REGISTRO DOI: 10.69849/revistaft/th102502171302
Yury Gabriel Tavares Rodrigues¹
Vitor Carvalho de Almeida²
Silvio Pereira Barreto³
Francisca Elisangela Sousa Ferreira⁴
Cleide Duila de Nazaré da Silva⁵
Edinelma da Silva Oliveira⁶
Elizabeth Queiroz de Jesus⁷
Joaquim Victor de Carvalho Sodré⁸
Larissa Cardoso Benício Palheta⁹
Marcilene Conceição Borges¹⁰
Thalia de Cássia Sousa Gomes¹¹
Hélio Márcio Amaral Mendes¹²
Lariza Perla e Silva Martins¹³
Luã Augusto Barros Cunha¹⁴
Wallace Fagner Silva da Conceição¹⁵
Diabetic neuropathy (DN) is a progressive degenerative disease with a slow evolution, whose main cause is a long-term high glycemic condition, uncontrolled diabetes mellitus. Due to an accumulation of oxidative factors, degenerative processes occur in the axons and nerve cells of the peripheral motor nerves, causing a type of NP called peripheral diabetic neuropathy. Since peripheral diabetic neuropathy is a clinical condition that is difficult to treat, this bibliographic review gathered about 50 academic articles as a basis for this work, with the intention of summarizing in a practical way the pathophysiological routes that are related to the emergence of this comorbidity and the treatments with the best results present in the literature.
KEYWORDS: Diabetic peripheral neuropathy. Polyol pathway. Hexosamine pathway. Reactive species. Aldose reductase inhibitors. Hexosamine inhibitor drug.
INTRODUCTION
By definition, neuropathy is the malfunction of the nerves, which can occur in any region of the body, due to a wide range of etiologic agents, and has four classifications: Focal neuropathy (mononeuropathy, polyneuropathy), cranial neuropathy, autonomic neuropathy and peripheral neuropathy 1. In turn, diabetic neuropathy (DN) is the name given to the degeneration of nerves due to persistent high levels of glucose, with diabetic peripheral neuropathy (DPN) being the most common chronic complication recurring to DN 2,3.
DPN neuronal damage is symmetrical and starts with distal nerves which are part of the toes and hands, described as a “stocking and glove” distribution pattern, and progressing proximally causing characteristic symptoms such as numbness, tingling, burning, hyperalgesia, pain, allodynia, pins/needles, and electric shock sensation, besides to be associated with increased mortality 4,5. Usually, the first nerves to be affected are the sensory nerves, due this the sensory axons are more vulnerable to high glucose levels, thus symptoms like loss of sensitivity is common. Later appear the damage the motor nervus and your symptoms like weakness and loss of strength 6.
There are two main types of diabetes mellitus (DM): type 1 (DM 1) and type 2 (DM 2). DM 1 is a disease in which pancreatic beta cells are destroyed because of an autoimmune process, resulting in low insulin production and high amount of blood glucose, while DM 2 is the most prevalent, progressive, in which the cells become quite resistant to insulin action, when there is little insulin production, being caused by poor eating habits and a sedentary lifestyle 1. A standard of DN is DM, as both DM 1 and DM 2 can generate DN, however, although glycemic control is effective in preventing DN in patients with DM 1, this does not apply to patients with DM 2, which represents the largest share of affected 7.
There are several routes that aim to explain how DN develops, among them: 1) The polyol pathway; 2) Sphingolipids; 3) Formation of advanced glycation products (AGEs); 5) Hexosamine route 8–10. In this sense, we aimed to provide a narrative review of DPN with focus on pathological route, mechanisms and possible pharmacological therapies to recovery nerve function or reduces symptoms associated with DN.
EPIDEMIOLOGY
DM is a disease with a high population prevalence and with a tendency to increase due to the aging of society, data from the International Diabetes Federation estimated that 537 million of adult people living with diabetes worldwide, global prevalence of 10%. Among this total, 30% of diabetics patients developed DN, with DM 2 being the one with the most patients affected 2,11,12. Some studies point out that 8% of the general population has peripheral neuropathy, further studies indicates that this number rises to 15% in individuals aged 40 years or older. In the Europe, research shows that the most common causes of peripheral neuropathy are pre-diabetes and type 2 diabetes, at least half of all pre-diabetic or type 2 diabetic patients develop some type of neuropathy during their lifetime 9,13.
