Cognitive impairment and hippocampal degeneration in aged rat models of type 2 diabetes with induced glycemic fluctuation: A pilot study.

Objective: Effective methods for establishing an aged animal model of diabetes and glycemic fluctuation have rarely been investigated. The aim of the study was to explore the feasibility of inducing glycemic fluctuation in aged Sprague-Dawley rats and to evaluate the corresponding changes in cognitive function.

Methods: Male rats aged 48 weeks were fed a high-fat and high-glucose diet and given streptozotocin intraperitoneally to establish a rat model of type 2 diabetes mellitus (T2DM). Then, glycemic fluctuation was induced via three different protocols: (1) intraperitoneal injection of glucose; (2) sequential fasting, insulin injection, and normal diet; and (3) intermittent intraperitoneal injections of glucose and insulin.

Results: All three protocols were effective at inducing glycemic fluctuation in aged rats with T2DM, with successful modeling rates of 60 %, 90 %, and 70 %, respectively. Aged T2DM rats with glycemic fluctuation showed significant increases in glycemic variability compared with controls, including in the mean blood glucose, postprandial glycemic excursion, largest amplitude of glycemic excursion, and standard deviation of blood glucose values (all P < 0.05). Additionally, rats with glycemic fluctuation had more severe insulin resistance and dyslipidemia (P < 0.05). Morris water maze testing showed a trend of longer escape latency in the navigation test for rats in the glycemic fluctuation groups, suggesting impaired cognitive function. Pathological analysis showed degenerative changes in the CA1 hippocampal region of rats in the glycemic fluctuation groups. Finally, differential gene expression analysis revealed 1323 significantly altered genes in the GV group, with 691 upregulated and 632 downregulated. The dysregulated genes were predominantly associated with the axon guidance pathway and potassium channel regulation.

Conclusions: The proposed protocols were effective at establishing an aged T2DM rat model with glycemic fluctuation, and rats with glycemic fluctuation exhibited diminished cognitive function.