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Background <p>Diabetic neuropathy (DN) affects ~ 50% of diabetes patients and remains the leading cause of non-traumatic limb amputation. It is caused by the combined effects of prolonged high blood sugar levels, oxidative stress, dysfunctional mitochondria, inflammation, and damage to small blood vessels. No disease-modifying therapy exists.</p> Purpose <p>To integrate recent advances in the cellular and molecular mechanisms of DN with emerging therapeutic strategies, focusing on oxidative stress, mitochondrial dysfunction, inflammation, and novel drug classes.</p> Key findings <p>Chronic hyperglycemia drives four interdependent pathways-polyol, advanced glycation end-product (AGE), protein kinase C (PKC), and hexosamine that converge on mitochondrial reactive oxygen species (ROS) overproduction. This leads to neuronal apoptosis, Schwann cell injury, and microvascular ischemia. Dyslipidemia and insulin resistance independently contribute to dorsal root ganglion (DRG) mitochondrial depolarization. Clinically, painful DN involves Nav, Cav, TRP, and HCN channel dysregulation. Current treatments (gabapentin, duloxetine, pregabalin) provide only symptomatic relief. However, emerging evidence supports neuroprotective effects of SGLT2 inhibitors (empagliflozin), GLP-1 agonists (liraglutide), and mitochondrial-targeted antioxidants (MitoQ, α-lipoic acid). Biomarkers (IENFD, corneal confocal microscopy) enable earlier diagnosis. Preclinical and early clinical studies suggested that SGLT2 inhibitors and GLP-1 receptor agonists may exert neuroprotective effects through modulation of oxidative stress, inflammation, and mitochondrial dysfunction. However, further large-scale clinical studies are required to establish their efficacy and therapeutic role in diabetic neuropathy.</p> Conclusion <p>Multimodal therapies combining glycemic control, lipid management, mitochondrial protection, and ion channel modulation are required. Future randomized controlled trials should test combinatorial regimens that target both pathogenesis and symptoms.</p> Graphical Abstract <p></p>

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Mechanistic Insights into Diabetic Neuropathy: Oxidative Stress, Mitochondrial Injury, and Translational Therapeutics

  • 期刊论文

  • 发表日期：

    2026年7月16日

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  • Muzafar Ahmad Mir,
  • Showkat ul Nabi,
  • Rakeeb Ahmad Mir,
  • Sofi Imtiyaz Ali,
  • Irfan Ahmed Noorani,
  • Shabista Muzaffar,
  • Ibraq Khurshid

摘要

Background

Diabetic neuropathy (DN) affects ~ 50% of diabetes patients and remains the leading cause of non-traumatic limb amputation. It is caused by the combined effects of prolonged high blood sugar levels, oxidative stress, dysfunctional mitochondria, inflammation, and damage to small blood vessels. No disease-modifying therapy exists.

Purpose

To integrate recent advances in the cellular and molecular mechanisms of DN with emerging therapeutic strategies, focusing on oxidative stress, mitochondrial dysfunction, inflammation, and novel drug classes.

Key findings

Chronic hyperglycemia drives four interdependent pathways-polyol, advanced glycation end-product (AGE), protein kinase C (PKC), and hexosamine that converge on mitochondrial reactive oxygen species (ROS) overproduction. This leads to neuronal apoptosis, Schwann cell injury, and microvascular ischemia. Dyslipidemia and insulin resistance independently contribute to dorsal root ganglion (DRG) mitochondrial depolarization. Clinically, painful DN involves Nav, Cav, TRP, and HCN channel dysregulation. Current treatments (gabapentin, duloxetine, pregabalin) provide only symptomatic relief. However, emerging evidence supports neuroprotective effects of SGLT2 inhibitors (empagliflozin), GLP-1 agonists (liraglutide), and mitochondrial-targeted antioxidants (MitoQ, α-lipoic acid). Biomarkers (IENFD, corneal confocal microscopy) enable earlier diagnosis. Preclinical and early clinical studies suggested that SGLT2 inhibitors and GLP-1 receptor agonists may exert neuroprotective effects through modulation of oxidative stress, inflammation, and mitochondrial dysfunction. However, further large-scale clinical studies are required to establish their efficacy and therapeutic role in diabetic neuropathy.

Conclusion

Multimodal therapies combining glycemic control, lipid management, mitochondrial protection, and ion channel modulation are required. Future randomized controlled trials should test combinatorial regimens that target both pathogenesis and symptoms.

Graphical Abstract