Chronic hyperglycemia impairs neuron function

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.

Publication

Neurons and Microglia; A Sickly-Sweet Duo in Diabetic Pain Neuropathy. (2019) Trevor Rajchgot, et al. Front Neurosci. 2019;13:25. Figure: F2. All organisms Drosophila melanogaster Homo sapiens

Disease mentions