Neural Regeneration Research ›› 2021, Vol. 16 ›› Issue (12): 2465-2474.doi: 10.4103/1673-5374.313051

Previous Articles     Next Articles

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).

PDF

458

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

CLC Number: