Diabetic neuropathy: cutting-edge research and future directions

Abstract

Diabetic neuropathy (DN) is a prevalent and debilitating complication of diabetes mellitus, significantly impacting patient quality of life and contributing to morbidity and mortality. Affecting approximately 50% of patients with diabetes, DN is predominantly characterized by distal symmetric polyneuropathy, leading to sensory loss, pain, and motor dysfunction, often resulting in diabetic foot ulcers and lower-limb amputations. The pathogenesis of DN is multifaceted, involving hyperglycemia, dyslipidemia, oxidative stress, mitochondrial dysfunction, and inflammation, which collectively damage peripheral nerves. Despite extensive research, disease-modifying treatments remain elusive, with current management primarily focusing on symptom control. This review explores the complex mechanisms underlying DN and highlights recent advances in diagnostic and therapeutic strategies. Emerging insights into the molecular and cellular pathways have unveiled potential targets for intervention, including neuroprotective agents, gene and stem cell therapies, and innovative pharmacological approaches. Additionally, novel diagnostic tools, such as corneal confocal microscopy and biomarker-based tests, have improved early detection and intervention. Lifestyle modifications and multidisciplinary care strategies can enhance patient outcomes. While significant progress has been made, further research is required to develop therapies that can effectively halt or reverse disease progression, ultimately improving the lives of individuals with DN. This review provides a comprehensive overview of current understanding and future directions in DN research and management.

Fig. 1

Risk factors for diabetic neuropathy. The development and progression of DN are influenced by multiple factors, including diabetes duration, poor glycemic control, advanced age, and MetS, which encompasses obesity, hypertension, and dyslipidemia. Other contributing factors include chronic low-grade inflammation, lifestyle choices such as smoking and alcohol abuse, and genetic predisposition. Risk factors for painful diabetic neuropathy are less well-defined, but overlap with those for diabetic nephropathy. These include poor blood glucose control, susceptibility genes, and independent factors such as female sex, increased neuropathy severity, renal dysfunction, and higher BMI. BMI body mass index, DN diabetic neuropathy, MetS metabolic syndrome

Fig. 2

Classification of diabetic neuropathy. Diabetic neuropathies comprise a diverse group of clinical syndromes, typically classified by the pattern of neurological involvement. Distal symmetric polyneuropathy (DSPN) is the most common form, which affects approximately 50% of patients with diabetes, characterized by sensory loss, pain, and motor dysfunction in the extremities. Autonomic neuropathy, affecting 20–40% of patients with diabetes, primarily involves the autonomic nervous system, impacting organs such as the heart, gastrointestinal tract, and urogenital system. Mononeuropathy, with an incidence of < 1%, usually involves isolated cranial nerves (e.g., oculomotor, facial) or peripheral nerves (e.g., facial). Radiculoplexus neuropathy, also occurring in <1% of diabetes cases, predominantly affects the lumbar or cervical plexus. DSPN distal symmetric polyneuropathy, DM Diabetes mellitus

Fig. 3

Pathogenesis of diabetic neuropathy. The cellular mechanisms underlying DN involve hyperglycemia, dyslipidemia, and altered insulin signaling. In diabetes mellitus, these factors drive excessive activation of the polyol, hexosamine, and PKC pathways, as well as receptors for RAGE activation. In T1DM, insulin deficiency leads to reduced insulin signaling, while in T2DM, insulin resistance results in impaired PI3K-AKT signaling. These disruptions, along with hyperlipidemia and dyslipidemia, either individually or in combination, contribute to pathological changes in neurons, Schwann cells, and vascular cells, leading to nerve dysfunction and neuropathy. Key pathological processes include DNA damage, ER stress, mitochondrial dysfunction, oxidative stress, neurodegeneration, loss of neurotrophic signaling, and microvascular dysfunction. These changes can also trigger inflammatory and immune-mediated neurotoxicity. The relevance of each pathway to neuropathy development varies based on the cell type, disease profile, and stage, as different cells exhibit varying susceptibility to metabolic dysfunction. AGE advanced glycation end-product, DAG diacylglycerol, ER endoplasmic reticulum, FFAs free fatty acids, GLUT glucose transporters, G-3-P glucosamine 3-phosphate, G-6-P glucosamine 6-phosphate, LDL low-density lipoprotein, LOX-1 oxidized LDL receptor-1, PKC protein kinase C, RAGE AGE-specific receptor, ROS reactive oxygen species, TLR4 Toll-like receptor 4, T1DM type 1 diabetes mellitus, T2DM type 2 diabetes mellitus, UDP-GlcNAc uridine diphosphate N-acetylglucosamine

