Environmental Enrichment and Metformin Improve Metabolic Functions, Hippocampal Neuron Survival, and Hippocampal-Dependent Memory in High-Fat/High-Sucrose Diet-Induced Type 2 Diabetic Rats

Abstract

Background: The Western-style diet-induced type 2 diabetes mellitus (T2D) may eventually trigger neurodegeneration and memory impairment. Thus, it is essential to identify effective therapeutic strategies to overcome T2D complications. This study aimed to investigate the effects of environmental enrichment (EE) and metformin interventions on metabolic dysfunctions, hippocampal neuronal death, and hippocampal-dependent memory impairments in high-fat/high-sucrose (HFS) diet-induced T2D rats. Methods: Thirty-two male rats (200–250 g) were divided into four groups: C group (standard diet + conventional cage); D group (HFS diet + conventional cage); DE group (HFS diet + EE cage/6hr daily); and DM group (HFS diet + metformin + conventional cage). Body weight was measured every week. T-maze tasks, anthropometric, biochemical, histological, and morphometric parameters were measured. The expression changes of hippocampal genes were also analyzed. Results: The anthropometric and biochemical parameters were improved in DE and DM groups compared with the D group. DE and DM groups had significantly higher T-maze percentages than the D group. These groups also had better histological and morphometric parameters than the D group. The interventions of EE and metformin enhanced the expression of hippocampal genes related to neurogenesis and synaptic plasticity (BDNF/TrkB binding, PI3K-Akt, Ras–MAPK, PLCγ–Ca2+, and LTP). Conclusion: Environmental enrichment (EE) and metformin improved metabolic functions, hippocampal neuron survival, and hippocampal-dependent memory in HFS diet-induced T2D rats. The underlying mechanisms of these interventions involved the expression of genes that regulate neurogenesis and synaptic plasticity.

Effect of Glycemic Control Using Different Antidiabetic Drugs on Cognitive Functions in Experimentally-Induced Type 2DM: A Comparative Study

“…Compared with Janumet group and Control group, there was a statistically significant decrease in serum insulin levels observed in Diabetic group. This finding was consistent with previous result (16,18) . In the current study, the decreased serum insulin levels observed in the Diabetic group may have been caused by the STZ administration.…”

“…Hippocampal tissue in Diabetic+Janumet group revealed apparent improvement in the thickness of layers and shape of cells but still showing very few shrunken pyramidal cells in CA1 and CA3 and also the granular layer of dentate gyrus restored its normal structure. These beneficial effects were consistent with other studies (1,16) .…”

“…. Diabetic patients may experience cognitive impairments as a result of cerebral vasculature complications or metabolic dysfunction (16) . Conversely, the results of our study indicated that Diabetic+ Janumet group exhibited a statistically significant increase in the proportion of spontaneous alternations in the Y-maze test and the duration of time spent in the target quadrant in the MWM test, respectively, compared with Diabetic group.…”

“…They were consistent with findings from another research (29) . By stimulating the formation of ROS via a multitude of cellular pathways including non-enzymatic glycation, aldose reductase and oxidative phosphorylation, hyperglycemia damages βcells and pancreatic tissue (16,29) . A heightened concentration of MDA in individuals diagnosed with diabetes suggests that peroxidative harm may contribute to the progression of diabetic complications.…”

“…The presence of uncontrolled hyperglycemia, dyslipidemia, inflammation, and oxidative stress can now be linked to the decline in learning and spatial memory in Diabetic group, as evidenced by the results of the MWM and Y-maze tests conducted in this research. Hyperglycemia is by far the most significant cause of cognitive impairment (16) . Accordingly, the improvement in the neurocognitive impairment in insulin-treated group and Janumet-treated group was attributed to their strong hypoglycemic effect.…”