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Unraveling the Pathogenic Mechanisms of Diabetic Distal Symmetric Diabetic Polyneuropathy: The Interplay of Oxidative Stress and Neuroinflammation

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Unraveling the Pathogenic Mechanisms of Diabetic Distal Symmetric Diabetic Polyneuropathy: The Interplay of Oxidative Stress and Neuroinflammation

  • Roopa Sharma 1
  • Zhao Zhong Chong 1
  • Daniel L. Menkes 2
  • Nizar Souayah 1*

1 Department of Neurology, Rutgers University, New Jersey Medical School, 90 Bergen Street DOC 8100, Newark, NJ 07101

2 Department of Neurology, Oakland University William Beaumont School of Medicine, 3555 West 13 Mile Road, Suite N120, Royal oak, MI 48073

* Corresponding Author: Nizar Souayah, Department of Neurology, Oakland University William Beaumont School of Medicine, 3555 West 13 Mile Road, Suite N120, Royal oak, MI 48073

Citation: R Sharma, Z Z Chong, D L Menkes, N Souayah. (2024). Unraveling the Pathogenic Mechanisms of Diabetic Distal symmetric diabetic polyneuropathy: The Interplay of Oxidative Stress and Neuroinflammation. Clinical Trials and Analysis, The Geek Chronicles. 1(1): 1-12

Received: February 12, 2024 | Accepted: February 16, 2024 | Published: February 24, 2024


Objectives:  To review mechanisms underlying the pathological process of diabetic neuropathy (DN) that are associated with oxidative stress and inflammation.

Methods: The literature review was focused on oxidative stress, inflammation, and their interactions developed during chronic hyperglycemia.

Results: Glucose undergoes aberrant processing through various pathways including the polyol pathway, hexose monophosphate shunt, protein kinase C (PKC) pathway, and glycosylation leading to advanced glycation end product (AGE) production. The activation of these pathways disrupts the delicate balance between oxidative and antioxidative mechanisms, resulting in an overproduction of reactive oxidative radicals. This induction of oxidative stress subsequently triggers inflammation in the perineurial environment, activating downstream inflammatory pathways such as AGE/RAGE, nuclear factor- κB, mitogen-activated protein kinase, and the poly (ADP-ribose) polymerase pathway. The synergistic effect of oxidative stress and inflammation injuries compromised axons, Schwann cells, and neurovascular flow, culminating in the development of a distal symmetric polyneuropathy.

Conclusions:  Nerve injury in DN has been linked to increased free radical formation and inflammatory reactions induced by aberrant metabolic pathways that result from chronic hyperglycemia.  Understanding these mechanisms provides an opportunity to identify potential therapeutic targets for DN.

Keywords: Diabetic neuropathy; oxidative stress; inflammation; advanced glycation end product; nuclear factor- κB; protein kinase C


Diabetes mellitus (DM) results in chronic hyperglycemia that often results in microvascular complications, including neuropathy.  The worldwide prevalence of diabetes was 9.3% (464 million) in 2019 and is projected to increase to 10.2% (578 million) by 2030 and to 10.9% (700 million) by 2045 (IDF Diabetes Atlas 2019).  This will lead to an increase in diabetic complications including diabetic neuropathy (DN) and associated amputations.

DN is the most prevalent and debilitating complication of diabetes, affecting nearly 8% of people at the time of diagnosis [1].   Notably, glucose intolerant or “pre-diabetic” patients may display early signs of neuropathy, particularly originating from small nerve fibers origin prior to developing DM of which approximately 50% develop DN  [2].  The literature indicates that older diabetic patients, especially those who are tall or have a history of obesity, dyslipidemia, or hypertension, have an increased risk of developing DN [3].  Distal symmetric diabetic polyneuropathy (DSP) represents the most common form of DN and is the primary pathology that necessitates non-traumatic amputation of the lower extremities [1].

Given the escalating global prevalence of DM, it is imperative to identify potential treatment options for DM before DSP ensues.  Nonetheless, the dearth of effective treatment options to forestall this late-stage complication arises from an incomplete comprehension of the pathophysiology of diabetic DSP.  The prevailing theory is that DSP results from  axon loss, thus implying irreversibility  [4].  While conduction slowing mediated by inflammation is generally considered reversible diabetic DSP cases, may respond to immunomodulatory therapy  [5-7].  Notably,  conduction slowing has been reported in 32% of individuals with DM, which has been attributed to immune-mediated neuropathy induced by chronic hyperglycemia [8].  Nerve conduction studies in diabetic patients have revealed demyelination-induced conduction slowing  [9]. Nerve biopsies have demonstrated pathological evidence of demyelination/remyelination in DSP [10].  Thus, elucidation of the mechanisms underlying demyelinating nerve pathology would permit the development of novel therapeutic measures for DSP.

