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Cited by 88Pain Mechanisms and TreatmentsPeripheral Neuropathies and DisordersAldose Reductase and Taurine

Can VEGF reverse diabetic neuropathy in human subjects?

Open access
Veves, Aristidis, King, George L.·2001·Journal of Clinical Investigation
DOI 10.1172/jci13038PMC PMC209306
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Abstract

Peripheral polyneuropathy is a common complication of diabetes that can clinically affect 30% of all diabetic patients and is the most common form of diabetic neuropathy. The main symptoms are numbness, tingling, burning, and shooting pain in the legs, whereas the physical findings include reduced pain, touch, and vibratory perception in a symmetrical stocking glove distribution (1, 2). Loss of protective sensation allows unperceived trauma and pressures of daily ambulation to cause foot ulcers, which can lead to prolonged immobilization or even amputation of the lower limb. The main histologic changes of diabetic polyneuropathy are loss of myelinated and unmyelinated fibers and segmental demyelination. Changes in the myelinated fibers can be measured functionally in vivo by quantitating nerve conduction velocities and amplitudes of evoked responses, which are objective techniques and can assess nerve function without relying solely on the patient’s subjective responses. In contrast, testing of small fibers is more difficult, as it is subjective and dependent on the patients’ active participation (3). Hyperglycemia, which has emerged as a major risk factor for the development of diabetic neuropathy, may affect the peripheral sensory nerves through several mechanisms (2). Several of the current hypotheses are shown in Figure ​Figure1.1. First, the increased flux through the polyol pathway in hyperglycemic patients may lead to intracellular sorbitol accumulation and, potentially, to osmotic increase or changes in the NAD/NADH ratio induced by the flux through the aldose reductase pathway. These changes can cause direct neuronal damage or decrease neuronal blood flow, indirectly leading to peripheral nerve hypoxia. Second, the activation of protein kinase C (PKC) in response to increased diacylglycerol levels via the de novo synthesis pathway can affect the Na, K ATPase, and other enzymes that are important for maintaining cellular membrane potential and nerve conduction. In addition, PKC activation can induce vasoconstriction and reduce neuronal blood flow. Third, the auto-oxidation of glucose causes increased production of reactive oxygen species and the formation of advanced glycation end products (AGEs) by nonenzymatic glycation of proteins. AGEs then bind to a cell-surface receptor and cause activation of the NF-κB, which is associated with endothelial dysfunction and reduced nerve blood flow. Finally, diabetes impairs the hepatic Δ-6 desaturation of dietary linolenic acid to γ-linolenic acid and results in reduced synthesis of vasoactive prostanoid in the vasa nervorum. This defect leads to reduced endoneurial blood flow and nerve hypoxia. Each of these models finds some support in the various biochemical abnormalities seen in peripheral nerves and vasculature of diabetic patients. Figure 1 Pathogenesis of diabetic neuropathy. Factors implicated in the pathogenesis of diabetic neuropathy include the activation of the polyol pathway, the activation of protein kinase C (PKC), increased oxidative stress, the impaired N-6 fatty acid metabolism, ... Other physiological changes that accompany the onset of diabetes may also contribute to peripheral neuropathy. In particular, decreased blood flow to these nerves is one of the earliest functional findings in the development or induction of diabetes. The resulting local hypoxia in the peripheral nerves is believed to be a major pathogenic factor, although impaired mitochondrial functions and apoptosis of neurons and Schwann cells also occurs with similar timing and may act independently of hypoxia to induce peripheral nerve dysfunction. In addition, reduction in neurotrophic factors such as nerve growth factor availability (including neurotrophin-3 [NT-3], brain-derived neurotrophic factor, and neurotrophin-4/5 [NT-4/5]) and aberrant phosphorylation of the neurofilaments that are responsible for the structural nerve axon integrity have also been implicated in the pathogenesis of diabetic neuropathy.

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  • Chronic hyperglycemia enhances formation of advanced glycation end-products (AGEs), which bind to specific receptors (RAGE) and activate inflammatory pathways.

    “Chronic hyperglycemia enhances formation of advanced glycation end-products (AGEs), which bind to specific receptors (RAGE) and activate inflammatory pathways.”

    From Diabetic gastroparesis: pathophysiology and impact on insulin timing choices (2026) · cites this paper as [37]

    The paper’s discussion of diabetic neuropathy (page not specified in our copy) says glucose auto-oxidation leads to AGE formation and that AGEs bind a cell-surface receptor and activate NF-κB. It does not identify that receptor as RAGE, so the claim’s receptor-specific detail is not supported by our copy. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Activation of the polyol pathway further increases oxidative stress, damaging neurons and endothelial cells and reducing blood supply to neural tissues.

    “Activation of the polyol pathway further increases oxidative stress, damaging neurons and endothelial cells and reducing blood supply to neural tissues [33–37].”

    From Diabetic gastroparesis: pathophysiology and impact on insulin timing choices (2026) · cites this paper as [37]

    The paper’s discussion of diabetic neuropathy says increased polyol-pathway activity may cause neuronal damage or reduce neuronal blood flow. Its Figure 1 caption (p. 1216) treats oxidative stress as an interrelated factor, but the paper attributes increased reactive oxygen species to glucose auto-oxidation and links endothelial dysfunction to advanced glycation end products—not specifically to polyol-pathway activation. (LLM, conf=0.87)

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Authors
Veves, A., & King, G. L.
Affiliations
Joslin Diabetes Center (US)
Corresponding author
King, George L.
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2001-05-15
Volume
107
Issue
10
Pages
1215-1218
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci13038
PMC
PMC209306
OpenAlex
W1974559742
Cited by
88
References
22
Citations by year
2026: 3 · 2025: 2 · 2024: 1 · 2023: 5 · 2022: 6 · 2021: 7 · 2020: 1 · 2019: 1 · 2018: 4 · 2017: 3 · 2016: 3 · 2015: 2 · 2014: 5 · 2013: 3 · 2012: 4
FWCI
2.18
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5r01dk059725-05, 5r01ey009178-10, 5r01ey005110-18)
  • National Eye Institute (EY09178, R01 EY 05110)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK36836, DK 59725, P30DK036836)
Topics
  • Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
  • Health Sciences › Medicine › Neurology › Peripheral Neuropathies and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
Keywords
vascular endothelial growth factor, diabetic neuropathy, polyneuropathy, hyperglycemia, nerve blood flow, protein kinase C, advanced glycation end products, NF-κB, vasa nervorum, gamma-linolenic acid, polyol pathway, aldose reductase, nerve regeneration, nerve conduction velocity, sensory nerve function, diabetic foot ulcer
MeSH terms
Diabetic Neuropathies, Humans, Lymphokines, Microcirculation, Peripheral Nerves, Vasa Nervorum, Endothelial Growth Factors, Vascular Endothelial Growth Factors, Vascular Endothelial Growth Factor A

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