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.