Progression Of Diabetic Polyneuropathy Research Articles

Effects of Short-Term Treatment with α-Lipoic Acid on Neuropathic Pain and Biomarkers of DNA Damage in Patients with Diabetes Mellitus.

Diabetes mellitus (DM) is a complex and heterogenous disease classified as a group of metabolic disorders characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both. It leads to various complications, some of which are macrovascular or microvascular complications, like diabetic polyneuropathy (DPN), having a profound impact on patients' quality of life. Oxidative stress (OS) is one of the significant mechanisms in the development and progression of DPN. Thus, targeting OS pathways by antioxidants, such as α-lipoic acid (ALA), could represent a promising therapeutic strategy for alleviating neuropathic symptoms. The aim of our study was to evaluate whether short-term (from 4 to 9 days) intravenous administration of ALA could cause any measurable improvement in subjects with DM. Sixteen subjects with DM (six type 1 and ten type 2) and sixteen nondiabetic subjects matched by sex and age were recruited to this study. Only subjects with DM received treatment with ALA (600 mg daily). Pain intensity and biomarkers of DNA damage including plasma concentration of 8-hydroxy-2'-deoxyguanosine (8-OHdG), frequency of micronucleated lymphocytes (MN), and frequency of sister-chromatid exchanges (SCEs), were measured before and after the treatment with ALA. Pain intensity and 8-OHdG levels were significantly lower in DM subjects after the ALA treatment than before the treatment. However, no changes in the frequency of SCEs and MN were observed. Our results show some evidence that even a short-term intravenous treatment with ALA could be beneficial for diabetic subjects, reducing pain intensity and concentration of 8-OHdG in blood plasma.

Stem Cell Therapy in Diabetic Polyneuropathy: Recent Advancements and Future Directions

Diabetic polyneuropathy (DPN) is the most frequent, although neglected, complication of long-term diabetes. Nearly 30% of hospitalized and 20% of community-dwelling patients with diabetes suffer from DPN; the incidence rate is approximately 2% annually. To date, there has been no curable therapy for DPN. Under these circumstances, cell therapy may be a vital candidate for the treatment of DPN. The epidemiology, classification, and treatment options for DPN are disclosed in the current review. Cell-based therapies using bone marrow-derived cells, embryonic stem cells, pluripotent stem cells, endothelial progenitor cells, mesenchymal stem cells, or dental pulp stem cells are our primary concern, which may be a useful treatment option to ease or to stop the progression of DPN. The importance of cryotherapies for treating DPN has been observed in several studies. These findings may help for the future researchers to establish more focused, accurate, effective, alternative, and safe therapy to reduce DPN. Cell-based therapy might be a permanent solution in the treatment and management of diabetes-induced neuropathy.

Multimodal Comparison of Diabetic Neuropathy in Aged Streptozotocin-Treated Sprague-Dawley and Zucker Diabetic Fatty Rats.

The development and progression of diabetic polyneuropathy (DPN) are due to multiple mechanisms. The creation of reliable animal models of DPN has been challenging and this issue has not yet been solved. However, despite some recognized differences from humans, most of the current knowledge on the pathogenesis of DPN relies on results achieved using rodent animal models. The simplest experimental DPN model reproduces type 1 diabetes, induced by massive chemical destruction of pancreatic beta cells with streptozotocin (STZ). Spontaneous/transgenic models of diabetes are less frequently used, mostly because they are less predictable in clinical course, more expensive, and require a variable time to achieve homogeneous metabolic conditions. Among them, Zucker diabetic fatty (ZDF) rats represent a typical type 2 diabetes model. Both STZ-induced and ZDF rats have been extensively used, but only very few studies have compared the long-term similarities and differences existing between these two models. Moreover, inconsistencies have been reported regarding several aspects of short-term in vivo studies using these models. In this study, we compared the long-term course of DPN in STZ-treated Sprague-Dawley and ZDF rats with a multimodal set of readout measures.

Magnetic Resonance Neurography Reveals Smoking-Associated Decrease in Sciatic Nerve Structural Integrity in Type 2 Diabetes.

