Cell metabolism pathways involved in the pathophysiological changes of diabetic peripheral neuropathy

Abstract

Diabetic peripheral neuropathy is a common complication of diabetes mellitus. Elucidating the pathophysiological metabolic mechanism impels the generation of ideal therapies. However, existing limited treatments for diabetic peripheral neuropathy expose the urgent need for cell metabolism research. Given the lack of comprehensive understanding of energy metabolism changes and related signaling pathways in diabetic peripheral neuropathy, it is essential to explore energy changes and metabolic changes in diabetic peripheral neuropathy to develop suitable treatment methods. This review summarizes the pathophysiological mechanism of diabetic peripheral neuropathy from the perspective of cellular metabolism and the specific interventions for different metabolic pathways to develop effective treatment methods. Various metabolic mechanisms (e.g., polyol, hexosamine, protein kinase C pathway) are associated with diabetic peripheral neuropathy, and researchers are looking for more effective treatments through these pathways.

Introduction

Current statistics indicate that more than 450 million patients have diabetes worldwide. The incidence of diabetes is expected to increase by 25% by 2030, and the global health expenditure for diabetes is expected to reach $825 billion (Saeedi et al., 2019). Diabetic peripheral neuropathy (DPN) is not only a typical complication of diabetes but also a common cause of neuropathy (Iqbal et al., 2018; So et al., 2022; Song and Wei, 2023). DPN, a precursor to infection, ulcers, amputation, and even death, poses a significant threat to patients’ physical and mental health (Ntavidi et al., 2022). A study including 17,353 patients with diabetic foot ulcers showed that the mortality rate within 2 years was approximately 23%, even after the ulcer had healed (Vadiveloo et al., 2018). Therefore, the increasing incidence of diabetes and its complications impose a heavy economic burden on many countries.

The treatment of DPN primarily involves controlling hematological symptoms such as blood glucose levels and relieving local symptoms such as nerve pain. The treatment limitations reflect both a lack of understanding of the current pathophysiological processes and mechanisms of DPN and detection and diagnostic technologies. The purpose of this review is to understand DPN from a metabolic perspective, summarize the recent advances in therapy directed at these mechanisms, and predict the development of future DPN therapy.

Database Search Strategy

For this narrative review, the references were obtained from the PubMed and Web of Science databases regarding the pathophysiology and treatment of DPN. The literature was searched using the Boolean logical connective with the following key terms: “diabetic peripheral neuropathy;” “DPN;” “peripheral nerve injury;” “peripheral nerve regeneration;” “pathophysiology;” and “metabolism.” Most of the cited references (over 70%) were published from January 2017 to January 2023.

Pathophysiology of Diabetic Peripheral Neuropathy

Researchers have explored several metabolic pathways in DPN, including the polyol, hexosamine biosynthetic (HBP), and protein kinase C (PKC) pathways and the overproduction of advanced glycation end products (AGE). Reactive oxygen species (ROS) damage and mitochondrial dysfunction may serve as their terminal pathway.

Polyol pathway

Carbohydrate metabolism, in which glucose eventually degrades to pyruvate, provides energy for most types of cells. In the context of high glucose in diabetes, the activity of hexokinase is increased. Redundant glucose switches to a secondary pathway of carbohydrate metabolism—the polyol pathway (Figure 1). In this pathway, glucose is metabolized into sorbitol by aldose reductase (AR, or ALR2), and sorbitol dehydrogenase turns sorbitol into fructose. AR, which belongs to the family of aldosterone reductases and is the regulatory target of the polyol pathway, is expressed by Schwann cells and the vascular endothelium (Niimi et al., 2018). Because of its high Michaelis constant and low glucose-binding capacity, it is only activated in high-glucose environments. Nicotinamide adenine dinucleotide phosphate (NADPH) is a reductive coenzyme that maintains redox balance in the body. Glutathione is a tri-peptide that resists oxidative damage in the body, and its redox balance is dependent on NADPH. ALR2 competitively inhibits the ability of glutathione to utilize NADPH. Reduced glutathione disrupts the redox balance, and oxidizing substances damage cells (Garg and Gupta, 2022). In addition, sorbitol cannot penetrate the cell membrane, and superfluous sorbitol increases the osmotic pressure in the cell, leading to osmotic stress-related cellular damage. Researchers are currently trying to manipulate AR by regulating its active center (Ciccone et al., 2022), which may benefit patients with DPN. The active center of AR is not rigid, allowing it to combine with a variety of structures (Quattrini and La Motta, 2019). This is the basis for AR inhibitor (ARI) development. Finally, the active center of AR has at least three elastic binding sites (Figure 2): the anion-binding pocket, the hydrophobic binding pocket, and the selectivity pocket (Kousaxidis et al., 2020).

