress and cognitive dysfunction induced by a high-sugar diet (HSD). METHODS: Male Wistar rats were divided into four groups: normal, normal-treated, diabetic, and diabetic-treated. Diabetes was induced via a 35 % sugar-water solution and a single streptozotocin (STZ) injection. Treated groups received oral Linagliptin (5 mg/kg/day) for eight weeks. Blood samples were analyzed for glucose, insulin, and oxidative stress markers. Hippocampal tissues were examined for oxidative stress biomarkers. Cognitive and anxiety-related behaviors were assessed using the Morris Water Maze (MWM), Elevated Plus Maze (EPM), and Buried Food Test. RESULTS: HSD increased fasting blood glucose, insulin resistance, and oxidative stress, impairing cognitive performance. Diabetic rats showed elevated HOMA-IR levels, decreased antioxidant enzyme activities (SOD, CAT, GLT), and increased malondialdehyde (MDA) levels in hippocampus, indicating oxidative stress. Behavioral tests revealed heightened anxiety and reduced memory function. Linagliptin treatment significantly improved glucose metabolism, reduced oxidative stress, and enhanced cognitive performance. CONCLUSION: In a rat model of type 2 diabetes induced by a high-sugar diet combined with streptozotocin injection, excessive sugar intake induces hippocampal oxidative stress and cognitive decline. Linagliptin effectively improves metabolic and cognitive outcomes by reducing oxidative damage and enhancing insulin sensitivity. These findings suggest a potential neuroprotective role for Linagliptin beyond glycemic control, warranting further investigation into its long-term effects.