PATHOPHYSIOLOGY OF DIABETIC PERIPHERAL NEUROPATHY
DPN is a nerve damage that encompasses several types of neuropathies, the main ones being sensory, motor and autonomic neuropathy. Nerve damage over time often goes unnoticed, so it is a progressively silent disease 14.
As it is an inflammatory process, for mechanisms that are not fully understood, the sensory nerves are the first to be affected, leading to symptoms that begin with numbness and/or tingling that begins in the feet, that is, in the extremities of the body and spreads later increases compressively. Its motor manifestation can be with vibratory impairment, joint impairment, pressure sensation and loss of ankle reflex 15,16.
Studies show that the pathophysiology can present itself in 2 ways: the loss of long fibers, which is characterized by painless symptoms, and the loss of small fibers that results in painful signs and symptoms, which is the autonomic manifestation of the disease, being associated with pain, burning and decrease in normal sensations, making the patient’s daily life difficult 17. However, as possible pathways related to the development of DPN are not completely elucidated and several seem to work in a way to maintain or worsen the patient’s condition, understanding the pathophysiology of the disease is necessary to propose more effective treatments.
2.1 POLYOL PATHWAY
The polyol pathway is one of the most studied pathways in DN and considered the main form of explanation for the emergence of the pathology. This metabolic pathway is divided into two steps, the first being the transformation of glucose into sorbitol, followed by the transformation of sorbitol into fructose, which is considered an indicator of cellular toxicity caused by DM, since it is only activated in the presence of a high concentration of intracellular glucose 18.
Intracellular glucose is normally phosphorylated by the enzyme hexokinase, in an initial step to glucose transformation into ATP; however, with the high rate of available glucose, the polyol pathway is activated by compensation. The enzyme aldose reductase transforms glucose to sorbitol through cofactor NADPH oxidation to NADP+. Sorbitol is a polyhydroxylated and strongly hydrophilic alcohol, so it does not pass through the lipid barrier of the cell and accumulates until activating sorbitol dehydrogenase, transforming sorbitol into fructose, using NAD+ as a cofactor, that turning into NADH, by reductive process. The resulting fructose normally goes through the glycolytic pathway (Figure 1) 19.
From NADPH reduction in the polyol pathway, two reactive species (RS) are released, the trioxocarbonate and nitrogen dioxide that can promote oxidative stress by oxygenation, nitrosation, and nitration reactions. Thus, the cascade of action of the polyol pathway results in the RS formation and accumulation RS, and consequently an increase in oxidative stress, leading to cumulative damage the myelin sheath of the axon of peripheral nerves, ultimately causing all the known pathophysiology 20.
HEXOSAMINE PATHWAY
Hexosamine is a secondary pathway in which it is associated with insulin resistance and DN pathogenesis 21,22. About 1 to 3% of the total glucose metabolized passes through the hexosamine pathway, however, for hyperglycemic individuals, the increase in intracellular glucose can raise this pathway activity (Figure 2) 23. This route begins with the action of glutamine fructose-6-phosphate amidotransferase (GFAT), which is the first and limiting enzyme and catalyzes the convertion of Fructose-6-phosphate and glutamine to glucosamine-6-phosphate (GlcN- 6-P) and glutamate 24.
After a few steps, GlcN-6-P is metabolized into the main product, the UDP-N-acetylglucosamine (UDP-GlcNAc), which regulates GFAT activity and thereby controls the flow of Hexosamine Pathway. On the other hand, the UDP-GlcNAc produced is O-GlcNAc transferase substrate that transfers N-acetylglucosamine in O-linkage (O-GlcNAc) to bind to serine/threonine residues in transcription factors such as Sp-1, leading to inflammation, lipid imbalance and tissue damage, like peripheral nerves 21,25.
ADVANCED GLYCATION END PRODUCTS
Advanced Glycation End Products (AGEs) is the name given to a set of heterogeneous substances that are synthesized through the spontaneous Maillard reaction, forming AGEs (Figure 3). This process consists in the non-enzymatic modification of proteins, lipids and nucleotides of DNA containing amines, by reducing sugars, forming at the end of the process AGEs that accumulate in tissues and organs, gradually affecting their structure, renewal and function 26–28. There are several compounds classified as AGEs in nature and it is not yet known which are the most pathogenic, however, there are three AGEs compounds well described and used as markers: Pentosidine, carboxymethyllysine (CML), and methylglyoxal (MG) 28,29.
