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Background <p>Cognitive impairment is a frequent but underrecognized complication of type 2 diabetes mellitus (T2DM), closely associated with hippocampal neuroinflammation, glial dysfunction, energy metabolism disruption, and tau hyperphosphorylation. Astrocyte polarization plays a pivotal role in these processes, yet its regulation and impact remain incompletely understood. This study aimed to investigate whether electroacupuncture (EA) alleviates cognitive dysfunction in T2DM rats by modulating astrocytic polarization and hippocampal energy metabolism via the Wnt/β-catenin signaling pathway.</p> Methods <p>T2DM was induced using a high-fat diet and streptozotocin (STZ) injection. Rats were divided into four groups: Control, Model, EA, and EA + DKK1 (Dickkopf-1, a Wnt/β-catenin inhibitor). EA was applied at Weiwanxiashu (EX-B3), Pishu (BL20), Zusanli (ST36), Yinlingquan (SP9), and Baihui (DU20) for 9&#xa0;weeks. Behavioral, molecular, and metabolic changes were assessed using the Morris Water Maze, Western blotting, quantitative PCR (qPCR), enzyme-linked immunosorbent assay (ELISA), immunostaining, and targeted metabolomics.</p> Results <p>EA improved spatial learning and memory, inhibited A1-type astrocyte marker C3, and enhanced A2-type marker S100A10. It also activated Wnt3a, p-GSK3β, nuclear β-catenin, and Ngn2, increased Glut1/Glut3 expression, restored ATP levels, and reduced glycolytic metabolite accumulation. Additionally, EA attenuated tau phosphorylation and neuronal injury. These effects were abolished by DKK1, confirming Wnt/β-catenin involvement.</p> Conclusions <p>EA ameliorates cognitive deficits in T2DM rats by regulating astrocyte polarization and improving hippocampal energy metabolism through activation of the Wnt/β-catenin signaling pathway. These findings suggest a promising non-pharmacological approach to treating diabetes-related cognitive impairment and highlight the role of astrocytic immunometabolism in diabetic neurodegeneration.</p>

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Electroacupuncture ameliorates cognitive dysfunction in T2DM rats by modulating astrocytic polarization and aberrant energy metabolism in the hippocampus via the Wnt/β-catenin pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月3日

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  • Xiaolu Li,
  • Rui Li,
  • Jiayi Lin,
  • Xiaoli Wu

摘要

Background

Cognitive impairment is a frequent but underrecognized complication of type 2 diabetes mellitus (T2DM), closely associated with hippocampal neuroinflammation, glial dysfunction, energy metabolism disruption, and tau hyperphosphorylation. Astrocyte polarization plays a pivotal role in these processes, yet its regulation and impact remain incompletely understood. This study aimed to investigate whether electroacupuncture (EA) alleviates cognitive dysfunction in T2DM rats by modulating astrocytic polarization and hippocampal energy metabolism via the Wnt/β-catenin signaling pathway.

Methods

T2DM was induced using a high-fat diet and streptozotocin (STZ) injection. Rats were divided into four groups: Control, Model, EA, and EA + DKK1 (Dickkopf-1, a Wnt/β-catenin inhibitor). EA was applied at Weiwanxiashu (EX-B3), Pishu (BL20), Zusanli (ST36), Yinlingquan (SP9), and Baihui (DU20) for 9 weeks. Behavioral, molecular, and metabolic changes were assessed using the Morris Water Maze, Western blotting, quantitative PCR (qPCR), enzyme-linked immunosorbent assay (ELISA), immunostaining, and targeted metabolomics.

Results

EA improved spatial learning and memory, inhibited A1-type astrocyte marker C3, and enhanced A2-type marker S100A10. It also activated Wnt3a, p-GSK3β, nuclear β-catenin, and Ngn2, increased Glut1/Glut3 expression, restored ATP levels, and reduced glycolytic metabolite accumulation. Additionally, EA attenuated tau phosphorylation and neuronal injury. These effects were abolished by DKK1, confirming Wnt/β-catenin involvement.

Conclusions

EA ameliorates cognitive deficits in T2DM rats by regulating astrocyte polarization and improving hippocampal energy metabolism through activation of the Wnt/β-catenin signaling pathway. These findings suggest a promising non-pharmacological approach to treating diabetes-related cognitive impairment and highlight the role of astrocytic immunometabolism in diabetic neurodegeneration.