Oxidative stress and inflammation have been identified as significant contributors to the progression of diabetes and diabetic neuropathy  [4,6-8,11-13].  DM generated byproducts can induce inflammation and oxidative stress.  In this review, we explore both euglycemic and hyperglycemic states, delving into the involvement of the polyol pathway, hexose monophosphate (HMP) shunt, protein kinase C (PKC), AGE products, and their roles in the pathogenesis of DSP.  Additionally, we discuss the downstream activation pathways, including nuclear factor (NF)-κB, mitogen-activated protein kinase (MAPK), as well as poly (ADP-ribose) polymerase (PARP) activation, which can result in the release of inflammatory cytokines. Furthermore, we explore the influence of genetic and environmental factors in the development of DSP.

Oxidative Stress and Aberrant Metabolism

Glucose metabolism under euglycemia

Under physiologic euglycemia, glucose levels are tightly regulated by insulin. Following a meal, increased blood sugar levels prompt pancreatic beta cells to release insulin. Insulin facilitates the uptake of glucose by insulin-sensitive tissues such as muscles and inhibits the liver’s production of new glucose through gluconeogenesis. Notably, organs with high glucose consumption, including the brain, liver, red blood cells, and gut, do not rely on insulin for their glucose uptake.

In the euglycemic state, approximately 80-90% of glucose metabolism occurs by a glycolytic pathway, subsequently entering the Krebs cycle. This process generates nicotinamide adenine dinucleotide (NADH) and Flavin adenine dinucleotide (FADH2), which undergo oxidative phosphorylation within the mitochondria, leading to the production of adenosine triphosphate (ATP). NADH transfers electrons to mitochondrial complex 1 of the electron transport chain (ETC), whereas FADH2 transfers electrons to mitochondrial complex 2 of the ETC. Additionally, under physiological conditions, 10-20% of glucose is metabolized through the hexose monophosphate (HMP) pathway [11,14,1].

Glucose metabolism under

In a hyperglycemic state, an excess influx of glucose enters glycolysis, leading to increased NADH production from NAD+. This heightened production of NADH places an increased burden on mitochondrial complex 1 of the electron transport chain (ETC) to oxidize NADH, resulting in the generation of excessive superoxide ions and inducing oxidative stress, as illustrated in Figure 1.

Figure 1: Glucose is converted to pyruvate through glycolysis, which then enters the mitochondria to by metabolized by the Krebs cycle. Under hyperglycemia, excessive production of NADH and FADH2 is utilized by complex 1 of electron transport chain to form superoxide ions, resulting in increased oxidative stress.

The elevated superoxide ions and the induction of oxidative stress impede the activity of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). This inhibition leads to a decrease in glucose metabolism through glycolysis and an accumulation of glucose precursor products that divert into alternative pathways. Under chronic hyperglycemic conditions, five significant alternative pathways become activated: the polyol pathway, hexose monophosphate (HMP) pathway, PKC pathways, as well as the production of AGEs, and autoxidation, which generate reactive oxidative species (ROS), as depicted in Figure 2 [11,14,15].

Figure 2: Reactive oxidative radicals (ROSs) generated by the electron transport chain and glycolysis inhibit GAPDH. This results in the accumulation of glycolysis precursor products that are metabolized through alternative pathways, including polyol, hexose monophosphate shunt (HMP), advanced glycation end products (AGEs), and protein kinase C pathways.

Figure 3: Polyol pathway and oxidative stress.  Excess glucose enters into this pathway, in which sorbitol utilizes NADPH that is required by glutathione reductase and nitric oxide (NO) synthase activity.  Osmotic stress due to accumulated sorbitol induces depletion of other osmolytes myoinositol which are required for Na+/K+ ATPase pump function and taurine, which is an antioxidant. Furthermore, an increased NADH/NAD+ ratio inhibits the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) inducing increased upstream glycolytic precursor diacylglycerol (DAG).  DAG further increases AGE production and increases cytokines and chemokines through the activation of the NF-κB and protein kinase C pathways

Figure 4: Oxidative stress due to hyperglycemia is augmented by HMP pathway, polyol pathway and AGE pathway which in turn leads to activation of MAPK, NF-κB and PARP pathways. This induces the release of proinflammatory cytokines, microvascular ischemia, and mitochondrial dysfunction resulting in diabetic neuropathy.