ObjectiveIt is controversially discussed in how far smoking contributes to diabetic polyneuropathy (DPN) in type 2 diabetes (T2D). Diffusion-weighted magnetic resonance neurography (MRN) at 3 Tesla has been shown to provide objective values for structural nerve integrity in patients with T2D. The aim of this study was to investigate the contribution of cigarette smoking on structural nerve integrity in T2D.MethodsThis cross-sectional prospective cohort study investigated the structural integrity of the sciatic nerve in 10 smokers, 40 never-smokers, and 20 ex-smokers with T2D and 10 healthy control subjects, using diffusion tensor imaging MRN at 3 Tesla and semi-automated nerve fiber tracking. Results were correlated with clinical, electrophysiological, and serological data.ResultsThe sciatic nerve’s fractional anisotropy (FA), a parameter for structural nerve integrity, was significantly lower in smokers with T2D when compared to controls (p = 0.002) and never-smokers (p = 0.015), and lower in ex-smokers when compared to controls (p = 0.015). In addition, sciatic nerve radial diffusivity, a marker of myelin damage, was increased in smokers versus controls and never-smokers (p = 0.048, p = 0.049, respectively). Furthermore, FA in T2D patients was negatively correlated with clinical and electrophysiological markers of DPN. FA also showed negative correlations with the pulse wave velocity, a marker of arterial stiffness and associated microangiopathy, in controls (r = −0.70; p = 0.037), never-smokers (r = −0.45; p = 0.004), ex-smokers (r = −0.55; p = 0.009), and a similar trend in smokers (r = −0.63; p = 0.076). Negative correlations were found between FA and skin auto-fluorescence, a marker of tissue advanced glycation end product accumulation and therefore long-term glycemic stress in T2D, in never-smokers (r = −0.39; p = 0.020) and smokers (r = −0.84; p = 0.004), but not in ex-smokers (r = −0.07; p = 0.765).ConclusionThe findings indicate that smoking contributes to sciatic nerve damage in T2D, potentially worsening DPN due to glycemic stress and less microangiopathy-associated myelin damage in active smokers, while angiopathic effects predominate in ex-smokers. To stop smoking may therefore pose a promising preventive measure to slow the progression of DPN in T2D.

Biomarkers for the Development and Progression of Diabetic Polyneuropathy

Biomarkers for the Development and Progression of Diabetic Polyneuropathy

Alterations of retinal thickness measured by optical coherence tomography correlate with neurophysiological measures in diabetic polyneuropathy.

Aims/IntroductionDiabetic polyneuropathy (DPN) and diabetic retinopathy (DR) are traditionally regarded as microvascular complications. However, these complications may share similar neurodegenerative pathologies. Here we evaluate the correlations in the severity of DPN and changes in the thickness of neuroretinal layers to elucidate whether these complications exist at similar stages of progression.Materials and MethodsA total of 43 patients with type 2 diabetes underwent a nerve conduction study (NCS), a macular optical coherence tomography, and a carotid artery ultrasound scan. Diabetic polyneuropathy was classified according to Baba’s classification using NCS. The retina was automatically segmented into four layers; ganglion cell complex (GCC), inner nuclear layer/outer plexiform layer (INL/OPL), outer nuclear layer/photoreceptor inner and outer segments, and retinal pigment epithelium (RPE). The thickness of each retinal layer was separately analyzed for the fovea and the parafovea.ResultsFourteen patients were classified as having moderate to severe diabetic polyneuropathy. The thicknesses of the foveal and parafoveal INL/OPL increased in patients with diabetic polyneuropathy compared with patients without. The thickness of the parafoveal retinal pigment epithelium decreased in patients with diabetic polyneuropathy. The thinning of parafoveal ganglion cell complex and foveal and parafoveal retinal pigment epithelium were positively correlated with deterioration of nerve functions in the nerve conduction study, but the thickening of INL/OPL was positively correlated with the nerve function deterioration. The thinning of parafoveal ganglion cell complex and foveal retinal pigment epithelium were positively correlated with the thickening of the carotid intima‐media.ConclusionsDepending on the progression of diabetic polyneuropathy, the ganglion cell complex and retinal pigment epithelium became thinner and the INL/OPL became thicker. These retinal changes might be noteworthy for pathological investigations and for the assessment of diabetic polyneuropathy and diabetic retinopathy.