AGEs have a variety of receptors, with the receptor for advanced glycation end products (RAGE) being the most frequently linked to ND 26,30. AGEs are present both in food and as part of human metabolism, however, when in large amounts, they cause damage due acts aspro-oxidants, leading to increased intracellular oxidative stress, neural inflammation and affecting axonal transport 31,32.
SPHINGOLIPID
In addition to well-established routes such as of the Polyol and AGEs, there is evidence to suggest that, once altered, sphingolipid metabolism may be an additional toxicity factor in which, especially in DM 2 (Figure 4). The formation of atypical deoxysphingolipids with diverse neurotoxic activities promote progressive peripheral axonopathy, death of pancreatic beta cells, beyond to interfering with insulin secretion, though molecular mechanisms still unknown 8,33–35. The reaction cascade that results in the formation of deoxysphingolipids occurs whenin the endoplasmic reticulum, the enzyme serine palmitoyltransferase (SPT) does not metabolize serine (which would be the natural route for the creation of sphingolipids) and ends up metabolizing glycine or alanine 8,36–38.
Once formed, deoxysphingolipids are toxic for nerves and pancreatic β-cells, being a biomarker and playing an important role in the pathogenesis of both DM1 and DM2 33,35.
REACTIVE OXYGEN SPECIES
Intracellular oxidative stress occurs when the production of free radicals, primarily reactive oxygen species (ROS) exceeds the cellular antioxidant capacity 39–41. Dyslipidemia and hyperglycemia pathophysiology courses with increases the amount of ROS, provoking causes stress in the endoplasmic reticulum, DNA damage, as well as pro-inflammatory activation, culminating damage to the nerves, impairing of neuronal function, loss of neurotrophic support, which can lead to neuronal apoptosis, being oxidative stress a major contributor to the development and progression of peripheral DN 8,41,42. O2 and free fatty acids (FFA) are the most common RS, and can create other RS through enzymatic or non-enzymatic reactions. The endogenous ROS production is based on the conversion of O2 into hydrogen peroxide (H2O2) through superoxide dismutase (-SOD), which helps permeation by generating ROS that can diffuse through membranes 43,44.
In order to reduce this impact, H2O2 undergoes enzymatic reduction through catalase and glutathione peroxidase, transforming itself into water and serving as an antioxidant, however, in a state of hyperglycemia, mitochondrial activity is high, generating greater generation of ROS in addition to those resulting from the others ways 45.
Once the endogenous antioxidant system is depleted, ROS accumulates in nerves, leading to progressive dysfunction of membranes, DNA organelles and later apoptosis. 43,46.
PHARMACOTHERAPY FOR PAIN
One of the clinical consequences of DPN is the neuropathic pain, that is usually spontaneous, needing no stimulus to occur and alternatively has symptoms such as paresthesia (abnormal sensation such as tingling, loss of sensation or itching), hyperalgesia (increased perception of pain from a stimulus that would cause pain) and allodynia (pain caused by a stimulus that under normal conditions would not cause pain) 47.
The neuropathic pain pharmacotherapy is defying to clinicians and is based on the treatment of symptoms and although there is no evidence of the effectiveness of drugs for specific conditions. Groups of pain study published an algorithm to manage neuropathic pain and grouped in six-line treatments, according the International Association for the Study of Pain (IASP) Neuropathic Pain Special Interest Group (NeuPSIG) 48.
First-line drugs are tricyclic antidepressants (TCAs), selective serotonin and norepinephrine reuptake inhibitors (SSNRIs, venlafaxine and duloxetine), and calcium channel α2- δ ligands (as pregabalin and gabapentin,), and topical lidocaine (lidocaine patch 5%). Specifically to DNP, all classes of medication were clinically tried, excepted lidocaine, and showed efficiency to pain control, however all treatments are for prolonged time and present side effects (sedation, nausea and dizziness)14,44,49,50.
Usually, second-line topical drugs are used to avoid the toxicity of first-line drugs for elderly or frail patients, making them the first-line treatment for these patients, or with exarcebation/inadequate responses to controle pain. It is as combination therapy or the use of tramadol, a weak μ-opioid agonist and inhibitor of serotonin and norepinephrine reuptake 48.