Polyol pathway

Among the various pathways triggered by hyperglycemia, the polyol pathway has garnered considerable attention for its pivotal role in the development and progression of DSP [16].  Initially, glucose undergoes conversion into sorbitol through aldose reductase, utilizing one NADPH in the process. Subsequently, sorbitol transforms into fructose through the catalysis of sorbitol dehydrogenase, resulting in the generation of NADH.

Under normal physiological conditions, aldose reductase demonstrates low affinity for glucose and does not subserve a significant role in glucose metabolism.  However, in instances of hyperglycemia, the polyol pathway may metabolize up to 30% of the available glucose with an increased activity of aldose reductase. Aldose reductase, along with glutathione reductase and nitric oxide (NO) synthase, relies on NADPH as a cofactor.

The overactivity of aldose reductase during hyperglycemia leads to the depletion of NADPH levels, consequently reducing the activity of glutathione reductase and NO synthase. Glutathione reductase converts oxidized glutathione to reduced glutathione, which is essential for glutathione peroxidase to catalyze the reduction of hydrogen peroxide. In hyperglycemia, the decrease in glutathione results in the downregulation of glutathione peroxidase, contributing to increased oxidative stress.

Simultaneously, reduced NO synthase activity leads to lower levels of the vasodilator nitric oxide (NO).  Vasoconstriction leads to ischemia inducing a neuropathy with reduced conduction velocities [17].

Furthermore, the heightened production of sorbitol induces osmotic stress on Schwann cells, resulting in the depletion of other osmolytes such as taurine and myoinositol. Reduced myoinositol levels have been demonstrated to downregulate the activity of the Na+/K+ ATPase, ultimately leading to a slowing of nerve conduction.22,24,25  Additionally, taurine functions as an antioxidant such that diminished taurine levels contribute to additional oxidative stress [18].

In the second enzymatic reaction involving sorbitol dehydrogenase, NAD+ is converted to NADH. The heightened cytosolic ratio of NADH to NAD+ inhibits the glycolytic enzyme GAPDH. Consequently, an accumulation of diacylglycerol (DAG) triggers the production of AGEs and ROS by activating NADPH oxidase and PKC [19]. Moreover, the increased production of fructose in the second step leads to the metabolic production of dicarbonyls, which contribute to the generation of toxic AGEs (such as 3-deoxyglucose and methylglyoxal) that adversely affect Schwann cells [20-25].


Hmp Pathway

The hexose monophosphate shunt, also referred to as the pentose phosphate shunt, subserves a crucial role in generating NADPH, which is a vital cofactor utilized in reductive reactions such as glutathione reduction, fatty acid synthesis, and cholesterol synthesis. Additionally, it provides ribose for nucleotide synthesis. In hyperglycemic conditions, the HMP pathway is one of the few pathways that efficiently utilizes excess glucose.

Excess fructose-6-phosphate undergoes an aminotransferase reaction facilitated by the enzyme glutamine fructose-6-phosphatase, resulting in the formation of glucosamine-6 phosphate. This compound is subsequently converted to uridine diphosphate-N-acetyl glucosamine (UDP-GlcNAc). UDP-GlcNAc subserves a pivotal role in modulating transcription factors by attaching to serine and threonine residues, thereby regulating the expression of its target genes. Notably, these include transforming growth factor-β1 (TGF-β1) and plasminogen activator inhibitor-1 (PAI-1) [14,15,26-28].

Elevated levels of TGF-β1 foster endothelial fibrosis by stimulating collagen production. Furthermore, the activation of PKC and the upregulation of the HMP pathway contribute to heightened levels of plasminogen activator inhibitor-1 (PAI-1). Increased PAI-1 levels effectively inhibit tissue plasminogen activator. While reduced levels of tissue plasminogen activator have been observed in diabetic nerves, a direct relationship with PAI-1 has yet to be definitively established [29].


PKC activation

The byproduct of glycolysis, diacylglycerol (DAG), is increased during hyperglycemia. DAG serves as an activator of PKC, which results in insulin resistance, stimulation of endothelin 1, and inhibition of endothelial nitric oxide (eNOS). These effects contribute to vasoconstriction, hypoxia, and neuronal injury [30]. Furthermore, PKC activation contributes to diabetic sensorimotor polyneuropathy by increasing the production of TGF-β, PAI-1, and VEGF, or indirectly by upregulating the expression of NF-κB. The subsequent rise in proinflammatory cytokines circulating in the bloodstream further impairs microvascular flow, thus exacerbating neuronal injury [31].  PKC also activates NADPH oxidase, introducing additional oxidative stressors to the perineurial environment [30,32].


