Under conditions of hyperglycemia, excess glucose saturates glycolysis in nerve cells, diverting it into the polyol pathway (Fig. 2). This pathway, involving aldose reductase and sorbitol dehydrogenase, converts glucose to sorbitol and then fructose, consuming nicotinamide adenine dinucleotide phosphate (NADPH) and generating NADH. This process markedly contributes to ROS production, driving OS (23).

The polyol pathway results in a decline in intracellular NADPH levels and an accumulation of NADH. The greater production of NADH serves as a substrate for NADH oxidase, leading to the production of ROS. Intracellular hyperosmolarity occurs due to an elevated polyol flow, which leads to the buildup of impermeable sorbitol and the efflux of other osmolytes. Consequently, the inhibition of adenosine triphosphate (ATP) production occurs (24). The conversion of glucose to sorbitol by the action of aldose reductase leads to the utilization of NADPH. Since NADPH is necessary for the reformation of reduced glutathione, this process directly adds to OS generation. Furthermore, the conversion of sorbitol into fructose contributes to glycation, leading to reduced NADPH availability and elevated AGEs, all of which contribute to a significant disruption in redox balance (25).

As regards DNP, the peripheral nerves of diabetic patients have been shown to exhibit an accumulation of sorbitol and fructose. Additionally, the shunting of glycolytic intermediates to the polyol pathway increases glycation and the generation of DAG in the dorsal root ganglia. These processes minimize the activity of Na⁺/K⁺-ATPase, suppressed axonal transport and the structural deterioration of nerves, ultimately manifesting as an abnormal action potential. Therefore, the suppression of the polyol pathway remains a focal point for therapeutic development in the control of diabetic neuropathy (26,27).

Diabetic complications, including DNP, may be caused by the shunting of excess glucose in nerve cells into another pathway rather than glycolysis, including the HBP, in addition to the polyol pathway (28). The most commonly proposed mechanism by which HBP contributes to DNP is the effect of intracellular uridine-5-diphosphat-N-acetylglucosamine (UDP-GlcNAc) on the modification of proteins (Fig. 3). Under healthy conditions, the HBP represents a minor pathway of the glycolytic system, with glutamine-fructose-6-phosphate aminotransferase (GFAT), the rate-limiting enzyme, converting only 2 to 5% of fructose-6-phosphate to glucosamine-6-phosphate (29).

However, under conditions of hyperglycemia, the increased generation of ROS inside the mitochondria hinders the action of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase, which inhibits fructose-6-phosphate from flowing through glycolysis (30). Subsequently, UDP-GlcNAc is established from glucosamine-6-phosphate, acetyl-CoA, and uridine-5-triphosphate. UDP-GlcNAc regulates the activity of O-linked N-acetylglucosamine transferase, which is present in both the nucleus and cytosol. The latter is an enzyme that transfers N-acetylglucosamine (GlcNAc) to certain serine and threonine residues on proteins, allowing for a reversible posttranslational modification. Notable proteins that have undergone O-GlcNAcylation, including glucose transporter 4 and insulin receptor substrates 1 and 2, result in insulin resistance (31,32).

Concerning DNP, there was a noticeable increase in GFAT activity and UDP-GlcNAc levels in the muscle of ob/ob mice. By contrast, mice with continuous caloric restriction exhibit a decrease in the UDP-GlcNAc concentration, which is accompanied by an improvement in insulin sensitivity in their muscles (33). Since peripheral nerves are highly metabolically active and insulin-dependent, this disruption directly links insulin resistance to neuronal injury, leading to axon degeneration, demyelination, and ultimately, DNP. However, the particular peripheral nerve proteins that can be altered by the activated HBP in response to DM have yet to be identified. Therefore, further investigations are required to fully elucidate the interplay between HBP and DNP (21).

