Abstract

Diabetic neuropathy (DN) is a debilitating complication of diabetes mellitus (DM), characterized by nerve damage resulting from chronic hyperglycemia. This condition affects a significant proportion of diabetic patients, leading to symptoms such as weakness, numbness, and pain, particularly in the extremities. The pathogenesis of DN is complex and involves metabolic, vascular, and neurotrophic factors. At the core of its development are various receptors that mediate and modulate the underlying biochemical and cellular processes. Key receptors implicated in DN include the advanced glycation end-product receptor (RAGE), which is involved in oxidative stress and inflammation. Additionally, transient receptor potential channels, namely TRP channels, particularly TRPV1 and TRPA1, play an important role in the sensation of pain and thermal stimuli, contributing to the sensory abnormalities observed in DN. Insulin and insulin-like growth factor receptors also play significant roles, as insulin signaling is crucial for neuronal survival and function. Furthermore, purinergic receptors, specifically the P2X and P2Y subtypes, are involved in neuroinflammation and pain transmission. Understanding the roles and interactions of these receptors provides valuable insights into the pathophysiology of DN and highlights potential therapeutic targets. Future research focusing on modulating these receptor pathways holds promise for developing effective treatments to alleviate symptoms and potentially reverse the progression of DN.

Introduction

DN is one of the most chronic and prevalent conditions described as supplementary nerve dysfunction symptoms in cases with DM, affecting over 50% of people with diabetes. According to data recently issued by the International Diabetes Federation (IDF), an estimated 537 million individuals worldwide currently have diabetes. By 2030 and 2045, that number is projected to rise to 643 million and 783 million, respectively, a significant cause of DN1, 2, 3. DN causes a variety of clinical symptoms, including pain and sensory loss. It also increases the chance of foot ulcers and amputation, an irreversible consequence for cases. Positive symptoms, such as painful DN, are endured by one-third of people with neuropathy and include paraesthesia, allodynia, and spontaneous pain. DN might appear as sensory, motor, focal/multifocal, or autonomic neuropathies. Diabetic distal symmetric polyneuropathy (DSPN) is the most common type of DN, making up over 75% of all diabetic neuropathies. The distal terminals of sensory neurons are gradually and stealthily damaged in DSPN cases, resulting in symptoms similar to tingling, discomfort, or lack of sensation in their toes. Because nerve damage and discomfort take longer to display in older persons (over 50), diabetic neuropathy is more common in this population. As per the Search for Diabetes in Youth study, the prevalence of peripheral DN in children up to the age group of 20 years is approximately 7% (those with type-I diabetes) and up to 22% (with type-II diabetes) respectively4, 5, 6, 7. Molecular neurobiological knowledge of human nervous tissues is required to produce the next generation of therapeutics for neurological disorders like chronic pain. Significant gene families and pathways were analyzed, including transcription factors (TFs), G-protein-coupled receptors (GPCRs), & ion channels8. Peripheral sensory neurons in the dorsal root ganglion (DRG) & trigeminal ganglion (TG) are specialized to detect & transduce different natural stimuli including touch, temperature, pain, etc., to the CNS. The recent resources and information available can guide future studies in comparative transcriptomics, simplify cell-type terminological differences across studies, and offer assistance in prioritizing targets for future pain treatment advancements9. Sensory neurons of the DRG are essential for maintaining tissue homeostasis by detecting & initiating reactions to stimuli. Whereas most preclinical studies of DRGs are conducted on rodents, much less is known about the mechanisms of sensory recognition in primates10. Pregabalin and duloxetine showed significant therapeutic impacts on painful DPN, but adverse events were too significant. The pain-relieving effects of ABT-894 and gabapentin need to be further studied with longer and larger RCTs. As an opioid drug, tapentadol has a significant pain-relieving impact, but due to its addiction potential, it needs to be used cautiously in clinical practice. Pregabalin, duloxetine, & tapentadol, three drugs are approved by the US Food and Drug Administration (USFDA) for the DPN treatment. Although lacosamide, mirogabalin, and capsaicin are more effective than placebo, their therapeutic impact is weaker than that of pregabalin. For satisfactory results, long-term studies are still required to confirm their efficacy and safety in the future11.

MECHANISM AND PATHOPHYSIOLOGY

As noted, DN is a distinct neurodegenerative condition affecting the peripheral nervous system, firstly impacting autonomic axons, sensory axons, and lower limb motor axons. It's unclear how DM affects sensory neurons. In progressive DN, the perikarya (cell bodies) are largely preserved while the terminal sensory axons in the periphery shrink and die back. DN is classified as a length-dependent neuropathy due to its involvement pattern, which resembles a "stocking & glove" pattern. According to this pattern, the longest sensory axons are first affected, with loss of distal leg epidermal axons occurring before loss in more proximal limbs. Schwann cells are targets in chronic hyperglycemia. Moreover, severe cases of DN in individuals involve features of demyelination, although DN is not considered to be predominantly a demyelinating neuropathy, since axons and Schwann cells may induce various changes in the axon. For instance, Schwann cells are crucial in controlling the cytoskeletal characteristics of axons, such as the parameters governing the trafficking of axons and the location of proteins at Ranvier's nodes. Faulty Schwann cell-axon ribosome transfer, inadequate cytoskeletal support, or lack of trophic factors, facilitate the intra-axonal translation of mRNA within the distal axons. Ribosome-filled Schwann cells in mice can regulate the synthesis of axonal proteins when introduced to demyelinated axons. When axons are under pressure or damaged, this ribosome transfer may make axon-Schwann cell connections even more pivotal12, 13.

