Metabolic and Vascular Factors in the Pathogenesis of Diabetic Neuropathy
Abstract
Reduced nerve perfusion is an important factor in the etiology of diabetic neuropathy. Studies in streptozotocin-induced diabetic rats show that nerve conduction velocity (NCV) and blood flow deficits are corrected by treatment with vasodilator drugs, with angiotensin II and endothelin-1 antagonists being particularly important. The AT1 antagonist ZD7155 also prevents diabetic deficits in regeneration following nerve damage, indicating that hypoperfusion is an important limitation for nerve repair. Metabolic changes include high polyol pathway flux, increased advanced glycosylation, elevated oxidative stress, and impaired ω-6 essential fatty acid metabolism. Aldose reductase inhibitors (ARIs) restore NCV via their effects on perfusion. ARI action probably depends on blocking the conversion of glucose to sorbitol, thus preventing depletion of vasa nervorum glutathione, an important endogenous free radical scavenger. Free radicals cause vascular endothelium damage and reduced nitric oxide vasodilation. Inhibition of advanced glycosylation and autoxidation (autoxidative glycosylation), major sources of free radicals, by aminoguanidine or transition metal chelators, corrects neurovascular dysfunction. Evening primrose oil supplies γ-linolenic acid (GLA) to improve vasodilator eicosanoid synthesis in diabetes, correcting nerve blood flow and NCV deficits. Interactions between some of these mechanisms have therapeutic implications. Thus, combined ARI and evening primrose oil treatment produced a 10-fold amplification of NCV and blood flow responses. Similarly, GLA effects are markedly enhanced when given in combination with ascorbate as ascorbyl-GLA. Thus, metabolic abnormalities combine to produce deleterious changes in nerve perfusion that make a major contribution to the etiology of diabetic neuropathy. The potential importance of multi-action therapy is stressed.
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Formation of hydroxyl radicals also contributes to impairment of vascular reactivity and nerve function in diabetes.
“Because metal chelators and hydroxyl radical scavengers have also been demonstrated to be effective in preventing diabetes-induced vascular and neural dysfunction, it is likely that the formation of hydroxyl radicals also contributes to impairment of vascular reactivity and nerve function in diabetes (46–51, 145).”
From Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010) · cites this paper as [47]
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Jain, M., Devan, S., Jaisankar, D., Swaminathan, G., Pardhan, S., & Raman, R. (2018) · Scientific Reports · doi:10.1038/s41598-018-24015-9 · Cited by 48 · see citing works
Sharma, S. S., Kumar, A., & Kaundal, R. K. (2008) · Life Sciences · doi:10.1016/j.lfs.2007.11.031 · Cited by 48 · see citing works
“Decreased NBF with resulting hypoxia is one of the mechanisms responsible for reduced nerve conduction velocity in diabetic conditions (Cameron and Cotter, 1997; Coppey et al., 2001).”
BackgroundKale, B., ksel, F. Y., z, B. E., et al. (2003) · Plastic & Reconstructive Surgery · doi:10.1097/01.prs.0000060100.80687.d9 · Cited by 47 · see citing works
Ramanathan, R. K., Rothenberg, M. L., de Gramont, A., Tournigand, C., Goldberg, R. M., Gupta, S., & André, T. (2009) · Annals of Oncology · doi:10.1093/annonc/mdp509 · Cited by 46 · see citing works
El-Bahr, S. M. (2013) · BMC Complementary and Alternative Medicine · doi:10.1186/1472-6882-13-368 · Cited by 45 · see citing works
Rapid onset pain induced by intravenous streptozotocin in the rat
Aley, K. O., & Levine, J. D. (2001) · Journal of Pain · doi:10.1054/jpai.2001.21592 · Cited by 46 · see citing works
Won, J. C., Kwon, H., Moon, S., Chun, S. W., Kim, C. H., Park, I. B., Kim, I. J., Lee, J., Cha, B. Y., & Park, T. S. (2019) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2019.0099 · Cited by 46 · see citing works
Sharma, S. S., & Sayyed, S. G. (2006) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/j.1440-1681.2006.04481.x · Cited by 43 · see citing works
“Free radicals, such as and OH, cause vascular endothelial damage and reduced NO-mediated vasodilatation.(39) Studies have provided evidence that the generation of and peroxynitrite impairs vascular function and endothelium-dependent vascular relaxation of epineural arterioles of the sciatic nerve from diabetic rats, w…”
Background
- Authors
- Cameron, N. E., & Cotter, M. A.
- Affiliations
- University of Aberdeen (GB)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 1997-09-01
- Volume
- 46
- Issue
- Supplement_2
- Pages
- S31-S37
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2151689386
- Cited by
- 312
- References
- 0
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 5 · 2023: 7 · 2022: 5 · 2021: 7 · 2020: 11 · 2019: 9 · 2018: 7 · 2017: 9 · 2016: 7 · 2015: 12 · 2014: 12 · 2013: 10 · 2012: 8
- FWCI
- 4.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Neurology › Peripheral Neuropathies and Disorders
- Keywords
- diabetic neuropathy, nerve blood flow, nerve conduction velocity, polyol pathway, advanced glycation end products, oxidative stress, aldose reductase inhibitors, sorbitol, glutathione, vasa nervorum, angiotensin receptor blockers, nerve regeneration, aminoguanidine, evening primrose oil, gamma-linolenic acid, nitric oxide, vasodilation, free radicals, endothelial injury
- MeSH terms
- Animals, Carnitine, Diabetes Mellitus, Experimental, Diabetic Neuropathies, Endothelium, Vascular, Fatty Acids, Essential, Glycosylation, Humans, Nerve Tissue, Oxidation-Reduction, Regional Blood Flow, Sugar Alcohols, Vasodilator Agents, Reactive Oxygen Species, Rats
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