Neurons and Microglia; A Sickly-Sweet Duo in Diabetic Pain Neuropathy

Abstract

Diabetes is a common condition characterized by persistent hyperglycemia. High blood sugar primarily affects cells that have a limited capacity to regulate their glucose intake. These cells include capillary endothelial cells in the retina, mesangial cells in the renal glomerulus, Schwann cells, and neurons of the peripheral and central nervous systems. As a result, hyperglycemia leads to largely intractable complications such as retinopathy, nephropathy, hypertension, and neuropathy. Diabetic pain neuropathy is a complex and multifactorial disease that has been associated with poor glycemic control, longer diabetes duration, hypertension, advanced age, smoking status, hypoinsulinemia, and dyslipidemia. While many of the driving factors involved in diabetic pain are still being investigated, they can be broadly classified as either neuron -intrinsic or -extrinsic. In neurons, hyperglycemia impairs the polyol pathway, leading to an overproduction of reactive oxygen species and reactive nitrogen species, an enhanced formation of advanced glycation end products, and a disruption in Na⁺/K⁺ ATPase pump function. In terms of the extrinsic pathway, hyperglycemia leads to the generation of both overactive microglia and microangiopathy. The former incites a feed-forward inflammatory loop that hypersensitizes nociceptor neurons, as observed at the onset of diabetic pain neuropathy. The latter reduces neurons' access to oxygen, glucose and nutrients, prompting reductions in nociceptor terminal expression and losses in sensation, as observed in the later stages of diabetic pain neuropathy. Overall, microglia can be seen as potent and long-lasting amplifiers of nociceptor neuron activity, and may therefore constitute a potential therapeutic target in the treatment of diabetic pain neuropathy.

Keywords: diabetes; hyperglycemia; microglia; neurons; neuropathy; oxidative stress; pain.

Figure 1

Schematic representation of a spinal dorsal horn tripartite synapse. Overview of the pre (A) and post- synaptic neurons interplay with microglia (B) in the spinal cord dorsal horn.

Figure 2

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 Na_V 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 Na_V 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.

Figure 3

Chronic hyperglycemia impairs microglial function. Circulating glucose is taken up by microglia, which enhances mitochondrial ATP production and electron transfer. The released electrons combine with intracellular oxygen to produce reactive oxygen species. Sensory neurons release ATP, which in turn activates microglial P₂X₄R; this drives microglial calcium influx, MAPK activation, receptor phosphorylation and protein transduction (cytokines, prostaglandins, BDNF) as well as NO production. These mediators are subsequently released by microglia, and either block inhibitory interneurons or enhance neuronal activation.