Figure 1.

Polyol pathway.

The top row shows a polyol metabolic pathway that increases osmotic pressure, and the bottom row shows a redox imbalance that damages the cell. ALR2 competes with glutathione for NADPH, leading to a reduction in antioxidants. Increased ROS leads to oxidative damage. ALR2: Aldose reductase; GSH: glutathione; GSSG: glutathione disulfide; NADP(H): nicotinamide adenine dinucleotide phosphate; ROS: reactive oxygen species; SD: sorbitol dehydrogenase.

Figure 2.

Structures of ALR2.

(A) Three-dimensional structure of aldose reductase (AR). (B) Three active binding sites of AR. Reprinted with permission from Kousaxidis et al., 2020, Copyright © 2020 Elsevier Masson SAS. Ala: Alanine; Cys: cystine; His: histidine; Leu: leucine; NADP⁺: nicotinamide adenine dinucleotide phosphate; Phe: phenylalanine; Thr: threonine; Trp: tryptophan; Tyr: tyrosine; Val: valine.

Several types of ARIs such as carboxylic acid derivatives, spirohydantoin, and phenolic derivatives are currently being tested (Thakur et al., 2021). The most popular one is epalrestat and has been listed in Japan, China, and India (Grewal et al., 2016). The current research on ARI and related treatments are insufficient (Rendell, 2021). ALR2 is essential for extrahepatic aldehyde metabolism, renal osmotic regulation, and sperm energy production. Not all ARIs can be targeted at the site of diabetic complications, such as the peripheral nervous system, which reduces their therapeutic efficacy (Feldman et al., 2017). Aldehyde reductase is structurally similar to ALR2. ARIs are not specific enough to avoid side effects. We will also discuss ARI in a subsequent section of the review.

HBP and PKC pathway

High glucose activates the HBP (Figure 3). Glycometabolism, fat metabolism, amino acid metabolism, and nucleotide metabolism are all involved in the HBP (Peterson and Hart, 2016). Glucosamine 6-phosphate forms UDP-N-acetylglucosamine in glycometabolism. Glutamine fructose 6-phosphate aminotransferase 1 is the critical enzyme in glucose metabolic process. The acylation of Ser-Thr residues is regulated by O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) and O-GlcNAcase (OGA). OGT and OGA participate in intracellular transport, signal transduction, transcription, and posttranslational modification, among other processes. In the case of DPN, specific knockout (KO) of the OGT gene in the sensory neurons of mice result in an increased threshold of neural responses to mechanical stimuli and temperature and a decreased number of cultured neuronal axons (Su and Schwarz, 2017). Previous studies have indicated that O-GlcNA acylation is critical in DPN (Kim et al., 2016; Su and Schwarz, 2017). Moreover, diacylglycerol is created from the intermediate products of glycolysis and subsequently launches the PKC-dependent pathway of nerve cells. Activated PKC damages nerves and endothelium by altering the Na-K pump and induces the opening of the transient receptor potential vanilloid 1 channel (Feldman et al., 2017).

Figure 3.

HBP and PKC pathway.

GFAT regulates glucose in the synthetic pathway of hexosamine. G-3-P leads to the accumulation of diacylglycerol, which activates the PKC signaling pathway. DAG: Diacylglycerol; F-6-P: fructose 6-phosphate; G-3-P: glyceraldehyde 3-phosphate; G-6-P: glucosamine 6-phosphate; GFAT: glutamine fructose6phosphate aminotransferase; HBP: hexosamine biosynthetic pathway; O-GlcNAc: O-linked β-N-acetylglucosamine; PKC: protein kinase C; Ser: serine; Thr: threonine; UDP-GLcNAc: uridine diphosphate-N-acetylglucosamine.

As the key molecules in the HBP, regulating glutamine fructose 6-phosphate aminotransferase 1, OGT, and OGA is expected to slow down the development of DPN. Although progress has been made regarding OGT (Ryan et al., 2021), the research and application of OGT-KO are somewhat lacking. As OGT participates in the cell cycle and mitosis during the embryonic period, OGT-KO has been shown to be lethal in embryonic mice (Issad et al., 2022). Additionally, modified O-GlcNAc acylation plays a role in numerous metabolic activities, including the promotion of endothelium migration (Xing et al., 2021). However, side effects resulting from blindly OGT-KO outweigh the therapeutic effects. Therefore, the ideal treatment should control O-GlcNAc acylation in a narrow but effective range through dynamic regulation via OGT and OGA.