Diabetic polyneuropathy: features of the clinical picture and electroneuromyographic parameters in the presence of comorbidity

Knowledges of certain key moments in the clinical course of diabetic polyneuropathy (DP) combined with varied comorbidity will allow the disease to be identified more effectively and treated comprehensively at different stages of onset. The aim of the research: was to investigate and summarize the features of the clinical picture, electroneuromyographic parameters in patients with DP in the presence of comorbidity. Materials and methods. 111 patients aged 19 to 69 years with DP were examined. The patients were divided into two groups: DP due to type I diabetes mellitus (DM) (group A; n = 61) and type II (group B; n = 50). According to the detected comorbidity, the following subgroups were identified: persons with DP as the result of type I, II DM with only one pathology (subgroup 1; n = 53) and the presence of multimorbidity (two or more pathologies) (subgroup 2; n = 21). The control group – 30 healthy persons representative by age and gender, 37 patients with DP without comorbidity. The patients were examined for neurological status, laboratory tests, instrumental examination methods. Results and discussion. In general, among the studied groups, the lowest nerve conduction velocity in the motor fibers was in abductor hallucis, tibialis on the left, extensor digitorum brevis, peroneus on the left and right, in sensory fibers – peroneus superficialis on the left and right, n. suralis on the left and right. Such changes primarily reflect the lesion of the distal extremities, which clinically looks like a distal symmetrical DP. Was dominated axonal and demyelinating type of nerve fiber damage. Conclusions. Comorbidity contributes to the progression of DP and deterioration of its clinical picture, electroneuromyographic rates, even in the presence of a single pathology, low duration of DM and HbA1c level.

Pathogenesis and Molecular Treatment Strategies of Diabetic Neuropathy Collateral Glucose-Utilizing Pathways in Diabetic Polyneuropathy.

Diabetic polyneuropathy (DPN) is the most common neuropathy manifested in diabetes. Symptoms include allodynia, pain, paralysis, and ulcer formation. There is currently no established radical treatment, although new mechanisms of DPN are being vigorously explored. A pathophysiological feature of DPN is abnormal glucose metabolism induced by chronic hyperglycemia in the peripheral nerves. Particularly, activation of collateral glucose-utilizing pathways such as the polyol pathway, protein kinase C, advanced glycation end-product formation, hexosamine biosynthetic pathway, pentose phosphate pathway, and anaerobic glycolytic pathway are reported to contribute to the onset and progression of DPN. Inhibitors of aldose reductase, a rate-limiting enzyme involved in the polyol pathway, are the only compounds clinically permitted for DPN treatment in Japan, although their efficacies are limited. This may indicate that multiple pathways can contribute to the pathophysiology of DPN. Comprehensive metabolic analysis may help to elucidate global changes in the collateral glucose-utilizing pathways during the development of DPN, and highlight therapeutic targets in these pathways.

Circulating Inflammatory Markers Are Inversely Associated with Heart Rate Variability Measures in Type 1 Diabetes.

Introduction A neuroimmune communication exists, and compelling evidence suggests that diabetic neuropathy and systemic inflammation are linked. Our aims were (1) to investigate biomarkers of the ongoing inflammation processes including cytokines, adhesion molecules, and chemokines and (2) to associate the findings with cardiovascular autonomic neuropathy in type 1 diabetes by measuring heart rate variability and cardiac vagal tone. Materials and Methods We included 104 adults with type 1 diabetes. Heart rate variability, time domain, and frequency domains were calculated from a 24-hour Holter electrocardiogram, while cardiac vagal tone was determined from a 5-minute electrocardiogram. Cytokines (interleukin- (IL-) 1α, IL-4, IL-12p70, IL-13, IL-17, and tumor necrosis factor- (TNF-) α), adhesion molecules (E-selectin, P-selectin, and intercellular adhesion molecule- (ICAM-) 1), and chemokines (chemokine (C-C motif) ligand (CCL)2, CCL3, CCL4, and C-X-C motif chemokine (CXCL)10) were assessed using a Luminex multiplexing technology. Associations between concentrations of inflammatory biomarkers and continuous variables of heart rate variability and cardiac vagal tone were estimated using multivariable linear regression adjusting for age, sex, disease duration, and smoking. Results Participants with the presence of cardiovascular autonomic neuropathy had higher systemic levels of IL-1α, IL-4, CCL2, and E-selectin than those without cardiovascular autonomic neuropathy. IL-1α, IL-4, IL-12, TNF-α, and E-selectin were inversely associated with both sympathetic and parasympathetic heart rate variability measures (p > 0.01). Discussion. Our results show that several pro- and anti-inflammatory factors, believed to be involved in the progression of diabetic polyneuropathy, are associated with cardiovascular autonomic neuropathy, suggesting that these factors may also contribute to the pathogenesis of cardiovascular autonomic neuropathy. Our findings emphasize the importance of the neuroimmune regulatory system in the pathogenesis of neuropathy in type 1 diabetes.

