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Oxidative stress at the crossroads of diabetic neuropathy: Mechanisms and implications of antidiabetics (Review)

  • Authors:
    • Khalil A. Hadid
    • Muthanna K. Zaki
    • Fawaz A. Alassaf
    • Mohammed N. Abed
  • View Affiliations / Copyright

    Affiliations: Department of Pharmacology and Toxicology, College of Pharmacy, University of Mosul, Mosul, Nineveh 41002, Iraq, Department of Clinical Laboratory Sciences, College of Pharmacy, University of Mosul, Mosul, Nineveh 41002, Iraq
    Copyright: © Hadid et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].
  • Article Number: 125
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    Published online on: November 5, 2025
       https://doi.org/10.3892/wasj.2025.413
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Abstract

Diabetic neuropathy (DNP) is among the most common complications of diabetes, affecting the majority of individuals with long‑standing diabetes. This painful microvascular condition is associated with a high risk of morbidity. While multiple factors are considered to contribute to the development of DNP, its exact cause remains unclear, although several theories have been proposed. Despite ample research aimed at detecting and attenuating the progression of DNP, effective treatment options remain limited. The present review delves into the connection between oxidative stress and neuropathy in patients with diabetes, with particular focus on the mechanisms through which antidiabetic medications may influence oxidative stress to help attenuate the advancement of DNP. For the purposes of the review, a search for relevant articles was performed using online sources, including the PubMed and Google Scholar databases, using key words, such as antidiabetics, antioxidant effects, diabetes, diabetic neuropathy and oxidative stress. It is currently considered that hyperglycemia and complex metabolic imbalances, particularly oxidative stress, play central roles in the development of DNP. Some antidiabetic drugs have antioxidant properties, either by boosting the body's own antioxidant enzymes or by reducing the production of harmful reactive oxidants. These antioxidant effects are linked to a lower risk of developing diabetic complications, including DNP. While certain antidiabetic medications may help prevent DNP from becoming more severe, others may have no effect or may even exacerbate the condition.
View Figures

Figure 1

Mechanisms of oxidant generation in
diabetic neuropathy: Hyperglycemia activates four main pathways
that lead to the formation of ROS and ultimately oxidative stress.
Oxidative stress leads to the activation of PARP along with
inflammatory process activation and reduces the level of Nrf2. With
time, these pathways lead to neuropathy (98,99).
AGEs, advanced glycation end products; DAG, diacylglycerol; NF-κB,
nuclear factor κB; Nrf2, nuclear factor 2; PARP, poly(ADP-ribose)
polymerase.

Figure 2

Contribution of the polyol pathway in
diabetic neuropathy: Hyperglycemia associated with diabetes results
in the shifting of normal glucose metabolic pathways, activating
the polyol pathway as an alternative pathway. The polyol pathway
converts glucose into sorbitol which is in turn converted to
fructose. This results in NADPH depletion and excess of NADH,
causing a decrease in ATP synthesis and an increase in ROS
production. As a result, nerve function is impaired, and this
results in DNP (100,101). NADPH, nicotinamide adenine
dinucleotide phosphate; NADH, nicotinamide adenine dinucleotide;
ATP, adenosine triphosphate.

Figure 3

Hexosamine biosynthetic pathway:
Under normal conditions, glucose undergoes a phosphorylation
process catalyzed by hexokinase, and phosphorylated glucose is
formed which is then converted to fructose that undergoes
glycolysis. In hyperglycemia, shifting from glycolysis into a
hexosamine biosynthetic pathway occurs resulting in the formation
of UDP-N-acetylglucosamine, the rate-limiting step is catalyzed by
GFAT. UDP-N-acetylglucosamine interferes with the action of
N-acetylglucosamine transferase, an enzyme that interferes with the
action of a number of proteins, including insulin receptor
substrate and glucose transporter protein (102,103). GFAT,
glutamine-fructose-6-phosphate aminotransferase; HBS, hexosamine
biosynthetic pathway; UDP, uridine diphosphate.
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Copy and paste a formatted citation
Spandidos Publications style
Hadid KA, Zaki MK, Alassaf FA and Abed MN: Oxidative stress at the crossroads of diabetic neuropathy: Mechanisms and implications of antidiabetics (Review). World Acad Sci J 7: 125, 2025.
APA
Hadid, K.A., Zaki, M.K., Alassaf, F.A., & Abed, M.N. (2025). Oxidative stress at the crossroads of diabetic neuropathy: Mechanisms and implications of antidiabetics (Review). World Academy of Sciences Journal, 7, 125. https://doi.org/10.3892/wasj.2025.413
MLA
Hadid, K. A., Zaki, M. K., Alassaf, F. A., Abed, M. N."Oxidative stress at the crossroads of diabetic neuropathy: Mechanisms and implications of antidiabetics (Review)". World Academy of Sciences Journal 7.6 (2025): 125.
Chicago
Hadid, K. A., Zaki, M. K., Alassaf, F. A., Abed, M. N."Oxidative stress at the crossroads of diabetic neuropathy: Mechanisms and implications of antidiabetics (Review)". World Academy of Sciences Journal 7, no. 6 (2025): 125. https://doi.org/10.3892/wasj.2025.413
Copy and paste a formatted citation
x
Spandidos Publications style
Hadid KA, Zaki MK, Alassaf FA and Abed MN: Oxidative stress at the crossroads of diabetic neuropathy: Mechanisms and implications of antidiabetics (Review). World Acad Sci J 7: 125, 2025.
APA
Hadid, K.A., Zaki, M.K., Alassaf, F.A., & Abed, M.N. (2025). Oxidative stress at the crossroads of diabetic neuropathy: Mechanisms and implications of antidiabetics (Review). World Academy of Sciences Journal, 7, 125. https://doi.org/10.3892/wasj.2025.413
MLA
Hadid, K. A., Zaki, M. K., Alassaf, F. A., Abed, M. N."Oxidative stress at the crossroads of diabetic neuropathy: Mechanisms and implications of antidiabetics (Review)". World Academy of Sciences Journal 7.6 (2025): 125.
Chicago
Hadid, K. A., Zaki, M. K., Alassaf, F. A., Abed, M. N."Oxidative stress at the crossroads of diabetic neuropathy: Mechanisms and implications of antidiabetics (Review)". World Academy of Sciences Journal 7, no. 6 (2025): 125. https://doi.org/10.3892/wasj.2025.413
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