Literature search and selection criteria

Our Literature Search Strategy begins with defining clear research objectives and questions to establish the scope of the search. Utilizing keywords including but not limited to Diabetic Peripheral Neuropathy, Diabetes, Therapies, Controversies, Epidemiology, Pathophysiology, Diagnostics, Risk factors, Prevalence and Boolean operators (AND, OR, NOT) facilitates targeted searches across databases such as PubMed, Scopus, Web of Science. Incorporating synonyms, truncations, and controlled vocabulary like MeSH terms ensured the retrieval of diverse yet relevant sources. Selection criteria, encompassing inclusion and exclusion parameters, are critical to refine the results. Our criteria included publication type (Primarily reviews and Metanalysis), date range (after year 2010 mostly recent, in very rare case older references are included), geographical context: Global with focus on Middle east and Saudi Arabia. Ultimately, a robust strategy involving multiple iterative editing by the authors ensured that selected literature accurately supports the study’s objectives and reflects a comprehensive understanding of the topic.

Discussion

Epidemiology of DPN

The burden of DPN in Saudi Arabia has been rising, parallel to the increasing prevalence of diabetes in the Kingdom. Saudi Arabia has one of the highest diabetes prevalence rates in the world, which consequently places the population at a higher risk for developing DPN. In 2021, the International Diabetes Federation (IDF) estimated that around 18.3% of the Saudi adult population has diabetes, which is significantly higher than the global average. As a complication of diabetes, DPN is expected to affect a considerable proportion of these individuals. The prevalence of DPN in Saudi Arabia varies across different studies, with reports suggesting that between 33% and 66% of diabetic patients are affected by DPN [5-6]. In a study conducted in Jeddah, a tertiary care hospital reported a DPN prevalence of 60% among Type 2 diabetes patients. Other cross-sectional studies confirm the high prevalence rates, especially in patients with poor glycemic control and a longer duration of diabetes [7]. These statistics reflect the growing burden of DPN as a direct consequence of the diabetes epidemic in the Kingdom, highlighting the need for public health interventions to address both prevention and management. Table. 1 summarizes the prevalence and contributing factors of DPN across the globe [5, 8].

Pathophysiology of Diabetic Peripheral Neuropathy (DPN)

Metabolic Factors in DPN

The primary driver of DPN is chronic hyperglycemia, which induces a cascade of biochemical alterations. The polyol pathway, advanced glycation end-products (AGEs) formation, hexosamine pathway, and protein kinase C (PKC) activation are key metabolic pathways involved in DPN [19].

·        Polyol Pathway: In hyperglycemic conditions, glucose is reduced to sorbitol by the enzyme aldose reductase, leading to an accumulation of sorbitol and fructose. This accumulation depletes essential co-factors like nicotinamide adenine dinucleotide phosphate (NADPH), which is critical for regenerating the antioxidant glutathione. As a result, oxidative stress increases, contributing to neuronal damage [20].

·        AGEs and Receptor for AGEs (RAGE): AGEs are the products of non-enzymatic glycation of proteins and lipids. Hyperglycemia accelerates the formation of AGEs, which accumulate in various tissues, including peripheral nerves. AGEs interact with their receptor (RAGE) to activate pro-inflammatory and pro-oxidant signaling pathways, further exacerbating nerve injury [21].

·        Hexosamine Pathway: Excess glucose is diverted into the hexosamine pathway, where fructose-6-phosphate is converted into uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), which modifies proteins through O-linked N-acetylglucosamine (O-GlcNAcylation). This modification affects numerous cellular processes, including transcription and insulin signaling, contributing to neurodegeneration [22].

·        PKC Activation: Hyperglycemia activates the diacylglycerol-PKC pathway, which affects vascular flow by increasing vascular permeability and inducing endothelial dysfunction. PKC activation also promotes inflammation and oxidative stress, leading to neuronal ischemia and damage [14].

