Impaired Skin Microvascular Reactivity in Painful Diabetic Neuropathy

Quattrini, Cristian; Harris, Nigel; Malik, Rayaz A.; Tesfaye, Solomon

doi:10.2337/dc06-2154

Cited by 91 publications

(85 citation statements)

References 38 publications

(40 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, the assessment of dermal NFD may provide more mechanistic insights into the pathogenesis of painful diabetic neuropathy, as it provides a measure of dermal blood vessel innervation and, hence, any potential impact on dermal blood flow. Indeed, we have previously demonstrated an impairment of cutaneous endothelium-related vasodilatation and C-fiber-mediated vasoconstriction in painful diabetic neuropathy and suggested that inappropriate local blood flow regulation may have a role in the pathogenesis of pain in diabetic neuropathy (22). A recent study confirms the validity of assessing alterations in dermal NFD in thin sections and has specifically demonstrated a reduction in arteriolar innervation in patients with smallfiber neuropathy (23).…”

Section: Discussionmentioning

confidence: 66%

Abnormal LDIflare but Normal Quantitative Sensory Testing and Dermal Nerve Fiber Density in Patients with Painful Diabetic Neuropathy

et al. 2009

Self Cite

View full text Add to dashboard Cite

OBJECTIVE -Abnormal small nerve fiber function may be an early feature of diabetic neuropathy and may also underlie painful symptoms. Methods for assessing small-fiber damage include quantitative sensory testing (QST) and determining intraepidermal nerve fiber density. We recently described a reproducible physiological technique, the LDIflare, which assesses small-fiber function and thus may reflect early dysfunction before structural damage. The value of this technique in painful neuropathy was assessed by comparing it with QST and dermal nerve fiber density (NFD).RESEARCH DESIGN AND METHODS -Fifteen healthy control subjects, 10 subjects with type 2 diabetes and painful neuropathy (PFN), and 12 subjects with type 2 diabetes and painless neuropathy (PLN) were studied. LDIflare and QST were performed on the dorsum of the foot, and dermal NFD was determined.RESULTS -Results of both large-and small-fiber quantitative sensory tests were abnormal in patients with PLN but not those with PFN compared with control subjects. Dermal NFD was also significantly reduced in the PLN group compared with control subjects (205.8 Ϯ 165.3 vs. 424.9 Ϯ 176.3 [mean Ϯ SD]; P ϭ 0.003) but not in the PFN group (307.6 Ϯ 164.5). In contrast, the LDIflare (square centimeters) was reduced in both PFN (1.59 Ϯ 0.41) and PLN (1.51 Ϯ 0.56) groups compared with control subjects (4.38 Ϯ 1.4) (P Ͻ 0.001 for both). NFD correlated significantly with the LDIflare (r ϭ 0.57, P Ͻ 0.0001).CONCLUSIONS -The LDIflare demonstrated impaired small-fiber function in patients with PFN when other assessments revealed no abnormality. We believe that this method has potential diagnostic value, particularly because it is noninvasive, has excellent reproducibility, and correlates with NFD. Furthermore, it may have an important role in assessing preventative therapies in early neuropathy. Diabetes Care 32:451-455, 2009

show abstract

Section: Discussionmentioning

confidence: 66%

Abnormal LDIflare but Normal Quantitative Sensory Testing and Dermal Nerve Fiber Density in Patients with Painful Diabetic Neuropathy

et al. 2009

Self Cite

View full text Add to dashboard Cite

show abstract

“…Finally, despite the overall low expression of HIF-1␣, it was inversely related to the intensity of pain assessed using the VAS. This finding requires confirmation but emphasizes that vascular factors may play an important role in the development of painful symptoms (28) and also provides a rationale for the use of vasodilating drugs in painful diabetic neuropathy (29).…”

Section: Dermal Microvessel Density and Vasodilator Responsesmentioning

confidence: 89%

Reduced Vascular Endothelial Growth Factor Expression and Intra-Epidermal Nerve Fiber Loss in Human Diabetic Neuropathy