Biomarkers of the development and progression of diabetic polyneuropathy

To study the diagnostic potential of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGFA) and their high affinity receptors (TrkB, VEGFR2) in the development and progression of diabetic polyneuropathy. The main group consisted of 65 patients with diabetes mellitus and confirmed DPN. The comparison group included 14 people with diabetes mellitus without DPN. The control group consisted of 15 healthy individuals. Clinical characteristics of DPN were evaluated with VAS, PainDetect, TSS, NSS, NDS scores. The degree of polyneuropathy was verified by electroneuromyography. Serum levels of the growth factors and their receptors were studied using enzyme-linked immunosorbent assay. Elevated expression of serum BDNF, VEGFA and TrkB was found in patients with DPN, regardless of the presence of symptoms. The severe stage of DPN is characterized by painless form of polyneuropathy, the deficiency of serum BDNF, VEGFA and VEGFR2 and the high serum level of TrkB. The high expression of BDNF affects the intensity of neuropathic pain, the severity of the clinical signs of DPN and is associated with the severity of axonal damage to sensory nerve fibers. The increase in the TrkB level is associated with the painless form of neuropathy and the degree of nerve fiber demyelination. Enhanced serum expression of BDNF and VEGFA is proposed as a biomarker for the development of DPN, while different concentrations of TrkB and VEGFR2 receptors can be considered as predictors of DPN severity.

ID 321 – Is intraepidermal nerve fiber density a reliable biomarker of progression in painful and painless diabetic polyneuropathy?

We aimed to confirm usefulness of intraepidermal nerve fiber density (IENFD) as a marker of progression of diabetic polyneuropathy (DPN) in patients with early type 2 diabetes mellitus (DM2). In a group of 23 healthy subjects (median age 57 years, 14 men) and 30 DM2 patients (median age 60 years, 17 men) we serially evaluated skin biopsies from distal leg. Eighteen DM2 patients complied with the criteria of symptomatic diabetic polyneuropathy (DPN) and 12 had no neuropathy (nDPN). Time interval between biopsies were >2 years (median, range: 29.6, 24.7–58.4, and 33.8, 25.5–54.1 months in controls and DM2 patients, respectively). At first skin biopsy, the IENFD was normal in all controls and nDPN patients compared to abnormal IENFD in 77.8% of DPN patients. Drop in IENFD expressed as a proportion of the 1st IENFD value in % per year in both painful and painless DPN patients was significantly higher (11.95[3.82]%/year, p In conclusion, decrease in IENFD values in early DM2 patients is about 12% of the initial IENFD value irrespective of symptoms and/or signs of DPN at initial evaluation and several times quicker compared to healthy subjects.

Predictors of improvement and progression of diabetic polyneuropathy following treatment with α-lipoic acid for 4 years in the NATHAN 1 trial

AimsWe aimed to analyze the impact of baseline factors on the efficacy of α-lipoic acid (ALA) over 4years in the NATHAN 1 trial. MethodsThis was a post-hoc analysis of the NATHAN 1 trial, a 4-year randomized study including 460 diabetic patients with mild-to-moderate polyneuropathy using ALA 600mg qd or placebo. Amongst others, efficacy measures were the Neuropathy Impairment Score of the lower limbs (NIS-LL) and heart rate during deep breathing (HRDB). ResultsImprovement and prevention of progression of NIS-LL (ΔNIS-LL≥2 points) with ALA vs. placebo after 4years was predicted by higher age, lower BMI, male sex, normal blood pressure, history of cardiovascular disease (CVD), insulin treatment, longer duration of diabetes and neuropathy, and higher neuropathy stage. Participants treated with ALA who received ACE inhibitors showed a better outcome in HRDB after 4years. ConclusionsBetter outcome in neuropathic impairments following 4-year treatment with α-lipoic acid was predicted by normal BMI and blood pressure and higher burden due to CVD, diabetes, and neuropathy, while improvement in cardiac autonomic function was predicted by ACE inhibitor treatment. Thus, optimal control of CVD risk factors could contribute to improved efficacy of α-lipoic acid in patients with higher disease burden.