It's uncertain whether diabetes triggers innate axonal programs that contribute to axonal deterioration. Exploration of Wallerian degeneration has revealed intracellular signaling pathways that activate axonal degeneration. One of these pathways’ major regulators appears to be mononucleotide adenylyl transferase (NMNAT), often referred to as NMN/NaMN adenylyl transferase. However, it's still unclear if diabetes activates these pathways14. Axon changes, particularly those affecting the distal terminals, are associated with changes in the neuronal perikarya. DRG sensory neurons change their phenotype in long-term experimental diabetes, which may be crucial for how they maintain the branches of distant axons. For example, the production and export of neurofilament polymers, essential for maintaining the structural scaffolding of the axon, are gradually lost in rats with chronic Type-1 Diabetes. This loss of neurofilament polymers has been suggested to be caused by reduced mRNA expression encoding neurofilament. Endoplasmic reticulum stress is also implicated in preclinical research with diabetic animals in diabetes-induced peripheral nerve injury that could affect nerve functions. Similarly, research conducted in vivo and in vitro in rodent models has shown that the expression patterns of heat shock proteins (HSPs) and poly (ADP-ribose) polymerase (PARP) in DRGs, as well as the function of synaptic plasticity molecules like growth-associated protein (GAP43 or known as neuromodulin) and β-tubulin, are altered due to hyperglycemia. Data indicate that in these pathways, any dysfunction promotes the processing of abnormal protein, oxidative damage, and mitochondrial dysfunction, leading to loss of peripheral nerve function, even when the mechanisms of damage are still being investigated.

This notion is supported by the observation that nerve function can be improved by modifying individual molecules in these pathways. For example, nerve conduction velocity (NCV) and responses to mechanical and thermal stimuli, both clinically relevant endpoints, were improved by controlling HSP90 activation, most likely as a result of enhanced mitochondrial function. Recent array studies have similarly demonstrated that DRG sensory neurons exposed to chronic diabetes exhibit a variety of mRNA and microRNA alterations. Preclinical models of Type-I DM and Type-II DM have shown increased expression of inflammation, bioenergetic, and lipid processing-related pathways in a variety of sciatic nerve cultures (Figure 1)15, 16, 17, 18, 19, 20.

Furthermore, a study comparing gene expression patterns in peripheral nerves from individuals with Type-I DM and Type-II DM with those from mouse models of DN identified several largely conserved pathways related to inflammation, lipid metabolism, and adipogenesis21. DN has also been associated with other specific changes in the DRG and nerve function, such as altered spliceosome function, changes in the production of survival motor neuron protein, and overexpression of GW-bodies (mRNA processing sites)22.

× Figure 1 . Pathogenesis of Diabetic Neuropathy . Figure 1 . Pathogenesis of Diabetic Neuropathy .

Table 1.

Receptors involved in diabetic neuropathy and their class, subtype, and allocation in the body

No Receptor Sub-types Class Distribution body References 1 Transient receptor potential channels (TRP channels) *TRPC(Canonical): TRPC1, TRPC2, TRPC3, TRPC6, TRPC7, TRPC4, TRPC5. *TRPV (Vanilloid), Six Trans-Membrane Helical Voltage-Gated Ion Channels, cation permeable plasma membrane channels with varying Ca 2+ selectivity Embryonic brain, liver, kidney tissues as well as adult heart, testes, ovaries, brain, Sensory Neuron, Plasma membrane, Intracellular Compartment 23 , 24 25 , 26 27 28 2 Toll-Like Receptors *V type-TLR Membrane-Bound Receptor Macrophages, dendritic cells (DCs), natural killer cells (NKs), mast cells, basophils, eosinophils (specialized immune cells) as well as normal cells etc . 29 , 30 , 31 , 32 3 Insulin Receptors IR-A IR-B Transmembrane Protein & Part of Tyrosine Kinase Receptor (Rtk) Pancreatic beta cells, some areas of CNS, Adipocytes, Myocytes, Hepatocytes, Skeletal Muscle 33 , 34 , 35 4 N-methyl-D- aspartate receptor GluN1/GluN2A GluN1/GluN2B GluN1/GluN2C GluN1/GluN2C Ligand-Gated Ion Channels Hippocampus, Spinal Cord, Neocortex, Cerebellum 36 , 37 , 38 5 Opioid Receptors m (mu): MOP, d (delta): DOP, k (kappa): KOP, FQ (N/OFQ) or NOP G protein-coupled receptors (GPCR) In CNS: Locus coeruleus, medulla, periaqueductal grey area, Midbrain, Limbic- Cortical Structures, Cerebellum, Caudate Nucleus, Nucleus Accumbens, Hippocampus, Cerebral Cortex, Putamen, Temporal Lobe, Hypothalamic Nuclei. In the periphery: neuronal & non-neuronal tissues including (neuroendocrine), immune cells, ectodermal cells, and smooth muscle cells & at the terminal of sympathetic & sensory peripheral neurons 39 , 40 , 41 , 42 , 43 6 AGE-RAGE receptor *Full-length RAGE (fl-RAGE) *N-Truncated RAGE *Dominant -ve RAGE