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      Cognitive deficits and Alzheimer-like neuropathological impairments during adolescence in a rat model of type 2 diabetes mellitus

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          Numerous studies have shown that many patients who suffer from type 2 diabetes mellitus exhibit cognitive dysfunction and neuronal synaptic impairments. Therefore, growing evidence suggests that type 2 diabetes mellitus has a close relationship with occurrence and progression of neurodegeneration and neural impairment in Alzheimer's disease. However, the relationship between metabolic disorders caused by type 2 diabetes mellitus and neurodegeneration and neural impairments in Alzheimer's disease is still not fully determined. Thus, in this study, we replicated a type 2 diabetic animal model by subcutaneous injection of newborn Sprague-Dawley rats with monosodium glutamate during the neonatal period. At 3 months old, the Barnes maze assay was performed to evaluate spatial memory function. Microelectrodes were used to measure electrophysiological function in the hippocampal CA1 region. Western blot assay was used to determine expression levels of glutamate ionotropic receptor NMDA type subunit 2A (GluN2A) and GluN2B in the hippocampus. Enzyme-linked immunosorbent assay was used to determine levels of interleukin-1β, tumor necrosis factor α, and interleukin-6 in the hippocampus and cerebral cortex, as well as hippocampal amyloid beta (Aβ) 1–40 and Aβ 1–42 levels. Our results showed that in the rat model of type 2 diabetes mellitus caused by monosodium glutamate exposure during the neonatal period, latency was prolonged and the number of errors increased in the Barnes maze. Further, latency was increased and time in the escape platform quadrant shortened. Number of times crossing the platform was also reduced in the Morris water maze. After high frequency stimulation of the hippocampus, synaptic transmission was inhibited, expression of GluN2A and GluN2B were decreased in the hippocampus, expression of interleukin 1β, interleukin 6, and tumor necrosis factor α was increased in the hippocampus and cortex, and levels of Aβ 1–40 and Aβ 1–42 were increased in the hippocampus. These findings confirm that type 2 diabetes mellitus induced by neonatal monosodium glutamate exposure results in Alzheimer-like neuropathological changes and further causes cognitive deficits and neurodegeneration in young adulthood.

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          Most cited references 55

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              The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes have been debated extensively. The concept that a feedback loop governs the interaction of the insulin-sensitive tissues and the beta cell as well as the elucidation of the hyperbolic relationship between insulin sensitivity and insulin secretion explains why insulin-resistant subjects exhibit markedly increased insulin responses while those who are insulin-sensitive have low responses. Consideration of this hyperbolic relationship has helped identify the critical role of beta-cell dysfunction in the development of Type 2 diabetes and the demonstration of reduced beta-cell function in high risk subjects. Furthermore, assessments in a number of ethnic groups emphasise that beta-cell function is a major determinant of oral glucose tolerance in subjects with normal and reduced glucose tolerance and that in all populations the progression from normal to impaired glucose tolerance and subsequently to Type 2 diabetes is associated with declining insulin sensitivity and beta-cell function. The genetic and molecular basis for these reductions in insulin sensitivity and beta-cell function are not fully understood but it does seem that body-fat distribution and especially intra-abdominal fat are major determinants of insulin resistance while reductions in beta-cell mass contribute to beta-cell dysfunction. Based on our greater understanding of the relative roles of insulin resistance and beta-cell dysfunction in Type 2 diabetes, we can anticipate advances in the identification of genes contributing to the development of the disease as well as approaches to the treatment and prevention of Type 2 diabetes.

                Author and article information

                Neural Regen Res
                Neural Regen Res
                Neural Regeneration Research
                Medknow Publications & Media Pvt Ltd (India )
                November 2018
                : 13
                : 11
                : 1995-2004
                [1 ]Department of Pathophysiology, Henan Medical College, Zhengzhou, Henan Province, China
                [2 ]Henan Key Laboratory of Degenerative Brain Disease, Henan Medical College, Zhengzhou, Henan Province, China
                [3 ]Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
                [4 ]Department of Pathology, Wuhan Children's Hospital, Wuhan, Hubei Province, China
                Author notes
                [* ] Correspondence to: Li Wang, kyk02@ 123456126.com .

                Author contributions: LW and LJ designed this study. LJ and YPL prepared all figures and wrote the manuscript. YPL and LR established experimental animal models and conducted the blood sample assays. YPL, LR and GJB performed the behavioral tests. QF and LJ conducted data analysis. LJ performed the western blot assay. YPL conducted the ELISA assays. All authors approved the final version of the paper.


                These authors contributed equally to this work.

                Copyright: © Neural Regeneration Research

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