Factors influencing sweat gland innervation in diabetes.

Using a stereologic approach, the density of nerve fibers innervating sweat gland (SG) fragments in patients with diabetes mellitus (DM) and healthy controls using protein gene product (PGP), tyrosine hydroxylase (TH), and vasoactive intestinal peptide (VIP) was measured to determine which marker best detected differences between the groups. Factors associated with SG nerve fiber (SGNF) innervation were assessed and the change in SG innervation over a 1-year time period was determined. Ninety-two control subjects and 2 groups of subjects with DM totaling 97 were assessed in this cross-sectional study. Intraepidermal nerve fiber density and SG innervation were determined from leg skin biopsies that were immunohistochemically stained for ubiquitin hydrolase, VIP, and TH. Factors associated with SG innervation were assessed and 15 subjects were longitudinally followed for 1 year. SGNF innervation was reduced in subjects with DM compared with controls. Lower SG innervation values were associated with increasing glycated hemoglobin A1c, body mass index (BMI), men compared with women, and tobacco use, but not diabetes type or age. Sex, A1c, and BMI remained significant in multivariate modeling. SG innervation measured by VIP+ fibers is a more sensitive marker for neuropathy than either PGP or TH. Fifteen subjects with DM followed for 1 year showed a significant decrease in SGNF innervation but not intraepidermal nerve fiber density. Stereologic measurement of SG innervation is feasible to assess postganglionic autonomic nerve fiber densities. SG innervation was reduced in subjects with DM compared with control subjects and was associated with sex, A1c, and BMI in multivariate modeling. VIP+ SGNF is more severely reduced in DM than TH+ or PGP9.5+-based assessments. Progression of diabetic polyneuropathy was detected by SGNF over a 1-year time period.

Correlación entre las concentraciones plasmáticas de homocisteína y la polineuropatía diabética evaluada con la prueba del monofilamento de Semmes-Weinstein en pacientes con diabetes tipo 2

Background and objectiveFew modifiable risk factors are known to be associated with the presence and progression of diabetic polyneuropathy (DPN). Material and methodWe have analyzed in 405 type 2 diabetic (T2DM) subjects (169 women) the association of plasma homocysteine with the presence of DPN measured with the Semmes-Weinstein (SW) monofilament test. A score below 4 was considered an altered SW monofilament test. Plasma homocysteine, vitamin B12 and folic acid were measured using standard procedures (ELISA). ResultsPatients with T2DM with altered SW test have significantly higher age, evolution of disease, HbA1c and lower creatinine clearance values. In addition, plasma homocysteine values were independently and significantly higher in T2DM with DPN measured as altered SW test (13.64±4.93 vs. 12.22±4.48μmol/l, P<.01) with similar vitamin B12 and folic acid values comparing the 2 groups. ConclusionPlasma homocysteine and HbA1c values are the 2 modifiable biological factors associated with the presence of DPN evaluated as an altered SW monofilament test in T2DM subjects.