Oxidative Stress and Mitochondrial Dysfunction

Oxidative stress is a central mechanism in the pathogenesis of DPN. Hyperglycemia-induced overproduction of reactive oxygen species (ROS) disrupts the mitochondrial electron transport chain, leading to mitochondrial dysfunction. This results in impaired energy metabolism and increased apoptosis of neuronal cells. The imbalance between ROS production and the body's antioxidant defenses (e.g., glutathione) exacerbates oxidative damage to DNA, proteins, and lipids within peripheral nerves. This oxidative damage leads to structural alterations in the nerves, including axonal degeneration and demyelination [23]. Mitochondrial dysfunction also plays a significant role in DPN by reducing ATP production, which is critical for maintaining neuronal function. The reduced energy supply impairs axonal transport, contributing to the progressive loss of nerve function observed in DPN patients.

Inflammation and Immune Response

Chronic inflammation is another crucial factor contributing to DPN. Hyperglycemia induces a low-grade inflammatory state by promoting the activation of pro-inflammatory pathways, including the nuclear factor kappa B (NF-κB) and c-Jun N-terminal kinase (JNK) pathways. These pathways upregulate the expression of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), which further amplify the inflammatory response and contribute to nerve damage. The activation of immune cells, such as macrophages and T cells, within peripheral nerves has also been implicated in the progression of DPN. These immune cells release cytokines and chemokines that promote a pro-inflammatory environment, exacerbating neuronal injury [24].

Vascular Dysfunction

Vascular dysfunction is a significant contributor to the pathophysiology of DPN. Hyperglycemia impairs endothelial function by reducing the availability of nitric oxide (NO), a critical vasodilator. The reduced NO levels lead to vasoconstriction and reduced blood flow to peripheral nerves, resulting in nerve ischemia. In addition, hyperglycemia induces the formation of AGEs, which cross-link with collagen in blood vessels, leading to stiffening of the vessel walls. This vascular stiffness further impairs blood flow, depriving nerves of essential nutrients and oxygen, thereby contributing to neuronal dysfunction [25]. Microangiopathy, characterized by thickening of the basement membrane and reduced capillary density, has also been observed in patients with DPN. This microvascular damage leads to chronic ischemia of peripheral nerves, exacerbating neuronal injury and promoting the development of neuropathic pain [25].

Neurotrophic Factors and Axonal Degeneration

The loss of neurotrophic factors, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and insulin-like growth factor-1 (IGF-1), plays a significant role in the development of DPN. These neurotrophic factors are essential for the maintenance of neuronal structure and function. In diabetic conditions, the production of these factors is reduced, leading to impaired axonal regeneration and increased susceptibility to nerve damage. The reduced availability of neurotrophic factors also contributes to the degeneration of sensory and motor neurons, which is a hallmark of DPN [9]. Axonal degeneration in DPN is characterized by the loss of both myelinated and unmyelinated fibers. This degeneration leads to a reduction in nerve conduction velocity and impaired sensory perception, manifesting as symptoms such as numbness, tingling, and pain in the extremities [26].

Clinical Manifestations of Diabetic Peripheral Neuropathy (DPN)

Clinical manifestations of DPN, including sensory, motor, and autonomic symptoms, pose a serious impact on patients’ quality of life. Here are the highlights of the underlying mechanisms contributing to these manifestations for DPN.

Sensory Manifestations

The most prominent clinical feature of DPN is the impairment of sensory function, which affects both large and small fibers. Sensory symptoms are typically the first to appear and often present in a "glove and stocking" distribution, affecting the distal extremities.

Positive Sensory Symptoms (Hyperalgesia and Allodynia): Patients with DPN frequently report positive sensory symptoms such as burning, tingling, or shooting pain, collectively referred to as hyperalgesia or allodynia. These symptoms arise from abnormal nerve excitability due to damage to small fibers [27-28]. Hyperalgesia occurs when normally non-painful stimuli, such as light touch, cause pain, while allodynia involves exaggerated pain responses to mild stimuli. The severity of these symptoms varies among individuals and can be debilitating, significantly affecting daily activities. Negative Sensory Symptoms (Numbness and Loss of Sensation): As DPN progresses, patients may experience negative sensory symptoms, including numbness and a loss of protective sensation. These symptoms are due to damage to large nerve fibers, leading to a diminished ability to perceive vibrations, temperature changes, and mechanical stimuli. The loss of sensation predisposes patients to injuries, such as foot ulcers, which can lead to infections and amputations if left untreated [29]. Loss of Vibration and Position Sense: Large fiber involvement also impairs proprioception, or the sense of joint position, and vibration sense. Patients may experience unsteadiness while walking and have difficulty maintaining balance, particularly in low-light conditions. This loss of proprioception is particularly concerning as it increases the risk of falls, further complicating the management of DPN.