AGEs are formed through the non-enzymatic glycosylation of proteins, lipids, and nucleic acids. This process is heightened by hyperglycemia and oxidative stress [33].  Both Schwann cells and endothelial cells have been demonstrated to express the extracellular receptor for Advanced Glycation End Products (RAGE). The binding of AGE to RAGE activates the NF-κB pathway, leading to an increase in transcription factors for genes associated with inflammatory cytokines [34-37].  AGEs also activate NADPH oxidase, further amplifying the production of free radicals.

The accumulation of AGEs has been associated with a reduction in myelinated nerve fiber density and neurovascular microangiopathy [38].  Hyperglycemia induces glycation of tubulin, neurofilament, the Na+/K+ ATPase pump of the axon, and the P0 protein of Schwann cells, resulting in nerve conduction slowing [36].   AGEs also contribute to diabetic DSP through indirect damage via glycation of extracellular matrix proteins including laminin and collagen of the basement membrane. This glycation process results in the thickening of the basement membrane, impairs its permeability, and elevates the levels of inducible nitric oxide synthase (iNOS) [34,35].

Inflammatory Pathways and Dsp

 The abnormal pathways of glucose metabolism previously described have been reported to contribute to the increased release of inflammatory cytokines. Additionally, increased free radical production resulting from hyperglycemia activates NF-κB, thereby enhancing the activation of MAPK and activator protein 1 (AP-1). This cascade leads to an increased production of inflammatory cytokines, chemokines, and adhesion molecules.

NF-κB, a transcription factor, promotes the transcription of genes associated with proinflammatory cytokines, chemokines, and cell adhesion molecules Nrf2, in conjunction with its primary negative regulator, the E3 ligase adaptor Kelch-like ECH-associated protein 1 (Keap1), which subserves a pivotal role in maintaining intracellular redox homeostasis. Nrf2 regulates its anti-inflammatory function by targeting the heme oxygenase-1 (HO-1) axis [39].

In the physiological state, the activation of both NF-κB and Nrf2 is coordinated to maintain cellular oxidative-reductive homeostasis. Increased ROS levels lead to the activation of both NF-κB and Nrf2. However, Nrf2 activation is transient, while NF-κB activation persists. This imbalance results in an excess of proinflammatory cytokines and a decrease in anti-inflammatory mechanisms, further contributing to neuroinflammation [40-42].

Elevated NF-κB activity in DN has been demonstrated to induce demyelination, leading to impaired motor nerve conduction, reduced neuronal blood flow, and decreased production of analgesic mediators, resulting in pain hypersensitivity [40,41,43]..

Reduced activity of Nrf2 is linked to heightened oxidative stress in neurons, resulting in the formation of AGEs, activation of PKC, PARP-mediated apoptosis of neurons, and subsequent allodynia and hyperalgesia due to damage to the sensory fibers [44].  Elevated levels of pro-inflammatory molecules and immune cell activation also contribute to nerve injury and sensitize pain receptors in patients with DSP.

MAPK activation

MAPK, a family of serine-threonine kinases, is activated by hyperglycemia-induced oxidative stress and proinflammatory cytokines produced by various alternative pathways of glucose metabolism [44].  The three primary subfamilies of MAPKs include p38-MAPK, extracellular signal-regulated protein kinase (ERK1/2), and c-Jun terminal kinase (JNK). JNK phosphorylation triggers apoptosis in neurons through the activation of caspase 3. Additionally, ERK1/2 subserves a role in the development of pain in DN [20,45,46]. The activation of MAPK leads to the upregulation of transient receptor potential vanilloid subtype 1 (TRPV1) expression, which is responsible for hyperalgesia [47-49].

PARP activation

PARP (Poly ADP-ribose polymerase) constitutes a group of enzymes intimately engaged in DNA repair mechanisms and programmed cell death. The hyperglycemic environment triggers an overactivation of PARP, responding to DNA damage induced by oxidative stress [20,33,50].  The hyperactivation of PARP leads to the depletion of NAD+ (nicotinamide adenine dinucleotide) and ATP, inducing a deceleration in both glycolysis and mitochondrial respiration. PARP’s metabolism of NAD+ into nicotinic acid and ADP-ribose contributes to this process. The accumulated ADP-ribose polymers inhibit the GAPDH enzyme, fostering the production of DAG. This, in turn, triggers the activation of PKC and facilitates the generation of AGEs (advanced glycation end products) [50,51].  The hyperactivation of PARP also triggers the stimulation of NF-κB, AP-1, and MAPK, leading to an upregulation in the production of proinflammatory chemokines, cytokines, and adhesion molecules [52,53]. Furthermore, heightened PARP activity induces stress within the mitochondria as a result of energy consumption, ultimately initiating programmed cell death through caspase activation [54].  PARP-1 expression has been observed in Schwann cells and endothelium, highlighting its established role in microvascular angiopathy [53,55].

