Evaluation of diabetic neuropathy through the quantitation of cutaneous nerves

Hirai, Akinori; Yasuda, Hitoshi; Joko, M; Maeda, Toshiro; Kikkawa, Ryuichi

doi:10.1016/s0022-510x(99)00290-7

Cited by 65 publications

(39 citation statements)

References 30 publications

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“…2), indicates that there is a significant decrease in both IENFD as compared to non-diabetic controls. These data results for IENFD in controls and diabetics are similar to previously published reports in rats and humans (Bianchi et al, 2004;Hirai et al, 2000;Leonelli et al, 2007).…”

Section: Animal Characteristics and Quantitative Measurementssupporting

confidence: 92%

“…The timing of increases in TGF-β mRNA and protein show an association with decreased nerve conduction velocities, paw withdrawal threshold, IENFD and fiber length in the STZ diabetic model. IENFD is a good marker of early neuropathy both in rodents and humans (Bianchi et al, 2004;Hirai et al, 2000;Leonelli et al, 2007;Polydefkis et al, 2004). Other models of nerve injury, for example sciatic cryoneurolysis and chronic constriction injury, show a similar increase in cytokine production including TGF-β in the spinal cord and dorsal and ventral roots Willenbring et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…Fifty µm sections were cut using a cryostat (Leica CM 1850) as described previously (Hirai et al, 2000). Briefly, endogenous peroxidase activity was blocked by incubation for 0.5 hr with 1% H 2 O 2 in 100% methanol.…”

Section: Skin Biopsymentioning

confidence: 99%

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Transforming growth factor-β induces cellular injury in experimental diabetic neuropathy

Anjaneyulu

Berent-Spillson

Inoue

et al. 2008

Experimental Neurology

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The mechanism/s leading to diabetic neuropathy are complex. Transforming growth factor-β1 (TGF-β1) has been associated with diabetic nephropathy and retinopathy but not neuropathy. In this study, changes in TGF-β isoforms were examined in-vivo and in-vitro. Two groups of animals, streptozotocin diabetic with neuropathy and non-diabetic controls were examined at 4 weeks (n=10/ group) and 12 weeks (n=8/group). In diabetic DRG using quantitative real-time PCR (QRT-PCR), TGF-β1 and TGF-β2 mRNA, but not TGF-β3, was increased at 4 and 12 weeks. In sciatic nerve TGF-β3 mRNA was primarily increased. Immunohistochemistry (DRG) and immunoblotting (sciatic nerve) showed similar differential protein expression. In sciatic nerve TGF-β formed homoand heterodimers, of which β 2 /β 3 , β 1 /β 1 , and β 1 /β 3 were significantly increased, while that of the TGF-β 2 /β 2 homodimer was decreased, in diabetic compared to non-diabetic rats. In-vitro, pretreatment of embryonic DRG with TGF-β neutralizing antibody prevents the increase in total TGF-β protein observed with high glucose using immunoblotting. In high glucose conditions, combination with TGF-β2 > β1 increases the percent of cleaved caspase-3 compared to high glucose alone and TGF-β neutralizing antibody inhibits this increase. Furthermore, consistent with the findings in diabetic DRG and nerve, TGF-β isoforms applied directly in vitro reduce neurite outgrowth, and this effect is partially reversed by TGF-β neutralizing antibody. These findings implicate upregulation of TGF-β in experimental diabetic peripheral neuropathy and indicate a novel mechanism of cellular injury related to elevated glucose levels. In combination, these findings indicate a potential new target for treatment of diabetic peripheral neuropathy.

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Section: Animal Characteristics and Quantitative Measurementssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Transforming growth factor-β induces cellular injury in experimental diabetic neuropathy

Anjaneyulu

Berent-Spillson

Inoue

et al. 2008

Experimental Neurology

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“…Loss of these fibres has been demonstrated in diabetic patients [38] and in streptozotocin-induced diabetic rats and mice [14,39]. Since small fibres are closely involved in thermal and nociceptive pathways, while NCV correlates mostly with the impairment of large myelinated fibres, it appears that islet transplantation acts on both populations.…”