AGE pathway

The chemical interaction between the aldehyde group of the reducing sugar and the amino group of the protein is called the Maillard reaction (Feldman et al., 2017), and AGEs are used to define these terminal substances. AGEs are enriched in nerve cells and can cause cell damage (Pramanik et al., 2022). AGEs also reduce the multiplication of Schwann cells and increase apoptosis (Xu et al., 2019b). Under high-glucose conditions, fructose generated from the polyol pathway converts to 3-deoxyglucosone (Figure 4). Furthermore, glyceraldehyde 3-phosphate is an intermediate product of the glycolytic process that is converted to methylglyoxal by glyceraldehyde 3-phosphate dehydrogenase. As a result, 3-deoxyglucosone and methylglyoxal promote the fabrication of AGEs (Mizukami and Osonoi, 2020). AGE receptors (RAGEs) are an immunoglobulin superfamily of polygenic receptors expressed in endothelial and Schwann cells that can bind to multiple ligands and activate different signaling pathways, resulting in injury (Pinto et al., 2022). RAGEs are regulated by nuclear factor-κB, which mediates the damage of downstream signals. Mediating AGE-RAGE interactions may be critical in treating diabetic and non-diabetic cardiovascular pathologies. For example, AGEs can impair the central nervous system, leading to cognitive impairment, and AGE accumulation in a high-glucose environment can lead to osteoarthritis (Li et al., 2021).

Figure 4.

AGE pathway.

Fructose produces 3-deoxyglucosone. Methylglyoxal can be generated from G-3-P during glycolysis. Methylglyoxal and 3-deoxyglucosone are intermediate products of AGE. AGE: Advanced glycation end product; F-6-P: fructose 6-phosphate; G-3-P: glyceraldehyde 3-phosphate; RAGE: advanced glycation end product receptors.

AGEs exist even in healthy elderly people. They can be produced in cells or taken up by the outside environment, and multiple sources generate AGEs in humans (Pinto et al., 2022). The diversity of the types and sources of AGEs and their interactions with numerous signaling pathways make their understanding more challenging. Recently, Wang et al. (2017) promoted diabetic wound healing by inhibiting the AGE-RAGE signaling pathway in macrophages. These results suggest that blocking the signaling pathways related to AGEs and RAGEs may be a feasible therapeutic approach for DPN.

Common Pathogenesis in Diabetic Peripheral Neuropathy

ROS damage

Oxidative stress (OS) caused by high blood sugar is the predominant mechanism underlying DPN (Pang et al., 2020). Oxidative and antioxidant substances are present in neurons and Schwann cells. Moreover, OS may be the common pathogenic aspect of the polyol, hexosamine, AGE, and PKC pathways. An enhanced polyol pathway depletes the quantity of NADPH, resulting in oxidative damage within nerve cells (Thakur et al., 2021). Increased glucose flow in the inner mitochondrial membrane forms a high proton gradient that disrupts the normal metabolism of ROS. The HBP in mitochondria decreases electron transfer efficiency in the respiratory enzyme complex, increasing ROS leakage (Eftekharpour and Fernyhough, 2022). Moreover, AGE-RAGE binding on vascular endothelial cells leads to impaired oxygen delivery. Finally, inflammatory damage associated with macrophage RAGEs leads to an increase in intracellular ROS.

Although multiple metabolic mechanisms collectively point to OS, the source of ROS may differ (Eftekharpour and Fernyhough, 2022). Sas et al. (2016) found that glucose metabolism increases in diabetic nephropathy and retinopathy through metabolomics and decreases in nerve tissue. These findings demonstrate the tissue specificity of metabolism. Even within the nervous system, the types of neurometabolic changes differ. For example, sciatic nerve metabolism was found to be upregulated in rats and downregulated in the root and cranial nerves (Freeman et al., 2016). Moreover, the capacity for tolerance differs among types of tissue, and cells with upregulated metabolism can also experience an energy deficiency at later stages. Therefore, further research is needed with respect to the process of metabolism.

Mitochondrial dysfunction

Mitochondria participate in the metabolic energy imbalance of DPN (Chowdhury et al., 2013). The proper quantity, quality, distribution, and normal state of fission and fusion are critical to mitochondrial function.

Mitochondria generate most of the ROS in the cell. In DPN, the mitochondrial respiratory chain efficiency in neurons decreases. Therefore, oxidative phosphorylation is decoupled from electron transport, and excessive generation of ROS results in reduced mitochondrial mass and quantity (Yao et al., 2022). Endoplasmic reticulum stress releases large amounts of calcium ions through calcium channels, leading to increased mitochondrial calcium concentrations that damage the mitochondria while releasing mitochondrial DNA (mt-DNA) into the cytoplasm to attract the migration of neutrophils toward the stressed cell (Vig et al., 2022). Neurotransmitter U damages mitochondrial function in terms of islet β-cell mitochondrial production and Ca²⁺ absorption (Zhang et al., 2020). Therefore, targeted inhibition of calcium channels provides a potential method for treating DPN. The calmodulin-dependent protein kinase kinase-β-adenosine monophosphate AMP-activated protein kinase sirtuin peroxisome proliferator-activated receptor-γ coactivator α axis signaling pathway may play a role in diabetic neuropathy-mitochondrial dysfunction (Long et al., 2016).