Quattrini

Jeziorska²,

Boulton³

et al. 2008

Diabetes Care

Self Cite

108

View full text Add to dashboard Cite

OBJECTIVE -To assess the relevance of vascular endothelial growth factor (VEGF) in the maintenance of peripheral nerve integrity in diabetic neuropathy we have assessed the expression of VEGF and intra-epidermal nerve fiber density (IENFD) in skin biopsy samples from diabetic patients.RESEARCH DESIGN AND METHODS -Fifty-three diabetic patients and 12 nondiabetic control subjects underwent neurological evaluation, electrophysiology, quantitative sensory, and autonomic function testing. Dermal blood flow responses were evaluated with laser Doppler flowmetry. Skin biopsies were performed on the dorsum of the foot, and IENFD was quantified and compared with the expression of vascular endothelial growth factor A (VEGF-A), its receptor vascular endothelial growth factor receptor 2 (VEGFR-2), hypoxia-inducible factor 1␣ (HIF-1␣), and microvessel density.RESULTS -IENFD decreased progressively with increasing severity of diabetic neuropathy (P Ͻ 0.001). The dermal blood flow response to acetylcholine was reduced in diabetic patients with mild and moderate neuropathy (P Ͻ 0.01), and the intensity of staining for epidermal VEGF-A was significantly reduced in diabetic patients compared with control subjects (P Ͻ 0.01). Epidermal HIF-1␣ and VEGFR-2 expression did not differ between groups.CONCLUSIONS -Progressive endothelial dysfunction, a reduction in VEGF expression, and loss of intra-epidermal nerve fibers occurs in the foot skin of diabetic patients with increasing neuropathic severity.

show abstract

“…7,8 A recent study with thalamic proton magnetic resonance spectroscopy implicates thalamic neuronal dysfunction. 9 Understanding the biochemical mechanisms underlying diabetic neuropathic pain and sensory disorders requires preclinical studies in animal models.…”

Section: Diabetic Pain and Sensory Loss: Prevalence Current Treatmenmentioning

confidence: 99%

Diabetic Painful and Insensate Neuropathy: Pathogenesis and Potential Treatments

2009

View full text Add to dashboard Cite

Summary:Advanced peripheral diabetic neuropathy (PDN) is associated with elevated vibration and thermal perception thresholds that progress to sensory loss and degeneration of all fiber types in peripheral nerve. A considerable proportion of diabetic patients also describe abnormal sensations such as paresthesias, allodynia, hyperalgesia, and spontaneous pain. One or several manifestations of abnormal sensation and pain are described in all the diabetic rat and mouse models studied so far (i.e., streptozotocin-diabetic rats and mice, type 1 insulinopenic BB/Wor and type 2 hyperinsulinemic diabetic BBZDR/Wor rats, Zucker diabetic fatty rats, and nonobese diabetic, Akita, leptin-and leptin-receptor-deficient, and highfat diet-fed mice). Such manifestations are 1) thermal hyperalgesia, an equivalent of a clinical phenomenon described in early PDN; 2) thermal hypoalgesia, typically present in advanced PDN; 3) mechanical hyperalgesia, an equivalent of pain on pressure in early PDN; 4) mechanical hypoalgesia, an equivalent to the loss of sensitivity to mechanical noxious stimuli in advanced PDN; 5) tactile allodynia, a painful perception of a light touch; and 5) formalin-induced hyperalgesia. Rats with short-term diabetes develop painful neuropathy, whereas those with longer-term diabetes and diabetic mice typically display manifestations of both painful and insensate neuropathy, or insensate neuropathy only. Animal studies using pharmacological and genetic approaches revealed important roles of increased aldose reductase, protein kinase C, and poly(ADPribose) polymerase activities, advanced glycation end-products and their receptors, oxidative-nitrosative stress, growth factor imbalances, and C-peptide deficiency in both painful and insensate neuropathy. This review describes recent achievements in studying the pathogenesis of diabetic neuropathic pain and sensory disorders in diabetic animal models and developing potential pathogenetic treatments. Key Words: Animal models, diabetic insensate neuropathy, diabetic painful neuropathy, formalin-induced hyperalgesia, mechanical hyper-and hypoalgesia, pathogenetic treatments of diabetic neuropathic pain and sensory loss, symptomatic treatments of diabetic pain, tactile allodynia, thermal hyper-and hypoalgesia.

show abstract

Impaired Skin Microvascular Reactivity in Painful Diabetic Neuropathy

Cited by 91 publications

References 38 publications

Abnormal LDIflare but Normal Quantitative Sensory Testing and Dermal Nerve Fiber Density in Patients with Painful Diabetic Neuropathy

Abnormal LDIflare but Normal Quantitative Sensory Testing and Dermal Nerve Fiber Density in Patients with Painful Diabetic Neuropathy

Reduced Vascular Endothelial Growth Factor Expression and Intra-Epidermal Nerve Fiber Loss in Human Diabetic Neuropathy

Diabetic Painful and Insensate Neuropathy: Pathogenesis and Potential Treatments

Contact Info

Product

Resources

About