Diabetic neuropathy and the sensory neuron: New aspects of pathogenesis and their treatment implications

Abstract

Diabetic polyneuropathy (DPN) continues to be generally considered as a “microvascular” complication of diabetes mellitus alongside nephropathy and retinopathy. The microvascular hypothesis, however, might be tempered by the concept that diabetes directly targets dorsal root ganglion sensory neurons. This neuron‐specific concept, supported by accumulating evidence, might account for important features of DPN, such as its early sensory neuron degeneration. Diabetic sensory neurons develop neuronal atrophy alongside a series of messenger ribonucleic acid (RNA) changes related to declines in structural proteins, increases in heat shock protein, increases in the receptor for advanced glycation end‐products, declines in growth factor signaling and other changes. Insulin is recognized as a potent neurotrophic factor, and insulin ligation enhances neurite outgrowth through activation of the phosphoinositide 3‐kinase–protein kinase B pathway within sensory neurons and attenuates phenotypic features of experimental DPN. Several interventions, including glucagon‐like peptide‐1 agonism, and phosphatase and tensin homolog inhibition to activate growth signals in sensory neurons, or heat shock protein overexpression, prevent or reverse neuropathic abnormalities in experimental DPN. Diabetic sensory neurons show a unique pattern of microRNA alterations, a key element of messenger RNA silencing. For example, let‐7i is widely expressed in sensory neurons, supports their growth and is depleted in experimental DPN; its replenishment improves features of DPN models. Finally, impairment of pre‐messenger RNA splicing in diabetic sensory neurons including abnormal nuclear RNA metabolism and structure with loss of survival motor neuron protein, a neuron survival molecule, and overexpression of CWC22, a splicing factor, offer further novel insights. The present review addresses these new aspects of DPN sensory neurodegeneration.

Raman spectroscopy of dorsal root ganglia from streptozotocin‐induced diabetic neuropathic rats submitted to photobiomodulation therapy

“…Investigations into DRG pathology in human diabetes are lacking because human DRG biopsies are not ethical to carry out and because there is a rapid degradation during the post‐mortem interval at autopsy . Therefore, it is difficult to obtain DRG for diagnosis and treatment of the biochemical alterations linked to diabetic neuropathy, for example.…”

“…Patients with untreated diabetic neuropathy develop a gradual and insidious damage to the sensory peripheral nerves, which also involves the neuronal cell bodies, located in the DRG . Satellite cells and the DRG neuronal cell bodies form a functional unit and as such contribute to the functioning of DRG in disease (for review, see Reference ).…”

Managing the multifaceted nature of type 2 diabetes using once‐weekly injectable GLP‐1 receptor agonist therapy

“…Diabetic neuropathy (DN) refers to a collection of clinically diverse disorders affecting the nervous system, with differing anatomic features, clinical courses and phenotypes 37 . Patients with DN have sensory loss or pain, but the symptoms differ depending on the nerves involved 18,38 . Diabetic polyneuropathy, which has a lifetime prevalence of approximately 50% in people with diabetes, is the most common complication from diabetes 39 .…”

Elevated peripheral blood levels of CXCL10 are associated with the presence of diabetic polyneuropathy in subjects with type 2 diabetes

“…Chronic hyperglycemia and increased levels of HbA1c lead to peripheral nerve injury through an array of complex mechanisms that include the overactivation of the polyol pathway and accumulation of sorbitol [4], alterations of myoinositol [5], protein synthesis deficiency (myelin among others) [6], formation of advanced glycation end products, and oxidative stress [6,7]. These interlinked metabolic pathways converge, activating the transcription factor NF-kB, which induces the expression of genes involved in inflammation, triggering pro-inflammatory and immune responses [3,[8][9][10]. Also, under hyperglycaemic conditions, microvascular alterations result and contribute to the development of DPN via tissue hypoxia and nerve ischemia [10][11][12].…”

“…These interlinked metabolic pathways converge, activating the transcription factor NF-kB, which induces the expression of genes involved in inflammation, triggering pro-inflammatory and immune responses [3,[8][9][10]. Also, under hyperglycaemic conditions, microvascular alterations result and contribute to the development of DPN via tissue hypoxia and nerve ischemia [10][11][12].…”