In addition, mitochondria maintain the physiological structure and exert their normal metabolic function through fission, fusion, and directional transport (Suárez-Rivero et al., 2016). Mitochondrial fusion proteins 1 and 2 and optic atrophy 1 regulate mitochondrial fusion, and mitochondrial fission 1, mitochondrial fission factor, and dynamin-related protein 1 regulate mitochondrial fission (Sidarala et al., 2022). Under normal circumstances, fission-fusion maintain a dynamic equilibrium. Fission can be central, which is involved in cell reproduction, or peripheral, which is used to remove damaged material (Kleele et al., 2021). Excessive fission activates the extracellular regulated protein kinase pathway. The pro-apoptotic protein, Bax triggers mitochondrial calcium to release cytochrome c and mt-DNA to render impairment through opening the voltage-driven anion channel 1 and mitochondrial permeability transition pore complex (Tricaud et al., 2022). Oxidized mt-DNA must be cleaved by flap-structure-specific endonuclease 1 before it can enter the cytoplasm to activate the inflammatory response via the mitochondrial permeability transition pore. Therefore, flap-structure-specific endonuclease 1 inhibitors may be effective targets for inflammatory injury (Xian et al., 2022).

Fusion-related proteins not only maintain mitochondrial function but are also involved in regulating the immune system. The expression of interleukin-17 decreases after KO of the optic atrophy-1 gene in Treg cells, and knocking out liver-associated kinase1 restores interleukin 17 expression (Baixauli et al., 2022). Whether mitotic fusion and division-related proteins in inflammatory cells in DPN are similarly regulated remains unclear. However, damage to mitochondria can also lead to nerve damage. Recent work by Rumora et al. (2019) on the effect of dyslipidemia on mitochondrial transport has shown that metabolic abnormalities contribute similarly to altered mitochondrial distribution.

Figure 5.

ROS and mitochondrial dysfunction.

ROS induce an imbalance in mitochondrial fission and fusion, leading to inflammation and cell death. Damaged mitochondria further increase ROS production, exacerbating the process. ATP: Adenosine triphosphate; Cyt-c: cytochrome c; MPTP: mitochondrial permeability transition pore; mt-DNA: mitochondria deoxyribonucleic acid; ROS: reactive oxygen species; VDAC1: voltage-dependent anion channel 1.

Figure 6.

The relationship among the metabolic pathways.

AGE: Advanced glycation end product; ALR2: aldose reductase; DAG: diacylglycerol; F-6-P: fructose 6-phosphate; G-3-P: glyceraldehyde 3-phosphate; G-6-P: glucosamine 6-phosphate; GFAT: glutamine fructose-6-phosphate aminotransferase; GSH: glutathione; GSSG: glutathione disulfide; HBP: hexosamine biosynthetic pathway; NADP(H): nicotinamide adenine dinucleotide phosphate; O-GlcNAc: O-linked β-N--acetylglucosamine; PKC: protein kinase C; RAGE: advanced glycation end product receptors; ROS: reactive oxygen species; SD: sorbitol dehydrogenase; Ser: serine; Thr: threonine; UDP-GLcNAc: uridine diphosphate-N-acetylglucosamine.

Immune system dysfunction

Immune dysfunction and DPN are closely related (Hotamisligil, 2006). On the one hand, there is an increase in immune cell infiltration in the tissues of DPN patients. A transcriptome sequencing study on human and rodent DPN has shown that various cytokines and chemokines might play a role in DPN (McGregor et al., 2018). A meta-analysis on tumor necrosis factor-α (TNF-α) in DPN showed that diabetic patients with DPN have higher serum levels of TNF-α than those without DPN and healthy individuals (Mu et al., 2017). The infiltration of regulatory T cells in the sciatic nerves of DPN patients is higher than in the control group (Xue et al., 2021).

On the other hand, inflammation-associated cytokines may impact the development of diabetic neuropathy. In the immune microenvironment of damaged nerves, various immune cells are involved in sequential inflammatory signaling (Wang et al., 2022). Macrophages, mast cells, and T cells all participate in the onset of DPN (Li et al., 2022b). Macrophages play a crucial role in nerve injury repair. Specifically, metabolically reprogrammed M2 macrophages exhibit enhanced oxidative phosphorylation and tissue repair capabilities (Yao et al., 2023a). The inflammatory process in DPN may be mediated by TNF-α (McGregor et al., 2018). However, the relationship between immune and metabolic dysregulation is akin to the “chicken and egg” issue. As mentioned earlier, previous research has primarily focused on metabolic aspects such as blood sugar control and enzyme activity regulation. Hence, modulation of the immune microenvironment in DPN is gradually gaining more importance.