The Serotonin-Specific Reuptake Inhibitors (SSRIS), anticonvulsants (as lamotrigine, carbamazepine, topiramate, and sodium valproate); and NMDA antagonists are used for patient who does not tolerate or fails to gain adequate pain relief from first- or second-line therapy 51. However, with regard to level of evidence, the NeuSPIG guidelines has rated all these as inconclusive 14.
The fourth-line is neuromodulation, which is not in the focus of this paper. Finally, the fifth-line treatment is the opioids in low doses, in this sense they have great pharmacological potency, which have low recommendation due to their adverse effects and capable to be a substance abused. Morphine, oxycodone, methadone and levorphanol are the substances of this class 14. In sixth-line we have the targeted drug delivery target, that is a system to deliver medications directly to their site of action at the dorsal horn of the spinal cord, avoiding first pass effect and the blood–brain barrier 48.
PHARMACOLOGICAL MANAGEMENT OF OXIDATIVE STRESS
Since oxidative stress is one of the main causes of degenerative processes in DN, current pharmacological treatments focus more on inhibiting its appearance than combating the oxidation already present. Some pathways have gained greater emphasis than others as a pathophysiological explanation for the development of DN, which makes them important targets for pharmacological management 44.
Aldose reductase inhibitors (ARI) are shown to be favorites in the search for new treatments with the intention of stopping degenerative processes in nerve fibers, acting as an inhibitor of the key enzyme for the polyol pathway. Its mechanism of action involves glucose flow reduction by inactivation of the enzyme that converts glucose into sorbitol, decreasing markers of oxidative stress related to this pathway. There are 3 important drugs belonging to this class, the fidarestat, epalrestat and ranirestat, among them fidarestat has a greater effects in DN controlling 44,52.
Another pathway with pharmacological importance is Hexosamine, since the oxidative stress resulting from this route can implies DN. Benfotiamine is a hexosamine inhibitor drug that acts by reducing the flow of glucose, and consequently decreases the oxidative stress resulting from its metabolism, in addition to which it also reduces pain associated with DN 53.
Some studies demonstrate a more efficient approach in the DPN treatment, which consists in the use of synergistic effects between selective inhibitors of specific pathways and the consumption of vitamin supplementation with known antioxidant properties. This combination demonstrates a substantial preventive effect, besides delays the development and appearance of DPN. Nonetheless, the works give greater emphasis to the use of Carnitine, as it appears to be the best choice 54.
One of the most known and studied polyvitamins in DPN is acetyl-L-carnitine, an acetylated ester that has antioxidant properties and shown significant reduction in pain in patients with this disease. Its action mechanism is linked to transport processes for mitochondria, where one of its functions is to bind with free radicals and assist in their elimination, consequently acting as an intermediary for the balance of enzymatic processes of energy production, which is proposed to be the initiation of several pathophysiological pathways of DPN 55.
All the pathways and pharmacological proposed are summarized in the figure 5.
CONCLUSION
This literature review presents important information about the development and potential treatment of DPN. Through analyze of the works gathered here, some points of convergence are observed, such as the polyol, hexosamine and ROS route. Oxidative stress appears to be the main cause of nerve degeneration and can be seen as a result of proposed pathways for the appearance of all DPN.
FUNDING SOURCES
This project has not received funding. Silva, G.V.L. is a PhD student and receive scholarship from Fundação de Ampara à Pesquisa do Estado de São Paulo (FAPESP) grant number: 2021/10494-7. Belém-Filho, I.J.A. is a postdoctoral researcher and receive scholarship from FAPESP grant number 2021/10014-5.
CRediT ROLES
Rodrigues, Y.G.T. and Almeida, V.C. wrote the first draft of this review and prepared the figures. Silva G.V.L and Luz, D.A. contributed and critically revised the manuscript. Belém-Filho, I.J.A. wrote, reviewed and editing the manuscript. All authors read and approved the final manuscript.
DECLARATION OF INTEREST
All authors have no conflicts of interest to declare.