Fig. 4

Peripheral and central mechanisms in diabetic neuropathy. Various alterations in peripheral and central neurons contribute to the pathophysiology of DN. In neuronal perikarya, hyperglycemia exacerbates endoplasmic reticulum stress, mitochondrial damage, and oxidative stress, while microvascular changes promote infiltration of inflammatory cells and factors at the neuronal and axonal levels, increasing the expression of voltage-gated sodium channels like Nav1.8, leading to hyperexcitability. Hyperglycemia in nerve fibers disrupts Schwann cell autophagy, increases the release of extracellular vesicles containing microRNAs and lipotoxic species, and reduces nerve growth factor secretion, impairing Schwann-axon interactions and myelin repair. These changes accelerate DN progression and contribute to hyperexcitability in myelinated axons by reducing the expression of shaker-type potassium channels, leading to heightened responses to stimuli and ectopic neuronal activity. Peripheral nerve damage triggers nociceptor hypersensitivity through inflammation, altered transducer activity (e.g., TRPV1, TRPM8, and P2X3R), and ion channel expression changes in sodium, potassium, and calcium channels. Methylglyoxal-induced glycation of nociceptor terminal ion channels forms AGEs, resulting in channel hyperfunction and neuronal hyperexcitability, including increased expression of Nav1.8. In DN, genetic variants (e.g., Nav1.7 and Nav1.8), methylglyoxal-modified TRPA1, SUMO-modified TRPV1, and HCN2 overactivation due to elevated cAMP contribute to neuronal hyperexcitability. Central sensitization results from an imbalance between facilitatory and inhibitory modulation of pain signals in the spinal cord and brain. This involves ascending pathways such as the spinothalamic tract (pain perception), the spinoreticular tract, and pathways through the parabrachial nucleus to the hypothalamus and amygdala, which are associated with autonomic function and emotional responses such as fear and anxiety. Descending pathways can inhibit or facilitate nociceptive signal transmission at the spinal level. The gut microbiota also plays a key role in DN, with dysbiosis linked to inflammation, metabolic disturbances, and nerve damage due to increased intestinal permeability and endotoxin translocation. Beneficial metabolites such as SCFAs, including butyrate, support nerve regeneration and reduce neuroinflammation, offering new therapeutic opportunities for DN management. AGEs advanced glycation end products, cAMP cyclic adenosine monophosphate, CNS central nervous system, DN diabetic neuropathy, DPN diabetic peripheral neuropathy, EVs extracellular vesicles, HCN2 hyperpolarization-activated cyclic nucleotide-gated 2, P2X3R P2X receptor subtype 3, SC Schwann cell, SCFAs short-chain fatty acids, TRPV1 transient receptor potential vanilloid 1, TRPA1 transient receptor potential ankyrin 1, TRPM8 transient receptor potential melastatin 8

Fig. 5

Management strategies for diabetic neuropathy. Maintaining good glycemic control helps prevent the development of neuropathy in patients with type 1 diabetes, though the effect is less pronounced in those with type 2 diabetes. Lifestyle modifications, such as a balanced diet and regular exercise, are recommended for all patients. Mechanism-based treatments focus on addressing the underlying pathophysiology of diabetic neuropathy to alleviate symptoms and slow disease progression. Current therapeutic strategies include neuroprotective agents (methylcobalamin), antioxidants (alpha-lipoic acid), aldose reductase inhibitors (epalrestat), microcirculation enhancers (prostaglandin E1), and metabolic enhancers (acetyl-L-carnitine). PDPN is a frequent and debilitating complication that severely impacts patients’ quality of life. First-line and second-line treatments for PDPN involve various drug classes, including anticonvulsants (pregabalin and gabapentin), serotonin-norepinephrine reuptake inhibitors (duloxetine and venlafaxine), sodium channel inhibitors (carbamazepine and oxcarbazepine), and tricyclic antidepressants (amitriptyline and nortriptyline). Opioids (tapentadol and tramadol) should be avoided due to their significant adverse effects and high potential for addiction. Non-pharmacological therapies, such as TENS, SCS, and acupuncture, are personalized based on individual patient needs. TENS transcutaneous electrical nerve stimulation, SCS spinal cord stimulation, PDPN painful diabetic peripheral neuropathy

Fig. 6

Emerging therapeutic strategies for diabetic neuropathy. A range of repurposed drugs and preclinically tested lead compounds are under investigation for the management of DN. Newer targeted therapies, including SGLT2 inhibitors and GLP receptor agonists, are being integrated into the prevention and treatment of DN. Additionally, novel ion channel modulators, such as voltage-gated sodium and calcium channel blockers, TRPA1 and TRPV1 antagonists, NMDAR antagonists, and P2X3 receptor antagonists, are employed to mitigate pain in patients with PDPN. Innovative approaches such as stem cell therapy, gene therapy, and fecal microbiota transplantation are also being explored to enhance DN management. Concurrently, emerging molecular biomarkers, including non-coding RNAs and neuronal injury markers, are under investigation to improve the clinical diagnosis and prognosis of DN. AGEs advanced glycation end products, AT2R angiotensin II type 2 receptor, BDNF brain-derived neurotrophic factor, DN diabetic neuropathy, FMT fecal microbiota transplantation, EPO erythropoietin, GLPR glucose-dependent insulinotropic polypeptide receptor, HDAC6 histone deacetylase 6, HGF hepatocyte growth factor, IL-1RA interleukin-1 receptor antagonist, iPSC induced pluripotent stem cells, MSCs mesenchymal stem cells, NF-κb nuclear factor kappa-light-chain-enhancer of activated B cells, NGF nerve growth factor, NLR neutrophil-to-lymphocyte ratio, NMDAR N-methyl-D-aspartate receptor, NSE neuron-specific enolase, PDPN painful diabetic peripheral neuropathy, pNF-H phosphorylated neurofilament heavy chain, P2X3R P2X receptor subtype 3, P2X4R P2X receptor subtype 4, SCFA short-chain fatty acids, SGLT2 sodium-glucose transport protein 2, SOD superoxide dismutase, TRPV1 transient receptor potential vanilloid 1, TRPA1 transient receptor potential ankyrin 1, TRPM8 transient receptor potential melastatin 8, VEGF vascular endothelial growth factor