Advances in Treatment of Diabetic Peripheral Neuropathy

A previous study showed that diabetic patients with fast glucose variability and postprandial hyperglycemia are at increased risk of painful DPN (Pai et al., 2021). A study of 1441 diabetic patients showed that patients with intensive glucose control (IGC) and lower glycated hemoglobin had a 64% lower chance of developing DPN (Braffett et al., 2020). Similarly, a retrospective investigation of 120 patients with type 2 diabetes showed that the closer the extended blood glucose control was to the regular content, the more likely it was to lower the risk of DPN (Li et al., 2022a). Additionally, the level of glycated hemoglobin l was reported to predict neurodegeneration in patients with DPN; thus, controlling glycemic stabilization may prevent persistent nerve injury (Hur et al., 2013). These studies demonstrate that regulating blood glucose may reduce the occurrence and progression of neurologic complications of diabetes. Therefore, systemic blood glucose control is necessary to treat complications.

However, studies have also shown that IGC cannot completely prevent these complications, whereas other studies have suggested that IGC does not significantly decrease the morbidity rate of DPN (Diabetes Control and Complications Trial Research Group et al., 1993; Callaghan et al., 2012). Furthermore, different types of diabetes respond differently to IGC (Mizukami and Osonoi, 2020). These phenomena suggest that different types of diabetes may have similar clinical manifestations but different pathogeneses, requiring different therapies (Feldman et al., 2019).

Nevertheless, some therapeutic options for DPN have been provided. Although drugs such as anticonvulsants, tramadol, serotonin-norepinephrine reuptake inhibitors, and capsaicin have some effect in relieving symptoms they do not act on the possible metabolic mechanisms or halt disease progression (Changjin, 2013). Therefore, future treatments should focus on the pathophysiological mechanisms of DPN to cure this disease.

ARIs

ARIs may ameliorate DPN by interfering with neural metabolic mechanisms such as inhibiting enzyme activity centers and reducing OS (Li et al., 2016). More than 15 types of ARIs have been discovered, the most representative of which are carboxylic acid derivatives, spirohydantoin, and phenolic derivatives (Grewal et al., 2016; Table 1). Their carboxylic acids, spirals, benzene rings, and hydroxyl groups have active lone pair electrons. Moreover, ARIs attach to different active sites through hydrogen bonds or van der Waals forces to inhibit enzymatic activity. The first ARI—tetramethylene glutaric acid—was developed in the 1960s (Changjin, 2013). Although the number of ARIs continues to increase, most are considered useless because of their low selectivity and low efficacy (Kuthati et al., 2020). Current ARI research focuses on identifying or synthesizing new ARIs; optimizing the pharmacokinetics (absorption, distribution, metabolism, excretion); and selecting appropriate drug delivery methods.

Table 1.

Common aldose reductase inhibitors

Classification	Name	Structural formula	Mechanism	Reference
Carboxylic acid	Alrestatin		Relieves clinical symptoms and decreases nerve conduction velocity, but may cause rash	Grewal et al., 2016
	Epalrestat		Accelerates the conductive speed of sensory and motor nerves. Alleviates subjective symptoms, but elevates liver enzyme levels and causes a gastrointestinal tract reaction, such as nausea, vomiting and diarrhea	Sharma and Sharma, 2008
	Tolrestat		Slows the conductive functional reduction of motor nerves and myelinated nerve fiber density and diameter	Morikawa et al., 2021
Spirohydantoi-n derivatives and their analogs	Sorbinil		Withdrawn because of adverse effects such as rashes, fever, and muscle pain	Dewanjee et al., 2018
	Fidarestat		Improves nerve blood flow, reduces oxidative damage, restores electrophysiological function of nerves, subjective symptom relief, no noticeable side effects	Strycharz et al., 2018
	Ranirestat		Promotes the conductive rate of sensory nerves and alleviates the decrease in fiber density in the epidermis	Asano et al., 2019
Phenolic compounds and their analogs	p-Coumaric acid ethyl ester		Affects the catalytic activity of aldose reductase by altering secondary and tertiary conformations of the enzyme	Yang et al., 2022b
	Quercitrin		Reduces mechanical and temperature hyperalgesia and relieves oxidative stress	Yan et al., 2022
	Gallic acid		Selectively inhibits aldose reductase, without reducing its ability to detoxify toxic substances such as lipid peroxidation products.	Balestri et al., 2020