Hyperglycemia increases the formation of AGEs by non-enzymatic reactions between reducing sugars and proteins, nucleic acids, or lipids. These groups tend to impair the biological activity of proteins, affecting cellular function. AGEs promote modification through glycation of the extracellular matrix protein laminin, which causes impaired regenerative activity in DNP. In addition, AGEs induce segmental demyelination; as a result, the nerves become susceptible to phagocytosis by macrophages. Axonal atrophy, degeneration and impaired axonal transport are consequences of AGE-modified major axonal cytoskeletal proteins such as tubulin, neurofilamen and actin (34). In the peripheral nerves of diabetics, the AGE receptor [receptor of advanced glycation end products (RAGE)] has been shown to colocalize with AGEs. It appears that AGEs and their interactions with RAGE cause OS in DNP (35). Consequently, this leads to an increase in nuclear factor κB (NF-κB) and numerous pro-inflammatory genes regulated by NF-κB. Furthermore, the blood of individuals with DM contains inflammatory mediators, such as C-reactive protein and TNF-α (5,36). The combined effects of AGE-induced biochemical damage include reduced neurotrophic support, nerve blood flow impairment, neuronal integrity disruption and compromised repair mechanisms (37).

Chronically increased levels of DAG occur in hyperglycemia as a result of an increased glycolytic intermediary, dihydroxyacetone phosphate. This intermediate is converted into glycerol-3-phosphate, which then enhances the production of DAG by de novo synthesis. The PKC family consists of 11 isoforms, of which nine are activated by DAG. The activation of the DAG-PKC pathway increases ROS production via NADPH oxidase, reinforcing OS, while simultaneously disrupting mitochondrial electron transport, uncoupling endothelial nitric oxide synthetase and influencing transcription factors, such as NF-κB, which promotes pro-inflammatory signaling (38).

Animal studies support the role of PKC in DNP, as inhibition using LY333531 has been shown to improve sciatic nerve blood flow, conduction and hyperalgesia (39). PKC activation contributes to neuropathy via two mechanisms: Reduced activity limits blood flow and alters conduction, while excessive activity disrupts neuronal function by affecting neurochemical signaling. Several PKC inhibitors, similar to aldose reductase inhibitors, also demonstrate antioxidant properties antioxidant (40).

PARP is a nuclear enzyme that facilitates the attachment of ADP-ribose units to DNA, histones and other DNA repair enzymes. This process has an impact on cellular functions (41). Recent evidence indicates that the overactivation of PARP and the occurrence of OS are two interconnected pathways. PARP activity is minimal under normal physiological circumstances. Nevertheless, in the presence of OS, DNA single-strand breaks become abundant and result in excessive activation of PARP. As regards DNP, research has demonstrated that the overactivation of PARP may contribute to the development of DNP, whereas preventing its function may impede the progression of this condition (42). PARP is found in both endothelial cells and Schwann cells inside the peripheral nerve. The activation of PARP is evident in DM and plays a role in diabetic endothelial dysfunction, which is a key contributor to DNP. Activation of PARP induces marked metabolic alterations and influences the expression of genes. Furthermore, PARP is necessary for the translocation of apoptosis-provoking factors from the mitochondria to the nucleus. This process plays a crucial role in PARP-mediated programmed cell death, which has recently been linked to the development of DNP (43).

Nrf2 is a major leucine zipper protein that mainly acts as a defense mechanism against cellular OS. It functions as a transcription factor to regulate the development of cytoprotective enzymes. Typically, Nrf2 is not active within cells; however, it becomes activated when there is stress or an increase in the generation of free radicals (44). Upon activation, Nrf2 translocates to the cell nucleus and selectively interacts with the DNA at the antioxidant response element, decreasing free radicals and OS. Similarly, in the presence of DM, elevated blood sugar levels lead to the activation of several neuroinflammatory pathways and the generation of free radicals. During the first phases of hyperglycemia, Nrf2 signaling plays a crucial role in controlling the activation of several cytoprotective genes. However, in cases of prolonged hyperglycemia, the levels of Nrf2 decline, leading to the development of DNP via linked neuroinflammatory pathways (3).

Metformin, a biguanide derivative, is primarily used for controlling type 2 DM. Adenosine monophosphate-activated protein kinase (AMPK) is a key prospective target of metformin since it serves as a cellular energy sensor that becomes activated in response to metabolic stress, leading to improved glucose uptake (50). Metformin can significantly reduce the OS associated with diabetic patients. Previous studies have demonstrated that metformin has the ability to inhibit mitochondrial complex I (NADH:ubiquinone oxidoreductase), which contributes to the antioxidant effect of metformin (51-53).

The cellular production of ROS may be greatly influenced by mitochondrial complex I. There is much documentation indicating that a blockage of this complex results in a decrease in the generation of reactive species. This is caused by a reduction in the transportation of electrons from NADH plus hydrogen. In addition, metformin has been demonstrated to scavenge oxygenated free radicals produced in vitro directly and to inhibit the opening of the mitochondrial permeability transition pore in both intact and permeabilized human epithelial carcinoma cells (KB cells), as well as in permeabilized human microvascular endothelial cells (HMEC-1 cells) (51,54).

