Ortiz Genaro G, Huerta Miguel, González-Usigli Héctor A, Torres-Sánchez Erandis D, Delgado-Lara Daniela Lc, Pacheco-Moisés Fermín P, Mireles-Ramírez Mario A, Torres-Mendoza Blanca Mg, Moreno-Cih Roxana I, Velázquez-Brizuela Irma E
Department of Philosophical and Methodological Disciplines, University Health Sciences Center, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico.
University Biomedical Research Center, University of Colima, Colima 28040, Mexico.
World J Diabetes. 2022 Apr 15;13(4):319-337. doi: 10.4239/wjd.v13.i4.319.
Insulin, a key pleiotropic hormone, regulates metabolism through several signaling pathways in target tissues including skeletal muscle, liver, and brain. In the brain, insulin modulates learning and memory, and impaired insulin signaling is associated with metabolic dysregulation and neurodegenerative diseases. At the receptor level, in aging and Alzheimer's disease (AD) models, the amount of insulin receptors and their functions are decreased. Clinical and animal model studies suggest that memory improvements are due to changes in insulin levels. Furthermore, diabetes mellitus (DM) and insulin resistance are associated with age-related cognitive decline, increased levels of β-amyloid peptide, phosphorylation of tau protein; oxidative stress, pro-inflammatory cytokine production, and dyslipidemia. Recent evidence shows that deleting brain insulin receptors leads to mild obesity and insulin resistance without influencing brain size and apoptosis development. Conversely, deleting insulin-like growth factor 1 receptor (IGF-1R) affects brain size and development, and contributes to behavior changes. Insulin is synthesized locally in the brain and is released from the neurons. Here, we reviewed proposed pathophysiological hypotheses to explain increased risk of dementia in the presence of DM. Regardless of the exact sequence of events leading to neurodegeneration, there is strong evidence that mitochondrial dysfunction plays a key role in AD and DM. A triple transgenic mouse model of AD showed mitochondrial dysfunction, oxidative stress, and loss of synaptic integrity. These alterations are comparable to those induced in wild-type mice treated with sucrose, which is consistent with the proposal that mitochondrial alterations are associated with DM and contribute to AD development. Alterations in insulin/IGF-1 signaling in DM could lead to mitochondrial dysfunction and low antioxidant capacity of the cell. Thus, insulin/IGF-1 signaling is important for increased neural processing and systemic metabolism, and could be a specific target for therapeutic strategies to decrease alterations associated with age-related cognitive decline.
胰岛素是一种关键的多效性激素，通过包括骨骼肌、肝脏和大脑在内的靶组织中的多种信号通路调节代谢。在大脑中，胰岛素调节学习和记忆，胰岛素信号受损与代谢失调和神经退行性疾病相关。在受体水平，在衰老和阿尔茨海默病（AD）模型中，胰岛素受体的数量及其功能会下降。临床和动物模型研究表明，记忆力的改善归因于胰岛素水平的变化。此外，糖尿病（DM）和胰岛素抵抗与年龄相关的认知衰退、β-淀粉样肽水平升高、tau蛋白磷酸化、氧化应激、促炎细胞因子产生和血脂异常有关。最近的证据表明，删除大脑胰岛素受体会导致轻度肥胖和胰岛素抵抗，而不会影响大脑大小和细胞凋亡的发展。相反，删除胰岛素样生长因子1受体（IGF-1R）会影响大脑大小和发育，并导致行为改变。胰岛素在大脑中局部合成并从神经元释放。在此，我们综述了提出的病理生理假说，以解释在糖尿病存在的情况下痴呆风险增加的原因。无论导致神经退行性变的确切事件顺序如何，有强有力的证据表明线粒体功能障碍在AD和DM中起关键作用。AD的三重转基因小鼠模型显示出线粒体功能障碍、氧化应激和突触完整性丧失。这些改变与用蔗糖处理的野生型小鼠中诱导的改变相当，这与线粒体改变与DM相关并促成AD发展的提议一致。DM中胰岛素/IGF-1信号的改变可能导致线粒体功能障碍和细胞抗氧化能力低下。因此，胰岛素/IGF-1信号对于增强神经处理和全身代谢很重要，并且可能是减少与年龄相关的认知衰退相关改变的治疗策略的特定靶点。