Carboxylic acid derivatives comprise the majority of ARIs. The carboxyl group binds stably to the anion-binding position of ALR2 through hydrogen bonds. One such example is epalrestat, the only drug on the market to treat DPN. Epalrestat, taken orally three times daily at a dose of 50 mg, results in increased sensory and motor function and ameliorates subjective symptoms in patients with diabetic neuropathy (Ramirez and Borja, 2008). However, its application is hindered because of its complicated usage, low half-life, and hepatotoxicity. Choudhary et al. (2021) designed ester- and amide-linked epalrestat-interacting precursors, and sustained release of these drugs increased the half-life of epalrestat. Moreover, combining antioxidants with the parent drug can enhance the therapeutic index of the drug. Another study found that methyl ferulate-conjugated epalrestat may act as a defensive agent against DPN (Choudhary et al., 2021). Another research group designed an oral lipid-based epalrestat nanoformulation to reduce the administration frequency and hepatotoxicity of the drug (Vishwakarma et al., 2022). In addition, many types of ARIs are currently undergoing clinical trials, but treatment prospects are not optimistic owing to various side effects. In general, ARIs are relatively effective drugs, but researchers are working to improve their efficacy and specificity by optimizing the structures, adjusting the pharmacokinetics, and reducing the side effects.

HBP and PKC pathway inhibitors

Researchers have proposed several inhibitors of the HBP and PKC pathways. Benfotiamine, which is a thiamine derivative, can direct fructose-6-phosphate into the hexose monophosphate pathway by activating transketolase, then reducing the substrate content of the HBP, and inhibiting the PKC pathway (Hammes et al., 2003). However, in an investigation involving 59 patients with type 1 diabetes, persistent benfotiamine treatment neither improved DPN symptoms nor eased inflammation (Fraser et al., 2012). In cytology experiments, the glutamine fructose 6-phosphate aminotransferase inhibitor, azaserine reversed the inhibition of insulin on neuroprotection in a high-glucose environment, resulting in reduced apoptosis and increased survival (Nakamura et al., 2001). Therefore, future investigations should focus more on stabilizing O-GlcNAc to maintain intracellular homeostasis. Su and Schwarz (2017) specifically knocked out OGT in small-diameter dorsal root ganglion in mice. Compared with the control group, glycemia levels decreased and the capacity of glucose tolerance increased in the OGT-KO group. However, this recovery came at the expense of reduced motor ability and thermal susceptibility. In particular, the density of the epidermal nerve fibers decreased, the axons became shorter, and the number of neuron branches decreased in OGK-GO mice. Moreover, this treatment somewhat increased the risk of diabetic peripheral nerve damage, foot ulcers, and amputations. Specifically, knocking out subtypes of OGT with various intracellular localizations may be critical and is the focus of current research. Recently, Pagesy et al. (2022) identified a subtype of OGA that targets mitochondria and is involved in ROS production within the mitochondria, which may open new avenues for therapy via the HBP. Furthermore, whether DPN can be treated with the PKC β-selective inhibitor, ruboxistaurin, (LY333531) remains unclear (Bansal et al., 2013). The poor efficacy of ruboxistaurin may be due to its inability to reach the peripheral nervous system; hence, new compounds with a greater therapeutic effect are warranted.

Reduced generation of AGEs

Aminoguanidine (AG, pimagedine), pyridoxine (and its analogs), and thiamine derivatives could mitigate DPN through the AGE pathway (Cameron et al., 2005). AG inhibits glycosylation products and prevents the synthesis of AGEs and the cross-linking of proteins in vitro and in vivo. AG was once expected to cure diabetic complications (Alhadid et al., 2022). However, side effects such as influenza-like symptoms, glomerulonephritis, and anemia have hampered further clinical studies (Bolton et al., 2004). Pyridoxal-AG adducts have shown better therapeutic prospects than AG because of their more potent antioxidant properties (Chen et al., 2004). Additionally, pyridoxine improves intraneural partial blood oxygen pressure and nerve conduction velocity (Cameron et al., 2005). Regarding thiamine derivatives, benfotiamine can also reduce AGE levels by reducing phosphate sugar synthesis, thereby improving intraneural blood flow (Hammes et al., 2003). Hence, reducing AGE expression at the genetic level may be an effective treatment for DPN. Neuregulin-4 alleviates diabetic nephropathy and tubulointerstitial fibrosis by attenuating AGE expression (Shi et al., 2019). Moreover, Shixiang plaster, a traditional Chinese medicine, reduces AGE expression by activating the RAGE/nuclear factor-kB and vascular endothelial growth factor/vascular cell adhesion molecule-1/endothelial nitric oxide synthase signaling pathways to treat diabetic ulcers in rats (Fei et al., 2019).