The use of metformin for the treatment of the manifestations of DNP in both animals and humans has yielded inconclusive results to date. Several studies have proven the positive benefits of metformin on DNP (55-58). Metformin has been shown to reduce the accumulation of AGEs in the sciatic nerves of rats with streptozotocin (STZ)-induced diabetes by activating AMPK, leading to improved nerve conduction velocity, and the attenuation of heat and mechanical hyperalgesia (59). It has also been shown to decrease serum malondialdehyde (MDA) levels and enhance SOD activity, highlighting its role in counteracting diabetes-induced OS (59).

Conversely, other studies suggest that metformin may worsen neuropathic outcomes, with reports of it functioning as an iatrogenic factor contributing to more severe neuropathy in type 2 DM (60). This negative effect has been partly attributed to the association of long-term metformin use with vitamin B12 deficiency, a known risk factor for DNP. These contrasting findings underscore the complexity of the effects of metformin on DNP, indicating a dual role where protective mechanisms against OS may be counterbalanced by adverse effects under certain conditions (61).

Sulfonylureas promote insulin secretion by their interaction with the ATP-sensitive potassium channel located on the β-cell of the pancreas. Sulfonylureas decrease the level of AGEs indirectly by controlling blood glucose levels (62). The administration of glimepiride has been shown to cause a decrease in the levels of peroxides and MDA, and an increase in the activity of SOD and glutathione peroxidase in rats following the administration of STZ; this suggests that glimepiride may effectively inhibit the development of OS in DM (63). Gliclazide also exerts a prominent antioxidant effect mainly due to the free radical scavenging effect. The main mechanism for this effect is not yet clearly understood; however, the characteristic of an azabicyclo-octyl ring grafted on a hydrazide group, a structure unique to gliclazide, may provide the compound with free radical scavenging properties (64). Glibenclamide, glipizide, tolazamide and other sulfonylureas do not exert antioxidant effects. Similar to sulfonylureas, meglitinides such as repaglinide and nateglinide form a bond with the KATP channel on the pancreatic beta cells, but at a different binding location. However, it has not been shown that these medications have any antioxidant properties (65).

In the aspect of DNP control, gliclazide is a novel sulfonylurea that inhibits the development of DNP. Regardless of blood glucose levels in mice with STZ-induced diabetes, gliclazide considerably reduces peripheral nerve morphological alterations and improves the slowing of motor nerve conduction velocity. The morphological alterations observed in diabetic rats compared to non-diabetic rats include an increase in nerve fiber density and a reduction in fascicular area, axon/myelin ratio and nerve fiber area (66). Animal research has demonstrated that potassium-ATP channel blockage by sulfonylurea may enhance glutamate-induced superoxide generation and neurotoxicity by selectively intensifying mitochondrial inhibitors; however, no such data have been reported for humans, at least to the best of our knowledge (67).

TZDs exert their insulin-sensitizing effects through the activation of the peroxisome proliferator-activated receptor γ (PPAR-γ) nuclear receptor, hence reducing insulin resistance. TZDs possess exert antioxidant effects. The potential mechanism may be attributed to the triggering of the transcription of several genes, including NADPH, SOD and catalase, via the activation of PPAR-γ receptors, resulting in the improvement of mitochondrial health (68). Some TZDs, such as troglitazone, provide direct antioxidant effects via a side chain that resembles α-tocopherol, in addition to their ability to indirectly upregulate antioxidant genes. Due to their ability to decrease NO production via the trans-repression of inducible nitric oxide synthetase, all TZDs exert intracellular antioxidant effects. Pioglitazone is beneficial in reducing OS via correction of the PKC pathway and pro-inflammatory process (69).

It has been shown that the administration of pioglitazone improves biochemical markers via reduced MDA levels and improved GSH and SOD activities (70). Pioglitazone has also been shown to be more effective than metformin in reducing OS, as seen by a decrease in MDA levels. However, only metformin exerts an antioxidant effect through an increase in SOD levels. The distinct mechanisms of action of the two medications on OS support the concurrent prescription of both treatments to enhance the result in ameliorating insulin resistance and diabetes complications (49). TZDs are associated with increased total serum soluble RAGE levels that may lead to a decrease in the harmful effects of AGEs. Furthermore, TZDs reduce the tissue expression of RAGE, resulting in decreased proinflammatory effects of AGEs (62).