Motor Manifestations

Although sensory symptoms predominate in DPN, motor dysfunction can also occur, particularly in more advanced stages of the disease. Motor symptoms are less common but can lead to significant disability.

Weakness and Muscle Atrophy: Damage to motor nerves can result in muscle weakness, particularly in the distal muscles of the lower limbs, such as the muscles controlling ankle and foot movements [30]. Patients may have difficulty lifting their feet (foot drop), which can cause tripping and falling. In severe cases, muscle atrophy can occur, leading to visible wasting of the muscles in the feet and lower legs [31]. Impaired Reflexes: Reduced or absent deep tendon reflexes, particularly the ankle jerk reflex, are common in DPN [3]. This is a sign of large-fiber neuropathy and is often one of the earliest detectable clinical signs of DPN. Reflex impairment contributes to difficulties with balance and gait. Gait Abnormalities: Patients with DPN often develop a characteristic "steppage" gait due to foot drop and loss of proprioception. This gait involves exaggerated lifting of the feet while walking to prevent tripping. Over time, these motor deficits can contribute to further complications, such as foot deformities and joint damage.

Autonomic Manifestations

Autonomic neuropathy is a less recognized but equally important manifestation of DPN. It affects the autonomic nervous system, which controls involuntary body functions, such as heart rate, digestion, and sweating.

Cardiovascular Symptoms: Cardiovascular autonomic neuropathy (CAN) is a common complication of DPN and can lead to resting tachycardia, orthostatic hypotension, and an increased risk of sudden cardiac death [32]. CAN impairs the heart’s ability to adjust to different levels of physical activity, resulting in exercise intolerance and an increased risk of fainting due to orthostatic hypotension (a sudden drop in blood pressure when standing. Gastrointestinal Symptoms: Autonomic neuropathy can affect gastrointestinal function, leading to gastroparesis, which is the delayed emptying of the stomach. Symptoms include nausea, vomiting, bloating, and abdominal discomfort, which can worsen blood glucose control. Constipation and diarrhea, especially at night, are also common gastrointestinal manifestations of autonomic neuropathy in DPN patients [33]. Genitourinary Symptoms: Autonomic neuropathy in DPN can cause bladder dysfunction, including urinary retention, incontinence, and an increased risk of urinary tract infections. Additionally, sexual dysfunction, such as erectile dysfunction in men and decreased vaginal lubrication in women, is a frequent complaint in patients with DPN [33]. Sweat Gland Dysfunction: Autonomic neuropathy affects the sweat glands, leading to abnormal sweating patterns. Patients may experience reduced sweating in the extremities (anhidrosis), which increases the risk of dry skin and foot ulcers. Conversely, compensatory hyperhidrosis (excessive sweating) may occur in other areas of the body [34].

Risk Factors for Diabetic Peripheral Neuropathy (DPN)

Understanding the risk factors associated with DPN is crucial for early identification and management of at-risk patients, thereby preventing progression to severe neuropathic complications like foot ulcers or amputations. Below we have discussed various risk factors contributing to the onset and progression of DPN, citing key research studies. Table. 2 summarizes the major risk factors for DPN

Advances in diagnosis of DPN

Early detection is crucial to prevent severe consequences, such as foot ulcers, infections, and amputations. This review focuses on the diagnosis of DPN, outlining clinical evaluation, advanced diagnostic tests, and emerging biomarkers.