REFERENCES
1. Khandelwal P, Khanna S. Diabetic Peripheral Neuropathy: An Insight into the Pathophysiology, Diagnosis, and Therapeutics. Elsevier Inc.; 2020. doi:10.1016/B978-0-12-816413-6.00004-6
2. Sun J, Wang Y, Zhang X, Zhu S, He H. Prevalence of peripheral neuropathy in patients with diabetes: A systematic review and meta-analysis. Prim Care Diabetes. 2020;14(5):435-444. doi:10.1016/j.pcd.2019.12.005
3. Yang H, Sloan G, Ye Y, et al. New Perspective in Diabetic Neuropathy: From the Periphery to the Brain, a Call for Early Detection, and Precision Medicine. Front Endocrinol (Lausanne). 2020;10(January):1-13. doi:10.3389/fendo.2019.00929
4. Iqbal Z, Azmi S, Yadav R, et al. Diabetic Peripheral Neuropathy: Epidemiology, Diagnosis, and Pharmacotherapy. Clin Ther. 2018;40(6):828-849. doi:10.1016/j.clinthera.2018.04.001
5. Juster-Switlyk K, Smith AG. Updates in diabetic peripheral neuropathy. F1000Research. 2016;5(0):1-7. doi:10.12688/f1000research.7898.1
6. Callaghan BC, Xia R, Reynolds E, et al. Association Between Metabolic Syndrome Components and Polyneuropathy in an Obese Population. JAMA Neurol. 2016;73(12):1468-1476. doi:10.1001/jamaneurol.2016.3745
7. Callaghan BC, Little AA, Feldman EL, Hughes RA. Enhanced glucose control for preventing and treating diabetic neuropathy. Cochrane Database Syst Rev. 2012;(6). doi:10.1002/14651858.cd007543.pub2
8. Callaghan BC, Gallagher G, Fridman V, Feldman EL. Diabetic neuropathy: what does the future hold? Diabetologia. 2020;63(5):891-897. doi:10.1007/s00125-020-05085-9
9. Feldman EL, Nave K, Jensen TS, Bennett DLH. New Horizons in Diabetic Neuropathy: Mechanisms, Bioenergetics, and Pain. Neuron. 2017;93(6):1296-1313. doi:10.1016/j.neuron.2017.02.005
10. Varacallo MABM. Peripheral Diabetic Neuropathy. NCBI.
11. Muzy J, Campos MR, Emmerick I, da Silva RS, de Andrade Schramm JM. Prevalence of diabetes mellitus and its complications and characterization of healthcare gaps based on triangulation of studies. Cad Saude Publica. 2021;37(5). doi:10.1590/0102-311X00076120
12. Saeedi P, Petersohn I, Salpea P, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract. 2019;157. doi:10.1016/j.diabres.2019.107843
13. Menke A, Casagrande S, Geiss L, Cowie CC. Prevalence of and Trends in Diabetes among Adults in the United States, 1988-2012. JAMA – J Am Med Assoc. 2015;314(10):1021-1029. doi:10.1001/jama.2015.10029
14. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: Systematic review, meta-analysis and updated NeuPSig recommendations. Lancet Neurol. 2015;14(2):162-173. doi:10.1016/S1474-4422(14)70251-0.Pharmacotherapy
15. Schmid AB, Fundaun J, Tampin B. Entrapment neuropathies: A contemporary approach to pathophysiology, clinical assessment, and management. Pain Reports. 2020;5(4). doi:10.1097/PR9.0000000000000829
16. Schreiber AK. Diabetic neuropathic pain: Physiopathology and treatment. World J Diabetes. 2015;6(3):432. doi:10.4239/wjd.v6.i3.432
17. Feldman EL, Callaghan BC, Pop-Busui R, et al. Diabetic neuropathy. Nat Rev Dis Prim. 2019;5(1). doi:10.1038/s41572-019-0092-1
18. Lorenzi M. The polyol pathway as a mechanism for diabetic retinopathy: Attractive, elusive, and resilient. Exp Diabesity Res. 2007;2007. doi:10.1155/2007/61038
19. Garg SS, Gupta J. Polyol pathway and redox balance in diabetes. Pharmacol Res. 2022;182(June):106326. doi:10.1016/j.phrs.2022.106326
20. Niimi N, Yako H, Takaku S, Chung SK, Sango K. Aldose reductase and the polyol pathway in Schwann cells: Old and new problems. Int J Mol Sci. 2021;22(3):1-14. doi:10.3390/ijms22031031
21. Du XL, Edelstein D, Rossetti L, et al. Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci U S A. 2000;97(22):12222-12226. doi:10.1073/pnas.97.22.12222
22. Mizukami H, Osonoi S, Takaku S, et al. Role of glucosamine in development of diabetic neuropathy independent of the aldose reductase pathway. Brain Commun. 2020;2(2):1-18. doi:10.1093/braincomms/fcaa168
23. Kitada M, Zhang Z, Mima A, King GL. Molecular mechanisms of diabetic vascular complications. J Diabetes Investig. 2010;1(3):77-89. doi:10.1111/j.2040-1124.2010.00018.x
24. Fantus IG, Goldberg HJ, Whiteside CI, Topic D. The Hexosamine Biosynthesis Pathway: Contribution to the Pathogenesis of Diabetic Nephropathy. Contemp Diabetes Diabet Kidney. 2010;(4):117-133.