Several studies have been conducted to demonstrate the efficacy of TZD in slowing or preventing the progression of DNP. In STZ-treated rats, troglitazone protected against nerve conduction velocity slowing and maintained normal myelinated fiber architecture and number (71). Pioglitazone has the triple advantage of lowering central sensitization, hyperglycemia and hyperalgesia; hence, TZDs are a desirable pharmacotherapy for those with neuropathic pain related to type 2 DM (7). Furthermore, pioglitazone has neuroprotective properties by enhancing nerve conduction velocity and diminishing macrophage infiltration in the sciatic nerve (72). Rosiglitazone reduces the OS in the sciatic nerve, thus reducing the progression of DNP (73).

SGLT-2 inhibitors block SGLT2, which are responsible for glucose reabsorption in renal proximal convoluted tubules, leading to glycosuria and a reduction in blood glucose level. Recently, SGLT-2 inhibitors have been identified as potent antioxidant agents that can prevent oxidative damage to tissues by lowering glucose levels, generating fewer free radicals, or by potentiating the antioxidant system (Table II). The observed therapeutic advantages of SGLT-2 inhibitors in diabetic complications may be attributed to the reduction of OS (74).

A previous meta-analysis of 89 articles in the field of DNP demonstrated that SGLT-2 inhibitors have the potential to preserve the nerves by significantly enhancing the speed at which sensory and motor nerves conduct signals (75). This improvement in nerve function leads to improved clinical manifestations for patients with DNP, with a reduction in the activity of the sympathetic nervous system (75). A follow-up study demonstrated that the use of SGLT-2 inhibitors for >3 years led to significant improvements in certain measures of neuropathy (76).

Combining dapagliflozin and mecobalamin may considerably reduce clinical symptoms in patients with DNP. This combination may lower blood glucose, control MDA, SOD and cyclooxygenase 2 levels, and prevent nerve cell damage. Additionally, it promotes sensory and motor nerve transmission. The approach of using dapagliflozin and mecobalamin is safe and warrants clinical promotion (77).

GLP-1 receptor agonists, as a class of antidiabetic medications, have been observed to enhance the secretion of insulin in response to glucose stimulation, inhibit the release of glucagon, and delay the process of stomach emptying. GLP-1 can reverse the oxidative action, as the administration of GLP-1 or its receptor agonist has been found to have a beneficial effect on OS markers, such as SOD, glutathione peroxidase, glutathione amount, glutathione reductase, catalase, lipid peroxidation and non-enzymatic glycosylated proteins, stimulated by different stress factors (78). The mechanism by which GLP-1 reduces OS in DM involves the activation of cyclic adenosine monophosphate (cAMP), PI3K and PKC pathways via receptors, as well as the activation of Nrf-2, increasing antioxidant capacity. These findings indicate that activating Nrf2 by GLP-1 and its subsequent antioxidative effects may have potential benefits in preventing and treating DM, as well as reducing the likelihood of complications. Also, GLP-1 receptor agonists were suggested to suppress OS generation induced by AGEs-RAGE and reduce tissue expression of RAGE via activation of cAMP pathways (79).

However, the effect of GLP-1s receptor agonists in DNP remain uncertain. Some clinical studies support the role of GLP-1 receptor agonists in improving DNP through a number of mechanisms including the antioxidant effect, the anti-inflammatory signaling through microglia/astrocyte modulation, improvement in peripheral nerve blood flow and endothelial function, and metabolic improvement (80,81). The antioxidant effect is one of the most effective mechanisms. GLP-1 receptor agonists activate SOD; however, they do not cause alterations in the distribution pattern of neuronal markers. Exenatide protects cells against apoptosis caused by OS and promotes neurite. These findings suggest that GLP-1 receptor agonists function as neuroprotective agents, considering their direct effects on neurons (82). Another study documented that the use of liraglutide alleviated DNP through antioxidant and anti-inflammatory effects, as well as via the remodeling of the extracellular matrix (81).

On the other hand, other research has demonstrated that GLP-1 receptor agonists have no significant effect in improving DNP (8). Despite the anti-inflammatory and antioxidant effects of liraglutide, no clinical improvement in autonomic neuropathy or polyneuropathy has been observed (83). In addition, exenatide has failed to provide a significant effect on DNP (84,85).