Clinical Diagnosis

Patient History and Symptom Assessment

The initial step in diagnosing DPN involves gathering a comprehensive patient history and evaluating symptoms. Patients typically present with sensory disturbances, including numbness, tingling, burning sensations, and shooting pains, usually in a "glove-and-stocking" distribution [46]. Sensory loss often begins distally and may progress proximally as the condition worsens.

Neurological Examination

A key component of the clinical diagnosis is a neurological examination, which assesses sensory deficits and motor impairments.

Monofilament Testing: The 10g monofilament test is a widely used method to assess protective sensation, particularly for detecting the risk of foot ulcers in individuals with DPN [47]. Vibration Perception: Vibration perception testing using a 128Hz tuning fork is an essential part of large-fiber neuropathy assessment. A reduction in vibration perception suggests early involvement of large nerve fibers. Pinprick and Temperature Sensation: These tests assess small-fiber function, which is typically impaired in the early stages of DPN. Pinprick sensation and the ability to distinguish between warm and cool stimuli are critical for detecting small-fiber neuropathy [48].

Scoring Systems

Several scoring systems have been developed to quantify DPN severity:

· Michigan Neuropathy Screening Instrument (MNSI): This scoring system combines a symptom questionnaire with a clinical examination to assess both small and large nerve fiber involvement (American Diabetes Association Professional Practice Committee, 2022, [49]).

· Neuropathy Symptom Score (NSS): This tool rates the severity of neuropathic symptoms and helps in grading the condition [48].

Electrophysiological Testing

Nerve Conduction Studies (NCS)

NCS remains the gold standard for diagnosing large-fiber neuropathy. This test evaluates nerve function by measuring conduction velocity and response amplitude. In patients with DPN, reduced nerve conduction velocities and low-amplitude responses indicate axonal damage or demyelination [50]. NCS is particularly valuable in differentiating DPN from other forms of neuropathy.

Electromyography (EMG)

EMG is used in conjunction with NCS to assess muscle activity and differentiate between neuropathic and myopathic conditions. While not always necessary in DPN diagnosis, EMG can be helpful in ambiguous cases [51].

Therapeutic Approaches for DPN

We have explored the various therapeutic strategies for DPN, focusing on current treatments, emerging approaches, and potential future therapies aimed at addressing the key mechanisms involved in the progression of DPN.

Current Therapeutic Approaches

The current management of DPN primarily focuses on glycemic control and symptomatic treatment. These approaches are essential to delay the progression of neuropathy and manage neuropathic pain, but they do not reverse nerve damage or directly target the underlying causes.

Glycemic Control: Tight glycemic control remains a cornerstone in the management of DPN, as chronic hyperglycemia is the primary factor driving nerve damage. Studies have shown that maintaining optimal blood glucose levels can reduce the risk of developing DPN and slow its progression [52]. However, in patients with established DPN, glycemic control alone is often insufficient to reverse nerve damage, highlighting the need for additional therapeutic strategies. Pain Management: Neuropathic pain is a common and debilitating symptom of DPN. First-line treatments for pain include anticonvulsants such as gabapentin and pregabalin, and serotonin-norepinephrine reuptake inhibitors (SNRIs) like duloxetine [13]. While these medications help alleviate pain, they do not address the underlying causes of DPN or prevent further nerve damage. Additionally, opioid analgesics may be used for severe pain, but their long-term use is associated with significant risks, including tolerance and dependence [2].

Emerging Therapeutic Approaches

In recent years, there has been significant progress in understanding the pathophysiology of DPN, leading to the development of novel therapeutic approaches aimed at targeting the mechanisms underlying nerve damage. These emerging therapies include antioxidant therapy, anti-inflammatory agents, neurotrophic factors, and gene therapy [53].