25. Buse MG. Hexosamines, insulin resistance, and the complications of diabetes: Current status. Am J Physiol – Endocrinol Metab. 2006;290(1). doi:10.1152/ajpendo.00329.2005
26. Barbosa JHP, Oliveira SL, Seara LT e. O papel dos produtos finais da glicação avançada (AGEs) no desencadeamento das complicações vasculares do diabetes. Arq Bras Endocrinol Metabol. 2008;52(6):940-950. doi:10.1590/s0004-27302008000600005
27. Jakuš V, Rietbrock N. Advanced Glycation End-Products and the Progress of Diabetic Vascular Complications. Physiol Res. 2004;53(2):131-142.
28. Vlassara H, Striker GE. The role of advanced glycation end-products in the etiology of insulin resistance and diabetes. US Endocrinol. 2010;6(1):14-19. doi:10.17925/use.2010.06.1.14
29. Uribarri J, Cai W, Peppa M, et al. Circulating glycotoxins and dietary advanced glycation endproducts: Two links to inflammatory response, oxidative stress, and aging. Journals Gerontol – Ser A Biol Sci Med Sci. 2007;62(4):427-433. doi:10.1093/gerona/62.4.427
30. Ramasamy R, Yan SF, Schmidt AM. Receptor for AGE (RAGE): Signaling mechanisms in the pathogenesis of diabetes and its complications. Ann N Y Acad Sci. 2011;1243(1):88-102. doi:10.1111/j.1749-6632.2011.06320.x
31. Papachristou S, Pafili K, Papanas N. Skin AGEs and diabetic neuropathy. BMC Endocr Disord. 2021;21(1):1-8. doi:10.1186/s12902-021-00697-7
32. Vlassara H, Striker GE. Advanced Glycation Endproducts in Diabetes and Diabetic Complications. Endocrinol Metab Clin North Am. 2013;42(4):697-719. doi:10.1016/j.ecl.2013.07.005
33. Güntert T, Hänggi P, Othman A, et al. 1-Deoxysphingolipid-induced neurotoxicity involves N-methyl-D-aspartate receptor signaling. Neuropharmacology. 2016;110:211-222. doi:10.1016/j.neuropharm.2016.03.033
34. Tran D, Myers S, McGowan C, et al. 1-Deoxysphingolipids, Early Predictors of Type 2 Diabetes, Compromise the Functionality of Skeletal Myoblasts. Front Endocrinol (Lausanne). 2021;12(December):1-12. doi:10.3389/fendo.2021.772925
35. Zuellig RA, Hornemann T, Othman A, et al. Deoxysphingolipids, novel biomarkers for type 2 diabetes, are cytotoxic for insulin-producing cells. Diabetes. 2014;63(4):1326-1339. doi:10.2337/db13-1042
36. Dohrn MF, Othman A, Hirshman SK, et al. Elevation of plasma 1-deoxy-sphingolipids in type 2 diabetes mellitus: A susceptibility to neuropathy? Eur J Neurol. 2015;22(5):806-e55. doi:10.1111/ene.12663
37. Othman A, Benghozi R, Alecu I, et al. Fenofibrate lowers atypical sphingolipids in plasma of dyslipidemic patients: A novel approach for treating diabetic neuropathy? J Clin Lipidol. 2015;9(4):568-575. doi:10.1016/j.jacl.2015.03.011
38. Sinnreich M, Taylor B V., Dyck PJB. Diabetic neuropathies: Classification, clinical features, and pathophysiological basis. Neurologist. 2005;11(2):63-79. doi:10.1097/01.nrl.0000156314.24508.ed
39. Kuchibhotla P, Rao BD. A methodology for fast scheduling of partitioned systolic algorithms. J VLSI Signal Process. 1995;10(2):111-126. doi:10.1007/BF02407030