Antioxidant therapy

Because OS is crucial in diabetic neuropathy, exogenous supplementation with a single or combined antioxidant to scavenge ROS may be a more effective therapeutic strategy. For example, alpha-lipoic acid (ALA) showed a favorable analgesic effect in an experiment involving 100 patients with type 2 diabetes with painful DPN (Won et al., 2020). Specifically, 600 mg oral ALA twice daily for 6 months was reportedly tolerated and resulted in improved neurological function scores, pain relief, and sensory recovery in patients, suggesting that ALA may be safe and effective in treating DPN (El-Nahas et al., 2020). A study has shown that continuous treatment for 12 months with tocotrienol-rich vitamin E, which possesses antioxidant properties, improves median and sural nerve conduction velocity in patients with diabetes (Chuar et al., 2021). Intracellular or mitochondrial antioxidants such as superoxide dismutase also anticipate in preventing OS (Zhong et al., 2016). Furthermore, a clinical trial combined succinic acid, inosine, nicotinamide, and riboflavin to effectively treat DPN (Kharitonova et al., 2022). Another treatment method combined superoxide dismutase, ALA, vitamin B12, and carnitine. Similarly, after 12 months of combined therapy, the nerve conduction velocity increased and pain was relieved in patients with DPN (Didangelos et al., 2020).

Notably, ROS-induced damage is a common terminal pathway of multiple metabolic routes, and exogenous antioxidant therapy only temporarily counteracts the excess ROS in nerve or Schwann cells. Once the exogenous antioxidant support is exhausted, the balance in redox is lost. Therefore, unless the sustained expression of antioxidants can be mediated to a reasonable extent, a drug with better pharmacokinetics is warranted.

Recovery of mitochondrial function

Currently, researchers are trying to improve the redox imbalance in mitochondria by increasing exogenous antioxidants, targeting the regulation of calcium homeostasis, and regulating the signal transduction pathway. For example, injecting nicotinamide mononucleotide, an NADH precursor, into SD rats effectively ameliorated the symptoms and neurological dysfunction of streptozocin-induced DPN (Chandrasekaran et al., 2022). Melatonin may also treat DPN by acting as an antioxidant (Shokri et al., 2021). Additionally, paeoniflorin, a traditional Chinese medicine increases antioxidants in the mitochondria of Schwann cells (Yang et al., 2022a). Sensory and pain thresholds are also improved because of reduced Schwann cell demyelination.

Voltage-driven anion channel 1 is a calcium channel of the outer mitochondrial membrane. Voltage-driven anion channel 1 inhibitor, TRO19622, prevents demyelination by modulating calcium homeostasis. In diabetic mice, treatment with TRO19622 elevated the conduction rate of nerves (Tricaud et al., 2022). Moreover, by inhibiting the activation of thioredoxin-interacting protein, verapamil alleviates neuropathy in diabetic mice (Xu et al., 2019a). However, some studies have suggested that thioredoxin-interacting protein is unnecessary for mitochondrial dysfunction and diabetic neuropathy (Rodriguez et al., 2021).

Muscarinic toxin 7 is an acetylcholine type 1 receptor antagonist that enhances the CaMKK β-AMPK-PGC-1α pathway by elevating the maximal mitochondrial respiratory capacity, thereby preventing and reversing neurodegeneration (Saleh et al., 2020). After 4 months of therapy with NSI-189, an active oral molecule, the neuronal mitochondrial function of rats improved through the facilitation of the AMP-activated protein kinase pathway, which restored the sensory nerve conduction velocity. NSI-189 also enhanced the temperature and tactile thresholds (Jolivalt et al., 2022). Polydatin is a resveratrol glycoside that has the ability to restore mitochondrial metabolism by stimulating SIRT1 and NRF2 (Bheereddy et al., 2021). Finally, Ku-596 improves DPN by increasing mitochondrial tolerance to stress and reducing mitochondrial clearance (Rodriguez et al., 2021).

Tissue engineering in DPN

Tissue engineering using nerve guide conduits to treat tissue regeneration has yielded promising results (Zhang et al., 2022; Chen et al., 2023; El Soury et al., 2023). Researchers are working to extend the use of these biomaterials to treat diabetic damage (Zhao et al., 2023). There are several prerequisites for suitable nerve repair materials, such as low or no toxicity, good physical chemistry, biocompatibility, and biodegradability (Jiang et al., 2020). When nerve tissue is damaged, inflammatory cells, endothelium, Schwann cells, and nerve cells migrate along the electrical, mechanical, and biological cues of the nerve guide conduits, thereby restoring nerve functions (Deng et al., 2022). Table 2 presents examples of different types of tissue engineering techniques for nerve repair in diabetic animals.

Table 2.