Section: Discussionmentioning

confidence: 99%

Regression of diabetic complications by islet transplantation in the rat

et al. 2009

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Aims/hypothesis Type 1 diabetes is a chronic disease leading to complications such as peripheral neuropathies, nephropathy and cardiovascular disease. Pancreatic islet transplantation is being extensively investigated for blood glucose control in animals and in human type 1 diabetic patients, but the question of whether it can reverse long-term diabetic complications has not been fully explored. We investigated the effects of islet transplantation on diabetic complications in a rat model of streptozotocin-induced diabetes.Methods Three groups of rats were used: healthy controls, diabetic and diabetic rats transplanted with microencapsulated islets at 2 months after diabetes induction, when neuropathy was detectable by a decrease in tail nerve conduction velocity (NCV) and impaired nociceptive thresholds. Blood glucose levels and body weight were measured weekly. The variables considered were: thermal (hot plate test) and mechanical sensitivity (Randal-Selitto paw withdrawal test), NCV and Na+, K+-ATPase activity in the sciatic nerve. At the end of the experiments hearts were removed for morphometric determination and myocyte number, and kidneys removed for histological examination. Results Islet transplantation in diabetic rats induced normoglycaemia in a few days, accompanied by a rapid rise in body weight and amelioration of impaired nociceptive thresholds, as well as normalisation of NCV and Na + , K + -ATPase, which were both about 25% below normal in diabetic rats. Myocyte loss was reduced (−34%) by islet transplantation and the observed mild kidney damage of diabetic rats was prevented. Conclusions/interpretation Besides controlling glycaemia, transplantation of microencapsulated pancreatic islets induced almost complete regression of neuropathy and prevented cardiovascular alterations.

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“…Epidermal changes have been correlated with reduced conduction velocity, suggesting that quantitative analysis of cutaneous innervation may be indicative of developing neuropathies (Herrmann et al, 1999;Hirai et al, 2000). However, the vast majority of studies addressing axon loss in diabetes have focused on C-fiber loss in the epidermis and information regarding dermal innervation by myelinated fibers has been largely ignored (see .…”

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confidence: 99%

Neurotrophic modulation of myelinated cutaneous innervation and mechanical sensory loss in diabetic mice

Christianson¹,

Ryals²,

Johnson³

et al. 2007

Neuroscience

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Human diabetic patients often lose touch and vibratory sensations, but to date, most studies on diabetes-induced sensory nerve degeneration have focused on epidermal C-fibers. Here, we explored the effects of diabetes on cutaneous myelinated fibers in relation to the behavioral responses to tactile stimuli from diabetic mice. Weekly behavioral testing began prior to STZ administration and continued until 8 weeks, at which time myelinated fiber innervation was examined in the footpad by immunohistochemistry using antiserum to NF-H and MBP. Diabetic mice developed reduced behavioral responses to non-noxious (monofilaments) and noxious (pin prick) stimuli. In addition, diabetic mice displayed a 50% reduction in NF-H-positive myelinated innervation of the dermal footpad compared to non-diabetic mice. To test whether two neurotrophins NGF and/or NT-3 known to support myelinated cutaneous fibers could influence myelinated innervation, diabetic mice were treated intrathecally for two weeks with NGF, NT-3, NGF and NT-3. Neurotrophin-treated mice were then compared to diabetic mice treated with insulin for two weeks. NGF and insulin treatment both increased paw withdrawal to mechanical stimulation in diabetic mice, whereas NT-3 or a combination of NGF and NT-3 failed to alter paw withdrawal responses. Surprisingly, all treatments significantly increased myelinated innervation compared to control-treated diabetic mice, demonstrating that myelinated cutaneous fibers damaged by hyperglycemia respond to intrathecal administration of neurotrophins. Moreover, NT-3 treatment increased epidermal Merkel cell numbers associated with nerve fibers, consistent with increased numbers of NT-3-responsive slowly adapting A-fibers. These studies suggest that myelinated fiber loss may contribute as significantly as unmyelinated epidermal loss in diabetic neuropathy, and the contradiction between neurotrophininduced increases in dermal innervation and behavior emphasize the need for multiple approaches to accurately assess sensory improvements in diabetic neuropathy. KeywordsNeuropathy; diabetes; dermis; innervation; myelinated axon NGF; NT-3 *Correspondence: Douglas Wright, Ph.D., Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, Phone:913-588-2713, Fax: 913-588-2710, email: dwright@kumc.edu. Section Editor: Donna HammondPublisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. , 1984). The predominant type of diabetic neuropathy is a distal, symmetrical, sensorimotor polyneuropathy and preferentially affects sensory function in the distal regions, i...

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Evaluation of diabetic neuropathy through the quantitation of cutaneous nerves

Cited by 65 publications

References 30 publications

Transforming growth factor-β induces cellular injury in experimental diabetic neuropathy

Transforming growth factor-β induces cellular injury in experimental diabetic neuropathy

Regression of diabetic complications by islet transplantation in the rat

Neurotrophic modulation of myelinated cutaneous innervation and mechanical sensory loss in diabetic mice

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