Esha V. Uddaraju

Background: Diabetic Peripheral Neuropathy (DPN) is a complication of Diabetes Mellitus that involves the degeneration of the peripheral nerves, leading to sensory deficits, neuropathic pain, and motor weakness.¹ Neural damage in DPN has a complex and interconnected pathophysiology that involves hyperglycemia, dyslipidemia, insulin signaling, metabolic dysfunction, and microvascular injury.^1,2 About 10-20% of patients with Diabetes Mellitus will develop DPN, and incidence rates increase as the disease progresses.² Treatment options for neuropathy are limited to symptomatic pain control and lifestyle changes to slow disease progression. Treatments aimed at improving microcirculation, decreasing oxidative stress, or using neurotropic drugs have potential for symptom relief, but their efficacy remains undesirable.³ Current research has focused on determining the mechanisms behind neural degeneration with the goal to improve DPN therapy.

Objective: In this literature review, the mechanisms behind microvascular injury and their contribution to Diabetic Peripheral Neuropathy were explored.

Methods: Journal articles written between 2018 and 2025 were obtained from PubMed databases using keywords related to  “Diabetic Peripheral Neuropathy,” “Microvascular Dysfunction,” “Hypoxia,” “Oxidative stress,” and “Blood-Nerve Barrier.”

Results: The major mechanisms behind neural damage include endothelial morphological changes, breakdown of the blood-nerve barrier, hypoxia in the neurovascular environment, and buildup of reactive oxygen species (ROS).¹ Various studies on animal models of DPN showed basement membrane thickening, endothelial cell proliferation, and impaired vasodilation, which leads to blood vessel stenosis, ischemia, and hypoxia.⁴ Tissue samples from patients with DPN demonstrated irregularly shaped blood vessel lumens with projections, gaps in the endothelium, smooth muscle deterioration, and a loss of mechanosensitive channel proteins.⁴ The breakdown of the blood nerve barrier was observed in diabetic rat models with a decrease in the expression of Claudin1 tight junctions and a loss in vessel-associated macrophages.⁵ Increased inflammation and thrombosis were observed with higher levels of fibrinogen, glial fibrillary acidic protein, and calcium-binding adaptor molecule 1 in DPN rat models.⁶ Excess ROS build up was noted in multiple studies to be a mechanism of neural injury.  Studies that examined treatment models focused on reducing inflammation, reducing excess ROS, and promoting angiogenesis and neurogenesis. A mouse study on the gene knockout of Hypoxia Inducible Factor 1α (HIF1α) indicated a faster and more severe disease progression with increased ROS levels compared to wild type mice, suggesting the protective effects of HIF1α.⁷ Studies show that stem cells help promote angiogenesis and decrease ROS levels, in addition to the reduction of pro-inflammatory cytokines and an increase in the level of neurotrophic factors.^8,9 Application of stem cells appears to improve DPN therapy.

Conclusion: Studies have shown that Diabetic Peripheral Neuropathy is associated with a variety of changes in the microvasculature that contribute to nerve injury and disease progression. While it is not the only component, microvascular injury is a critical factor contributing to the causes and progression of DPN. Therefore, managing the function and structure of microcirculation by reducing inflammation and oxidative stress might be a potential treatment for DPN. More research is needed to determine how microvascular injury interacts with other causal factors of DPN, as well as treatment methods focused on reversing microvascular damage.

Works Cited:

1.  Horton WB, Barrett EJ. Microvascular dysfunction in diabetes mellitus and cardiometabolic disease. Endocr Rev. 2021;42(1):29–55. https://www.ncbi.nlm.nih.gov/pubmed/33125468. doi: 10.1210/endrev/bnaa025.
2. Eid SA, Rumora AE, Beirowski B, et al. New perspectives in diabetic neuropathy. Neuron. 2023;111(17):2623–2641.doi: 10.1016/j.neuron.2023.05.003.
3. Zhu J, Hu Z, Luo Y, et al. Diabetic peripheral neuropathy: Pathogenetic mechanisms and treatment. Front Endocrinol (Lausanne). 2024;14:1265372. https://www.ncbi.nlm.nih.gov/pubmed/38264279. doi: 10.3389/fendo.2023.1265372
4. Garcia-Mesa Y, Cabo R, González-Gay M, et al. Relationship of PIEZO1 and PIEZO2 vascular expression with diabetic neuropathy. Frontiers in physiology. 2023;14:1243966. https://search.proquest.com/docview/2898955681. doi: 10.3389/fphys.2023.1243966.
5. Ben-Kraiem A, Sauer R, Norwig C, et al. Selective blood-nerve barrier leakiness with claudin-1 and vessel-associated macrophage loss in diabetic polyneuropathy. J Mol Med. 2021;99(9):1237–1250. https://link.springer.com/article/10.1007/s00109-021-02091-1. doi: 10.1007/s00109-021-02091-1.
6. Gu W, Li Z, Zhang S, et al. Role of fibrinogen in type-2 diabetes mellitus with diabetic neuropathy and its preliminary mechanism. Protein and peptide letters. 2023;30(6):486–497. http://www.eurekaselect.com/openurl/content.php?genre=article&issn=1875-5305&volume=30&issue=6&spage=486. doi: 10.2174/0929866530666230509140515.
7. Rojas DR, Tegeder I, Kuner R, Agarwal N. Hypoxia-inducible factor 1α protects peripheral sensory neurons from diabetic peripheral neuropathy by suppressing accumulation of reactive oxygen species. J Mol Med. 2018;96(12):1395–1405. https://link.springer.com/article/10.1007/s00109-018-1707-9. doi: 10.1007/s00109-018-1707-9.
8. Liu Y, Chen J, Liang H, et al. Human umbilical cord-derived mesenchymal stem cells not only ameliorate blood glucose but also protect vascular endothelium from diabetic damage through a paracrine mechanism mediated by MAPK/ERK signaling. Stem cell research & therapy. 2022;13(1):1–258. https://www.proquest.com/docview/2678208037. doi: 10.1186/s13287-022-02927-8.
9. Xie J, Rao N, Zhai Y, et al. Therapeutic effects of stem cells from human exfoliated deciduous teeth on diabetic peripheral neuropathy. Diabetol Metab Syndr. 2019;11(1):38–38. https://www.ncbi.nlm.nih.gov/pubmed/31131042. doi: 10.1186/s13098-019-0433-y.