Summary of tissue engineering technology

Style	Model	Function	Reference
Electrical stimulation 2 Hz, 1 mA, 15 min	Female Wistar rats	BMSC exosomes neuromuscular recovery	Singh et al., 2021
ADSCs/graphene foam hydrogel scaffolds	Diabetic mice (BKS, Cg-m+/+Leprdb),	Reduces oxidative stress, prevents targeted muscle atrophy, and promotes myelination and neurovascularization	Huang et al., 2022
βFGF-NGF/heparin-poloxamer thermosensitive hydrogel	Male STZ SD rats	Loading βFGF and NGF, increases Schwann cell proliferation, axon regeneration, and myelin sheath regeneration, and nearly normalizes wet muscle mass	Li et al., 2018
Chitosan conduits	Diabetic Goto–Kakizaki rats	Increases axon size, activates Schwann cells, reduces apoptosis, increases matrix thickness in conduits, and regulates tissue niches	Stenberg et al., 2016
Gelatin methacryloyl/silk/graphene conduit	Diabetic mice (BKS.Cgm+/+Leprdb/j)	Gradient concentration of netrin-1 in the conduit promotes Schwann cell migration, increases axon diameter, and promotes the recovery of neural function	Cai et al., 2022

ADSC: Adipose-derived stem cells; BMSC: bone mesenchymal stem cells; FGF: fibroblast growth factor; NGF: nerve growth factor; STZ: streptozocin.

Electrical cues can increase the diameter and speed of the regenerative axon and aid in muscle reconstruction (Du et al., 2016). Electroactive materials can be broadly divided into conductive and piezoelectric biomaterials, according to the source of power generation (Yao et al., 2021). Researchers are currently searching for suitable electrical stimulation parameters, as inappropriate electrical stimulation can lead to immune rejection (Qian et al., 2019). Because the current parameters in experimental animals cannot be directly applied to humans, the clinical translational ability of electrical stimulation to promote nerve regeneration remains uncertain. In contrast, piezoelectric biomaterials may have better application prospects. Some electrospun scaffolds have suitable piezoelectric properties and good electrical activity during mechanical deformation (Gryshkov et al., 2021), and the excellent properties of the piezoelectric composite have been demonstrated in vitro. Researchers planted adult Schwann cells on the material’s surface, which had low cytotoxicity and cell growth-promoting properties, suggesting that this material may be safe and effective for nerve damage repair.

The topology of the inner surface of a biomaterial regulates cellular behavior by adjusting the cell-material interface and promoting neuronal repair (Zhan et al., 2022). Yao et al. (2023b) produced a spatial anisotropic scaffold by loading adipose-derived stem cells. Nano-grooves on the platform promoted stem cell differentiation into a neurotrophic phenotype.

Failure of repair in DPN is usually caused by severe energy deficiency (Li et al., 2022c), which is the metabolic energy basis for applying tissue-engineered grafts to diabetic neuropathy. Jiang et al. (2022) produced melatonin-loaded redox graphene polycaprolactone scaffolds using electrospinning technology. These scaffolds promoted nerve regeneration by improving mitochondrial function in Schwann cells. This method should be extended to diabetic neuropathy.

Whether suitable nerve guide scaffolds can be fabricated depends primarily on the material used (Li et al., 2022c). However, managing DPN ultimately depends on the underlying pathophysiological processes. Understanding energy and metabolic changes are paramount to developing effective therapeutic strategies for diabetic neuropathy (Feldman et al., 2019).

Discussion

DPN, which is characterized by symmetrical numbness and tingling of the distal extremities, is a prevalent and serious complication of diabetes. It affects more than half of all diabetic patients. Understanding DPN from a pathophysiological perspective may help treat the disease based on its metabolic characteristics. However, a comprehensive understanding of the metabolic alterations of DPN and the related signaling pathways is lacking, resulting in a lack of sufficient treatment based on the pathogenesis of DPN. Symptom relief and prevention remain the primary management strategies for diabetic neuropathy. Understanding the metabolic and energy changes of DPN is essential to solve this problem.

This review focused on the pathophysiological changes in the peripheral nervous system. However, the changes in the brain and spinal cord in patients with DPN were beyond the scope of our discussion. No specific therapy has been developed for DPN, but symptom relief and blood sugar control are the primary therapeutic methods used. The polyol, hexosamine, AGE, and PKC pathways have been found to be related to DPN. Other possible mechanisms including OS and mitochondrial dysfunction are currently under investigation. Therapeutic regimens with multiple and metachronous targets are promising, and new tissue engineering techniques are being developed to treat peripheral nerve injuries in diabetic patients based on the above-mentioned mechanisms.

In conclusion, multiple metabolic pathways, including ROS and mitochondrial dysfunction are involved in the onset and progress of DPN. We recommend that research efforts be focused on elucidating the extent to which different metabolic pathways are involved in the disease and developing therapies that target major pathways or common mechanisms.

Additional file: Open peer review report 1 ^{(77.5KB, pdf)} .