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.