Thioctic Acid for Patients with Symptomatic Diabetic Polyneuropathy

Diabetic neuropathy represents a major health problem, as it is responsible for substantial morbidity, increased mortality, and impaired quality of life. Near-normoglycemia is now generally accepted as the primary approach to prevention of diabetic neuropathy, but is not achievable in a considerable number of patients. A growing body of evidence suggests that oxidative stress resulting from enhanced free-radical formation and/or defects in antioxidant defense is implicated in the pathogenesis of diabetic neuropathy. Markers of oxidative stress such as superoxide anion and peroxynitrite production are increased in diabetic patients in relation to the severity of polyneuropathy. In experimental diabetic neuropathy, oxygen free-radical activity in the sciatic nerve is increased, and treatment with thioctic acid, a potent lipophilic antioxidant, results in prevention or improvement of the diabetes-induced neurovascular and metabolic abnormalities in various organ systems. Pharmacodynamic studies have shown that thioctic acid favorably influences the vascular abnormalities of diabetic polyneuropathy such as impaired microcirculation, increased indices of oxidative stress, and increased levels of markers for vascular dysfunction, such as thrombomodulin, albuminuria, and nuclear factor-kappaB. Thus far, seven controlled randomized clinical trials of thioctic acid in patients with diabetic neuropathy have been completed (Alpha-Lipoic Acid in Diabetic Neuropathy [ALADIN I-III], Deutsche Kardiale Autonome Neuropathie [DEKAN], Oral Pilot [ORPIL], Symptomatic Diabetic Neuropathy [SYDNEY], Neurological Assessment of Thioctic Acid in Neuropathy [NATHAN] II) using different study designs, durations of treatment, doses, sample sizes, and patient populations. Recently, a comprehensive analysis was undertaken of trials with comparable designs that met specific eligibility criteria for a meta-analysis to obtain a more precise estimate of the efficacy and safety of thioctic acid (600mg intravenously for 3 weeks) in diabetic patients with symptomatic polyneuropathy. This meta-analysis included the largest sample of diabetic patients (n = 1258) ever to have been treated with a single drug or class of drugs to reduce neuropathic symptoms, and confirmed the favorable effects of thioctic acid based on the highest level of evidence (Class Ia: evidence from meta-analyses of randomized, controlled trials). The following conclusions can be drawn from these trials: (i) short-term treatment for 3 weeks using intravenous thioctic acid 600 mg/day reduces the chief symptoms of diabetic polyneuropathy to a clinically meaningful degree; (ii) this effect on neuropathic symptoms is accompanied by an improvement of neuropathic deficits, suggesting potential for the drug to favorably influence underlying neuropathy; (iii) oral treatment for 4-7 months tends to reduce neuropathic deficits and improve cardiac autonomic neuropathy; and (iv) clinical and postmarketing surveillance studies have revealed a highly favorable safety profile of the drug. Based on these findings, a pivotal long-term multicenter trial of oral treatment with thioctic acid (NATHAN I) is being conducted in North America and Europe to investigate effects on progression of diabetic polyneuropathy, using a clinically meaningful and reliable primary outcome measure that combines clinical and neurophysiological assessment.

Therapy with antioxidants in human diabetic neuropathy

Increased oxidative stress has been implicated in the pathogenesis of diabetic polyneuropathy (DPN). Antioxidant treatment with alpha‐lipoic acid (ALA) has been shown to prevent or ameliorate experimental diabetic neuropathy, providing the rationale for treatment in humans. A recent meta‐analysis including four controlled clinical trials provided evidence that treatment with ALA (600 mg/day i.v.) over 3 weeks is safe and significantly improves both neuropathic symptoms and deficits to a clinically meaningful degree in patients with symptomatic DPN. Moreover, oral treatment for 4–7 months tends to ameliorate neuropathic deficits and cardiac autonomic neuropathy. Clinical and postmarketing surveillance studies have revealed a highly favorable safety profile of this drug. Based on these findings, a pivotal long‐term multicenter trial of oral treatment with ALA (NATHAN 1 Study) is under way aimed at slowing the progression of DPN.

Role of neuropoietic cytokines in development and progression of diabetic polyneuropathy: from glucose metabolism to neurodegeneration.

Diabetic neuropathy develops as a result of hyperglycemia- induced local metabolic and microvascular changes in both type I and type II diabetes mellitus. Diabetic neuropathy shows slower impulse conduction, axonal degeneration, and impaired regeneration. Diabetic neuropathy affects peripheral, central, and visceral sensorimotor and motor nerves, causing improper locomotor and visceral organ dysfunctions. The pathogenesis of diabetic neuropathy is complex and involves multiple pathways. Lack of success in preventing neuropathy, even with successful treatment of hyperglycemia, suggests the presence of early mediators between hyperglycemia-induced metabolic and enzymatic changes and functional and structural properties of Schwann cells (SCs) and axons. It is feasible that once activated, such mediators can act independently of the initial metabolic stimulus to modulate SC-axonal communication. Neuropoietic cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), tumor necrosis factor alpha (TNF-α), and transforming growth factor beta (TGF- β), exhibit pleiotrophic effects on homeostasis of glia and neurons in central, peripheral, and autonomic nervous system. These cytokines are produced locally by resident and infiltrating macrophages, lymphocytes, mast cells, SCs, fibroblasts, and sensory neurons. Metabolic changes induced by hyperglycemia lead to dysregulation of cytokine control. Moreover, their regulatory roles in nerve degeneration and regeneration may potentially be utilized for the prevention and/or therapy of diabetic neuropathy.

