The Goto-Kakizaki (GK) rat is a model of spontaneously developing non-obese type 2 diabetes mellitus (T2DM). With age, GK rats exhibit insulin resistance, decreased pancreatic function, and hyperglycemia. Studies have shown that GK rats experience cognitive impairment concurrent with hyperglycemia, but the mechanisms is unclear. In this study, we aimed to elucidate the potential link between hyperglycemia and cognitive impairment in this unique T2DM model. Longitudinal assessments of fasting blood glucose (FBG) were performed in male GK rats and age-matched Wistar rats. Our results showed that FBG in GK group was significantly higher than that in the Wistar group starting from 6 weeks of age, and there was progressive fasting hyperglycemia in GK group. In the spatial probe test of Morris water maze (MWM) at 33 weeks old, the GK rats spent less time in the target quadrant (12.16 ± 2.18s vs. 22.17 ± 1.21, P<0.001) and took more time to reach the location of the formerly hidden platform (36.78 ± 6.141 vs. 6.422 ± 0.8783s, P<0.001) than Wistar rats, suggesting that GK rats showed spatial memory deficits. In mechanistic studies, insulin receptors (IR) and synaptic proteins were down-regulated and impaired insulin signaling pathways in the hippocampus of GK rats (Figure), suggesting impaired neuroplasticity and neuropathological processes may lead to cognitive dysfunction.


L. Chen: Board Member; Hua Medicine. J. Ni: None. L. Feng: Employee; Hua Medicine. X. Zhang: None. Q. Wang: None. Y. Chen: Stock/Shareholder; Silaiputai (Shanghai) Biopharmaceutical Company.


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