Genetic and Environmental Factors in DSP

Genetic and environmental factors may intertwine with intricate metabolic and inflammatory conditions in DSP, subserving a role in the disease’s pathogenesis. A systematic review exploring genetic polymorphisms and the risk of DN identified several variations (ACE I>D, MTHFR 1298A/C and 677C>T, GPx‐1 rs1050450, and CAT ‐262C/T) associated with an elevated likelihood of developing DN [56].

Angiotensin-converting enzyme (ACE) assumes a crucial role in the renin-angiotensin system by converting angiotensin Ang I to Ang II. Elevated levels of Ang II are associated with endothelial damage and microcirculatory dysfunction, potentially contributing to the development of DSP [57].  The ACE I/D polymorphism has been closely associated with the risk of diabetic nephropathy according to a study [58].  Further analysis revealed that Caucasians with the DD and ID genotypes exhibited a significantly elevated risk of developing diabetic nephropathy.

Methylenetetrahydrofolate reductase (MTHFR) is as a pivotal enzyme in homocysteine metabolism whose deficiency may result in hyperhomocysteinemia [59].  Another study reported a robust association between elevated homocysteine levels and the development of diabetic nephropathy emphasizing a significant association with hyperhomocysteinemia [60].  In vitro investigations have demonstrated that hyper-homocysteinemia may induce injury to the nervous system either by direct cytotoxicity or oxidative damage [61].  Both MTHFR 677C>T and 1298A/C polymorphisms have been reported to elevate the risk of diabetic nephropathy among patients’ with type 2 diabetes, although there are some inconsistent results among these studies [62,63].

Glutathione peroxidase-1 (GPx1) encodes an antioxidant enzyme that protects cells against oxidative damage, particularly against hydrogen peroxide and organic peroxidases [64]. Gpx1 rs105045 genotype was significantly associated with the risk of diabetic nephropathy in patients with type II diabetes [65].  The rs1050450 variant is known to reduce the activity of the enzyme, which may contribute to microvascular damage and an increased risk for developing diabetic nephropathy [56].

Catalase (CAT) is a ubiquitous enzyme that catalyzes the decomposition of H2O2 to water and oxygen, effectively neutralizing excess ROS and peroxides associated with oxidative stress in diabetic nephropathy [66].  The CAT 262T>C promoter polymorphism of the catalase gene has been linked to DN in individuals with type 1 diabetes, as indicated by research findings.

Accumulating evidence indicates that diabetic nephropathy is associated with multiple modifiable risk factors. The development of this entity is linked not only to glycemic control and diabetes duration but also to higher body mass index, elevated cholesterol and triglyceride levels, smoking, as well as hypertension [67].  At baseline, the presence of cardiovascular disease was associated with a twofold increase in the incidence rate of neuropathy [67].  In many contributing factors, oxidative stress and inflammation appear to be a common pathway that leads to diabetic nephropathy.


Despite the plethora of studies on diabetic DSP, the pathophysiology of its underlying mechanisms remains limited. Over the past two decades, there has been a shift in research focus from a glucose-centric view to recognizing the importance of oxidative stress and neuroinflammation. The development of diabetes and its complications is now acknowledged as a result of persistent, low-grade inflammation and oxidative stress. Specifically, nerve injury in DN has been linked to increased free radical formation and inflammatory reactions induced by aberrant metabolic pathways that result from chronic hyperglycemia. Understanding these mechanisms provides an opportunity to identify potential therapeutic targets for DN. Furthermore, the complex interactions of diverse pathways and their role in exacerbating neuropathy remains incompletely understood.  Thus, a comprehensive understanding of DN pathogenesis is imperative such that early diagnostic biomarkers be identified such that novel treatments can reduce the probability of developing diabetic complications.

Funding Details: This work was supported in part by RAM Capital II, start-up fund for Dr. Nizar Souayah from the Department of Neurology and Neurosciences at New Jersey Medical School.

Author Contributions:  RS: Wrote the primary manuscript; ZZC: Modified, Organized and edited the manuscript; DLM: Proofread and edited the manuscript; NS: Conceived and designed the study.

Conflict of Interest: The authors declare that they have no conflict of interest.


Copyright: © 2024 Nizar Souayah, this is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.