Effects of liraglutide and insulin on hippocampal-dependent memory and neurodegeneration in diabetes-related cognitive decline in rats

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by impaired regulation of blood glucose and hyperglycaemia. In Type 2 DM (T2DM), insulin resistance reduces cellular responsiveness to insulin, limiting glucose uptake and adversely affecting synaptic function, memory, and cognitive processes. Increasing evidence suggests that insulin plays a role in synapse formation and may slow cognitive decline. Notably, disruptions in insulin signalling observed in T2DM share similarities with mechanisms implicated in Alzheimer’s disease, indicating a potential pathological link between the two conditions. Glucagon-like peptide-1 (GLP-1) receptor agonists are widely used in T2DM treatment due to their ability to enhance insulin sensitivity. Liraglutide, a long-acting GLP-1 receptor agonist, has attracted attention not only for its peripheral metabolic effects but also for its capacity to cross the blood–brain barrier, suggesting potential neuroprotective properties. Furthermore, combining insulin with other antidiabetic agents may provide greater benefits on cognitive function than monotherapy, potentially mitigating diabetes-related cognitive impairment more effectively.

This study aimed to evaluate the potential protective and therapeutic effects of liraglutide and a liraglutide–insulin combination on cognitive dysfunction associated with T2DM using an experimental rat model. The study also investigated the effects of these treatments on glycaemic control and cognitive performance in a T2DM model.

T2DM was induced in rats using a high-fat diet followed by low-dose streptozotocin administration. Animals were divided into experimental groups receiving liraglutide, insulin, a liraglutide–insulin combination, or control treatments. Blood glucose levels were measured to assess metabolic control. Cognitive performance was evaluated using the Novel Object Recognition Test (NORT) and the Passive Avoidance Test (PAT). Additionally, brain tissues were subjected to histological analysis to examine neurodegenerative changes. All experimental procedures were conducted at the Marmara University Experimental Animals Application and Research Center, following approval from the Marmara University Animal Experiments Local Ethics Committee (approval no: 4.2025mar5).

Diabetic control rats exhibited significantly elevated fasting blood glucose levels compared to the non-diabetic control group (p<0.001). Treatment with liraglutide resulted in a significant reduction in blood glucose levels (p<0.01), while the liraglutide–insulin combination produced a more pronounced decrease (p<0.001), indicating improved glycaemic control. In cognitive assessments, diabetic rats showed a significant impairment in both NORT and PAT performances (p<0.01). Liraglutide treatment significantly improved recognition index and latency times compared to untreated diabetic rats (p<0.05). Notably, the combination therapy demonstrated greater improvements in both tests (p<0.01vs. diabetic control), suggesting enhanced cognitive recovery. Histological analyses supported the behavioural findings. In the diabetic group, marked neuronal degeneration, reduced neuronal density, and structural disorganization were observed in both the cerebral cortex and hippocampus. Liraglutide-treated rats showed partial preservation of neuronal architecture, with reduced signs of degeneration. The combination treatment group exhibited significantly improved histological outcomes, including increased neuronal density, better-preserved cortical layering, and reduced neuronal damage in hippocampal regions. In conclusion, liraglutide, particularly in combination with insulin, may represent a promising therapeutic strategy for preventing or alleviating cognitive impairment associated with T2DM.

This study was supported by TÜBİTAK (2209-A, 2024/1, No:1919B012471212). The authors also acknowledge TÜBİTAK 2224-A for supporting conference attendance.

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