Antioxidant Therapy: Oxidative stress plays a crucial role in the pathogenesis of DPN by causing damage to neurons and Schwann cells. Antioxidants such as alpha-lipoic acid (ALA) have been shown to reduce oxidative stress and improve nerve function in patients with DPN [54]. ALA acts by scavenging reactive oxygen species (ROS) and enhancing mitochondrial function, thereby reducing neuronal apoptosis. Additionally, acetyl-L-carnitine has been investigated for its neuroprotective properties and has shown promise in clinical trials for improving nerve conduction and reducing pain [55]. Anti-inflammatory Agents: Chronic inflammation is another key factor contributing to the progression of DPN. Several studies have investigated the use of anti-inflammatory agents, including nonsteroidal anti-inflammatory drugs (NSAIDs) and cytokine inhibitors, to reduce inflammation and prevent further nerve damage. Drugs targeting the nuclear factor kappa B (NF-κB) pathway, which is a major regulator of inflammation, have shown potential in preclinical studies [56]. Additionally, therapies targeting pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) are being explored as potential treatments for DPN [30]. Neurotrophic Factors: The loss of neurotrophic factors, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), contributes to neuronal degeneration in DPN. Experimental therapies aimed at increasing the levels of these neurotrophic factors have shown promise in promoting nerve regeneration and preventing further damage. NGF mimetics and BDNF analogs are currently being investigated for their potential to enhance neuronal survival and improve functional outcomes in DPN patients [57]. Gene Therapy: Gene therapy represents a novel approach for treating DPN by targeting the genetic pathways involved in nerve damage and repair. Preclinical studies have demonstrated that gene therapy can increase the expression of neurotrophic factors, enhance mitochondrial function, and reduce oxidative stress in animal models of DPN [9]. Although gene therapy is still in the early stages of development, it holds significant potential as a long-term treatment option for DPN. Stem Cell Therapy: Stem cells have the ability to differentiate into various cell types, including neurons and Schwann cells, making them an attractive option for regenerating damaged nerves. Mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs) have shown promise in preclinical models of DPN by promoting nerve regeneration and reducing inflammation [58, 42]. Clinical trials are currently underway to evaluate the safety and efficacy of stem cell therapy in patients with DPN.

Mitochondrial Dysfunction and Therapeutic Approaches

Mitochondrial dysfunction contributes to diabetic peripheral neuropathy (DPN) by impairing energy production and increasing oxidative stress. Therapeutic strategies include: Mitochondrial-Targeted Antioxidants: MitoQ reduces oxidative stress, protects mitochondria, and preserves neuronal function in preclinical DPN models. Clinical trials are underway to evaluate its efficacy [39]. Pharmacological Agents for Biogenesis: PGC-1α activators enhance mitochondrial biogenesis, improving ATP production and reducing neuronal damage [59].

Targeting Vascular Dysfunction in DPN

Vascular dysfunction exacerbates nerve ischemia in DPN. Key therapeutic approaches include: Vasodilators: NO donors and phosphodiesterase inhibitors improve blood flow, restoring oxygen and nutrients to ischemic nerves [60]. Anti-Angiogenic Therapies: VEGF inhibitors reduce abnormal blood vessel growth, enhancing vascular function in preclinical studies.

Immunotherapy in DPN

Immune system involvement in DPN progression highlights potential immunotherapeutic targets: Immune Modulation: Therapies inhibiting T-cell activation and modulating macrophage polarization reduce inflammation and promote repair. Checkpoint Inhibitors: Borrowing from cancer treatments, these agents enhance immune-mediated nerve repair by blocking inhibitory immune signals.

Controversies Regarding Diabetic Peripheral Neuropathy (DPN)

Despite widespread occurrence and significant impact of DPN on patients' quality of life, several controversies exist regarding its diagnosis, classification, management, and understanding of its pathophysiological mechanisms. We have delved deep into the various controversies surrounding DPN, drawing on recent scientific discussions and clinical debates.

Controversies in Diagnosis and Classification

One of the major controversies in DPN is the lack of standardized diagnostic criteria. Multiple guidelines recommend different diagnostic tools and thresholds, leading to significant variability in how DPN is identified across clinical settings [61]. Some clinicians rely on nerve conduction studies (NCS), while others emphasize clinical examinations or patient-reported outcomes. The use of NCS is often considered the gold standard, but it has limitations, including its sensitivity in detecting small fiber neuropathy, which is an early form of DPN [61]. In terms of classification, DPN is traditionally divided into two broad categories: painful and painless neuropathy. However, some studies suggest that this dichotomy oversimplifies the condition, as patients may experience fluctuating symptoms, and some may not fit neatly into these categories. Additionally, distinguishing between DPN and other neuropathies (e.g., idiopathic or chemotherapy-induced) remains challenging, particularly in older populations where multiple comorbidities can obscure the diagnosis [61].