DPP-IV inhibitors prevent the breakdown of endogenous GLP-1, consequently enhancing the incretin action. DPP-IV, a cell surface enzyme found in endothelial cells and some lymphocytes, is responsible for the degradation of various peptides. DPP-IV inhibitors have been observed to stimulate insulin secretion without causing hypoglycemia or weight gain (86). Clinical studies have demonstrated that DPP-IV inhibitors exert antioxidant effects by reducing ROS generation and promoting the activity of antioxidant enzymes, including increased nitric oxide, SOD, catalase and reduced glutathione (87,88).

Furthermore, it has been discovered that the production of ROS caused by the AGE-RAGE interaction leads to the release of DPP-4. DPP-4 inhibitors prevent this release (89). Additionally, another study demonstrated that the use of vildagliptin, a DPP-4 inhibitor, was associated with decreased AGEs to a certain extent (90).

As regards DNP, sitagliptin plays protective roles on neurons via activating GLP-1 receptor, resulting in an anti-apoptotic effect, improving microtubule stabilization and axon regeneration, ameliorating mitochondrial dysfunction, and promoting locomotor functional recovery. The mechanism of action of sitagliptin in DNP is related to AMPK/peroxisome proliferator-activated receptor coactivator 1α (PGC-1α) signaling pathway. The activation of the AMPK/PGC-1α signaling pathway results in the development of neurites and the regeneration of axons (9). It is well-established that when teneligliptin is orally administered, it produces analgesic properties in humans specifically against thermal pain. It has been demonstrated that teneligliptin exerts mild antinociceptive effects in response to acute pain; however, it exerts, significant analgesic effects against DNP. Furthermore, teneligliptin can improve the synthesis of glutathione antioxidants inside the cellular environment (91,92). Vildagliptin improves glucose intolerance and increases serum insulin and GLP-1 levels, accompanied by the amelioration of delayed nerve conduction velocity and neuronal atrophy (93).

Alpha-glucosidase inhibitors attenuate the process of starch digestion in the gastrointestinal tract, resulting in a slow release of glucose into the circulation. The currently used alpha-glucosidase inhibitors consist of acarbose and miglitol. Thus far, there have been no documented antioxidant properties observed for these medications (65). However, a previous study demonstrated that miglitol improved the activity of catalase, SOD, glutathione peroxidase, glutathione reductase and thioredoxin reductase (94).

Glycemic control is the primary goal of DNP treatment. The pathogenesis of the complication is regarded as the primary focus of interest while developing pharmaceutical DNP targets. Although there is no curative treatment for DNP, several medications can alleviate the symptoms. When managing diabetic neuropathy, it is important to select antidiabetics with antioxidant properties that attenuate the progression of the disease, in addition to controlling the blood sugar levels (75-77,95).

The use of metformin should be accompanied by routine vitamin B12 monitoring and supplementation to maximize its benefit in DNP, while minimizing deficiency-related risks. The use of pioglitazone may be considered in patients with neuropathic pain due to its neuroprotective potential, although caution is advised due to its side-effect profile. Combination therapy with metformin, pioglitazone and vitamin B12 supplementation may provide the most prominent protective effect against DNP (7,49,72,96). Concerning sulfonylureas, gliclazide is a novel sulfonylurea that inhibits the development of DNP (65). However, the use of sulfonylureas or insulin in combination with metformin and pioglitazone may worsen DNP (75,76,97). SGLT-2 inhibitors, particularly dapagliflozin, may be incorporated into diabetes therapy where neuropathy is a concern, with potential added benefit when combined with cobalamin (77).

The effect of GLP-1 receptor agonists in DNP is uncertain, and the use of such medications in DNP requires further investigations (8,80,81,83-85). Sitagliptin, as a DPP-IV inhibitor, on the other hand, plays a protective role in neurons by improving the actions of GLP-1. The administration of sitagliptin in conjunction with metformin leads to enhanced grip strength and increased pain sensitivity, while also demonstrating neuroprotective effects (95).

Future studies for the management of DNP are required to focus on identifying medications that can directly interfere with the main pathways of ROS generation, including the polyol pathway and HBP. Furthermore, additional studies may be required to provide sufficient insight into the role of antidiabetic combinations in preventing DNP, and to determine which combinations are the most effective.