CreativeWork

Chronic hyperglycemia impairs neuron function. Sensory neurons have a limited capacity to regulate their uptake of glucose. In the context of chronic hyperglycemia, such as in diabetes, high glucose concentrations drive mitochondria to produce ATP and transfer electrons. Excess glucose is also metabolized through the polyol pathway, leading to the production of advanced glycation end products. The electrons from the mitochondrial respiratory chain combine with intracellular oxygen and nitric oxide to produce ROS and RNS. Consequently, RNS, ROS, and AGE activate nuclear transcription factors, which enhance the expression of ion channel transducers (TRP and NaV channels) in addition to impairing neurons' capacity to self-repair. At the same time, microglia-released mediators (cytokines, ATP, BDNF, NO) stimulate GPCR and tyrosine kinase receptors, triggering downstream signaling cascades, which lead to the phosphorylation of TRP and NaV channels. A decrease in the activation threshold of these ion channel transducers can augment the influx of cations, which ultimately results in action potential firing and ectopic discharges. These effects enhance pain perception and signaling to the CNS. Chronic hyperglycemia also increases oxidative stress in the blood vessels that supply oxygen and nutrients to neuron terminals. This oxidative stress can cause microangiopathy, a phenomenon characterized by the loss of capillaries, which starves neuronal energy supplies. These phenomena are responsible for the loss of neuron terminals and pain insensitivity, as typically observed in later stage of DPN.

慢性高血糖损害神经元功能。感觉神经元调节其葡萄糖摄取的能力有限。在慢性高血糖的背景下，例如糖尿病，高血糖浓度驱动线粒体产生ATP并转移电子。过量的葡萄糖还通过多元醇途径代谢，导致晚期糖基化终末产物（AGEs）的产生。线粒体呼吸链中的电子与细胞内氧气和一氧化氮结合，产生活性氧（ROS）和活性氮（RNS）。因此，RNS、ROS和AGEs激活核转录因子，不仅损害神经元的自我修复能力，还增强离子通道转导器（TRP和NaV通道）的表达。同时，小胶质细胞释放的介质（细胞因子、ATP、BDNF、NO）刺激G蛋白偶联受体和酪氨酸激酶受体，触发下游信号级联反应，导致TRP和NaV通道的磷酸化。这些离子通道转导器的激活阈值降低，可增加阳离子的内流，最终导致动作电位发放和异常放电。这些效应增强了疼痛感知和对中枢神经系统的信号传递。慢性高血糖还增加了供应神经元末梢氧气和营养物质的血管中的氧化应激。这种氧化应激可引起微血管病变，其特征是毛细血管丧失，导致神经元能量供应不足。这些现象是神经元末梢丧失和疼痛不敏感的原因，通常在糖尿病神经病变的晚期观察到。