Pathophysiological Debates

The underlying pathophysiology of DPN is another area of controversy. While hyperglycemia-induced nerve damage is well-established as a primary driver of DPN, several other mechanisms have been proposed, including oxidative stress, mitochondrial dysfunction, and inflammation. However, the exact interplay between these factors remains unclear. For instance, it is debated whether oxidative stress is a primary cause of nerve damage or a byproduct of hyperglycemia, and whether targeting oxidative pathways would provide substantial therapeutic benefit [61].

Another contentious issue is the role of advanced glycation end-products (AGEs) in DPN progression. While AGEs are known to accumulate in diabetic patients and contribute to nerve damage, some researchers argue that their role may be overstated and that other factors, such as dyslipidemia and inflammation, may play equally significant roles [61].

Moreover, recent evidence points to the involvement of mitochondrial bioenergetics and dysfunction in DPN. This has led to debates about the potential for treatments that target mitochondrial health, although clinical trials have produced mixed results [61]. The lack of consistent findings in this area further complicates the understanding of DPN pathogenesis.

Controversies in Pain Management

The management of pain in DPN is fraught with controversy. The mainstay treatments for painful DPN include anticonvulsants (e.g., pregabalin, gabapentin), antidepressants (e.g., duloxetine, amitriptyline), and opioids. However, there is significant debate over the efficacy and safety of these treatments. For example, while pregabalin is widely prescribed, its effectiveness in real-world settings has been questioned due to issues with patient adherence and its side effects, such as dizziness and weight gain [61]. Opioid use in DPN is especially controversial due to the risks of addiction and overdose. Despite the potential for opioids to provide short-term pain relief, many experts argue against their use for chronic DPN due to the high risk of dependency and the relatively modest benefits observed in clinical trials [61]. This has led to a push for non-opioid alternatives, although finding effective replacements remains a challenge.

Discrepancies in Treatment Guidelines

Another area of controversy lies in the discrepancies between various treatment guidelines for DPN. For instance, while the American Diabetes Association (ADA) emphasizes glycemic control as the cornerstone of DPN prevention and management, other guidelines, such as those from the European Federation of Neurological Societies (EFNS), place more emphasis on symptomatic treatment and pain management [61]. These differences can lead to confusion among clinicians about the best course of action, particularly in patients with complex presentations.

Furthermore, while tight glycemic control is advocated for preventing DPN, especially in type 1 diabetes, there is ongoing debate about its effectiveness in type 2 diabetes. Some studies suggest that intensive glycemic control in type 2 diabetes may have only modest effects on reducing DPN risk, while increasing the risk of hypoglycemia and other complications [61]. This has led to calls for more individualized treatment plans that consider the patient’s overall health and risk profile.

Genetic Predisposition and Environmental Factors

There is also considerable debate about the role of genetic predisposition in the development of DPN. While some studies have identified genetic variants associated with an increased risk of DPN, these findings have not been consistently replicated across different populations (Schreiber et al., 2015). Additionally, the interplay between genetic factors and environmental exposures, such as diet and physical activity, remains poorly understood, further complicating efforts to predict which patients are at highest risk [61].

Personalized Medicine for Diabetic Peripheral Neuropathy (DPN)

Traditional treatment approaches for DPN have largely been generalized, focusing on symptom management rather than addressing the underlying pathophysiological differences among patients. Personalized medicine, which tailors’ medical treatment to the individual characteristics of each patient, offers a promising approach to improve outcomes in DPN management [42]. The heterogeneity in presentation of DPN underscores the need for personalized treatment strategies that consider the unique genetic, environmental, and lifestyle factors influencing each patient’s condition [62]. Table 3 summarizes the key aspects of Personalized Medicine Approaches for Diabetic Peripheral Neuropathy.

Tables and Figures

Conclusion