中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2021, Vol. 16 ›› Issue (12): 2465-2474.doi: 10.4103/1673-5374.313051

• 原著:退行性病与再生 • 上一篇    下一篇

海马胰岛素抵抗与糖尿病诱发认知功能障碍中的Sirtuin 1信号通路

  

  • 出版日期:2021-12-15 发布日期:2021-05-15
  • 基金资助:

    国家自然科学基金项目（81874464）；湖南省自然科学基金项目（2019JJ50464）；湖南中医药大学中医药国内一级学科建设开放基金（2018ZYX46）

Hippocampal insulin resistance and the Sirtuin 1 signaling pathway in diabetes-induced cognitive dysfunction

Hui Yang1, 2, Lin Tang1, Zhan Qu3, Shi-Hui Lei1, Wei Li1, Yu-Hong Wang2, *   

  1. 1The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan Province, China; 2Science and Technology Innovation Center, Hunan University of Chinese Medicine, Changsha, Hunan Province, China; 3School of Nursing, Health Science Center, Xi’an Jiaotong University, Xi’an, Shaanxi Province, China
  • Online:2021-12-15 Published:2021-05-15
  • Contact: Yu-Hong Wang, PhD, wyh_107@163.com.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, No. 81874464 (to YHW); the Natural Science Foundation of Hunan Province of China, No. 2019JJ50464 (to HY), and the Open Fund of the Domestic First-class Discipline Construction Project of Chinese Medicine of Hunan University of Chinese Medicine, No. 2018ZYX46 (to HY).

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摘要：

在周围神经系统中，激活Sirtuin 1可改善胰岛素抵抗；而Sirtuin 1在中枢神经系统胰岛素抵抗的作用，尚不明了。此次实验以单次链脲佐菌素注射建立糖尿病大鼠模型。（1）8周后，Morris水迷宫和western blot检测证实，糖尿病模型大鼠出现学习和记忆缺陷，且海马中存在胰岛素抵抗，Sirtuin 1表达下调；（2）鼻腔给予胰岛素和胰岛素受体抑制剂S961，以研究胰岛素信号对Sirtuin 1的调控。结果显示胰岛素可改善糖尿病大鼠的认知功能，并增加海马中磷酸化胰岛素受体、磷酸化胰岛素受体底物1和Sirtuin 1的表达。而S961可加剧认知功能障碍，并降低海马中磷酸化胰岛素受体、磷酸化胰岛素受体底物1和Sirtuin 1的表达；（3）最后侧脑室注射Sirtuin 1的激活剂SRT2104和抑制剂Sirtinol。发现激活Sirtuin 1可上调糖尿病大鼠大脑海马中雷帕霉素受体复合物1、磷酸化环磷腺苷效应元件结合蛋白和脑源性神经营养因子的表达，同时海马树突长度和树突棘密度增加，而应用抑制剂Sirtinol对上述蛋白和树突形态的作用则与激动剂相反；（4）结果表明Sirtuin 1信号通路在糖尿病大鼠胰岛素抵抗诱导的认知功能障碍中起重要作用。研究于2018年11月经湖南中医药大学附属第一医院动物伦理委员会批准，批准号ZYFY201811207。

https://orcid.org/0000-0003-2285-6339 (Yu-Hong Wang)

关键词: 糖尿病, 认知功能, 海马, 胰岛素拮抗, sirtuin 1, 雷帕霉素受体复合物1, 脑源性神经营养因子, 树突结构

Abstract: In the peripheral nervous system, the activation of Sirtuin 1 can improve insulin resistance; however, the role played by Sirtuin 1 in the central nervous system remains unknown. In this study, rat models of diabetes mellitus were generated by a single injection of streptozotocin. At 8 weeks after streptozotocin injection, the Morris water maze test and western blot assays confirmed that the diabetic model rats had learning and memory deficits, insulin resistance, and Sirtuin 1 expression could be detected in the hippocampus. Insulin and the insulin receptor inhibitor S961 were intranasally administered to investigate the regulatory effects of insulin signaling on Sirtuin 1. The results showed that insulin administration improved the impaired cognitive function of diabetic model rats and increased the expression levels of phosphorylated insulin receptor, phosphorylated insulin receptor substrate 1, and Sirtuin 1 in the hippocampus. Conversely, S961 administration resulted in more severe cognitive dysfunction and reduced the expression levels of phosphorylated insulin receptor, phosphorylated insulin receptor substrate 1, and Sirtuin 1. The Sirtuin 1 activator SRT2104 and the inhibitor Sirtinol were injected into the lateral ventricle, which revealed that the activation of Sirtuin 1 increased the expression levels of target of rapamycin complex 1, phosphorylated cAMP-response element-binding protein, and brain-derived neurotrophic factor. Hippocampal dendritic length and spine density also increased in response to Sirtuin 1 activation. In contrast, Sirtinol decreased the expression levels of target of rapamycin complex 1, phosphorylated cAMP-response element-binding protein, and brain-derived neurotrophic factor and damaged the dendritic structure. These findings suggest that the Sirtuin 1 signaling pathway plays an important role in the development of insulin resistance-related cognitive deficits in diabetic rats. This study was approved by the Animal Ethics Welfare Committee of the First Affiliated Hospital of Hunan University of Chinese Medicine (approval No. ZYFY201811207) in November 2018. 

Key words: brain-derived neurotrophic factor, cognitive function, dendritic structure, diabetes, hippocampus, insulin resistance, Sirtuin 1, target of rapamycin complex 1

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