40. Pang L, Lian X, Liu H, et al. Understanding diabetic neuropathy: Focus on oxidative stress. Oxid Med Cell Longev. 2020;2020. doi:10.1155/2020/9524635
41. Pop-Busui R, Sima A, Stevens M. Diabetic neuropathy and oxidative stress. Diabetes Metab Res Rev. 2006;22(4):257-273. doi:10.1002/dmrr.625
42. Babizhayev MA, Strokov IA, Nosikov V V., et al. The Role of Oxidative Stress in Diabetic Neuropathy: Generation of Free Radical Species in the Glycation Reaction and Gene Polymorphisms Encoding Antioxidant Enzymes to Genetic Susceptibility to Diabetic Neuropathy in Population of Type I Diabetic Patient. Cell Biochem Biophys. 2015;71(3):1425-1443. doi:10.1007/s12013-014-0365-y
43. Figueroa-Romero C, Sadidi M, Feldman EL. Mechanisms of disease: The oxidative stress theory of diabetic neuropathy. Rev Endocr Metab Disord. 2008;9(4):301-314. doi:10.1007/s11154-008-9104-2
44. Hosseini A, Abdollahi M. Diabetic neuropathy and oxidative stress: Therapeutic perspectives. Oxid Med Cell Longev. 2013;2013. doi:10.1155/2013/168039
45. Brezniceanu ML, Liu F, Wei CC, et al. Catalase overexpression attenuates angiotensinogen expression and apoptosis in diabetic mice. Kidney Int. 2007;71(9):912-923. doi:10.1038/sj.ki.5002188
46. Leinninger GM, Edwards JL, Lipshaw MJ, Feldman EL. Mechanisms of disease: Mitochondria as new therapeutic targets in diabetic neuropathy. Nat Clin Pract Neurol. 2006;2(11):620-628. doi:10.1038/ncpneuro0320
47. Cavalli E, Mammana S, Nicoletti F, Bramanti P, Mazzon E. The neuropathic pain: An overview of the current treatment and future therapeutic approaches. Int J Immunopathol Pharmacol. 2019;33. doi:10.1177/2058738419838383
48. Bates D, Carsten Schultheis B, Hanes MC, et al. A Comprehensive Algorithm for Management of Neuropathic Pain. Pain Med (United States). 2019;20:S2-S12. doi:10.1093/pm/pnz075
49. Khdour MR. Treatment of diabetic peripheral neuropathy: a review. J Pharm Pharmacol. 2020;72(7):863-872. doi:10.1111/jphp.13241
50. O’Connor AB, Dworkin RH. Treatment of Neuropathic Pain: An Overview of Recent Guidelines. Am J Med. 2009;122(10 SUPPL.):S22-S32. doi:10.1016/j.amjmed.2009.04.007
51. Dworkin RH, O’Connor AB, Audette J, et al. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc. 2010;85(3 Suppl):S3-14. doi:10.4065/mcp.2009.0649
52. Stevens M, Shakher J. Update on the management of diabetic polyneuropathies. Diabetes, Metab Syndr Obes Targets Ther. 2011:289. doi:10.2147/dmso.s11324
53. Edwards JL, Vincent AM, Cheng HT, Feldman EL. Diabetic neuropathy: Mechanisms to management. Pharmacol Ther. 2008;120(1):1-34. doi:10.1016/j.pharmthera.2008.05.005
54. Negi G, Kumar A, Joshi RP, Ruby PK, Sharma SS. Oxidative stress and diabetic neuropathy: Current status of antioxidants. IIOAB J. 2011;2(6):71-78.
55. Longo N, Frigeni M, Pasquali M. Carnitine transport and fatty acid oxidation. Biochim Biophys Acta. 2016;1863(10):2422-2435. doi:10.1016/j.bbamcr.2016.01.023