Electrophysiologic measures of diabetic neuropathy: Mechanism and meaning

Whole nerve electrophysiologic procedures afford a battery of measures that can provide a noninvasive and objective index of the onset and progression of diabetic polyneuropathy (DPN). Advances in physiologic procedures, digital hardware, and mathematical models have allowed assessment of activity in slower conducting fibers, as well as measures that reflect changes in refractory periods and threshold excitability. These expanded options can augment standard measures of maximal conduction velocity and compound amplitude and greatly enhance the sensitivity of whole nerve measure to both structural (e.g. demyelination) and "nonstructural" (e.g. redistribution of ion channels) deficits associated with DPN. The mechanisms underlying the physiologic events in DPN are multifactorial and their sequence in complex, with different mechanisms contributing to change at overlapping, but distinct points in the progression. Factors influencing early change in velocity may differ from those contributing to chronic deficits and these mechanisms may also differ in their response to various putative therapies. This review attempts to summarize the pattern of whole nerve electrophysiologic change associated with DPN, outlines the strengths and limitations of the various measures that are feasible, and discusses the specific impact of know pathophysiologic mechanisms on these end points.

New developments in the diagnosis of diabetic neuropathy

The development of new treatments to slow or arrest the progression of diabetic polyneuropathy (DPN) has increased the importance of the early and accurate identification of this complication. It is likely that effective intervention will be possible only during the subclinical or early phase of dysfunction. Accurate diagnosis of DPN is a formidable task because of the diversity of presentations, involvement of different nerve fiber types, and the common dissociation of symptoms from objective measures of neural function. Several diagnostic tools are available or in development, each with strengths and limitations. Electrophysiology is a sensitive, objective, and targeted measure of DPN, but it reflects, almost exclusively, the activity of large-caliber, myelinated axons. Newly refined skin-punch biopsy procedures use morphometric and immunohistochemical methods to examine thinly myelinated and unmyelinated nerve fibers. The integrity, density, and distribution of these fibers may provide a sensitive index of small-fiber distal axonopathy. Improvements in quantitative sensory testing include better control of stimulation characteristics and the use of computer-assisted testing algorithms (e.g., CASE IV), as well as the ability to examine a distal to proximal gradient of sensation (Physitemp NTE-2a). Composite scales, which combine the assessment of signs, symptoms, electrophysiology, and specific quantitative sensory measures, have also been proposed and, in some cases, validated. The existing diagnostic tools and newly emerging methods provide a battery of tests that can be used to assess multiple aspects of neural function and increase sensitivity to detect the onset and progression of DPN.

Effects of Pancreatic Transplantation on Diabetic Neuropathy

Reestablishment of the euglycemic state by successful transplantation of the pancreas might halt or reverse diabetic neuropathy. To test this possibility we evaluated neurologic function by clinical examination, nerve conduction studies, and autonomic-function tests in patients with insulin-dependent (Type I) diabetes mellitus before and after successful pancreatic transplantation. Sixty-one patients were studied before and 12 months after transplantation, 27 again after 24 months, and 11 again after 42 months. A control group of patients with Type I diabetes treated with insulin underwent the same studies at similar intervals--48 patients before and after 12 months had elapsed, 21 again after 24 months, and 12 again after 42 months. In the control group, neuropathy tended to worsen during the follow-up period. The scores on the clinical examination indicated increased impairment after 12 months. Composite indexes of the degree of abnormality found on neurophysiologic testing of the function of peripheral motor, sensory, and autonomic nerves indicated decreased autonomic function after 12 months. The examination score and the three index values worsened slightly but not significantly in the patients followed for 24 and 42 months. In contrast, in the patients who had received pancreatic transplants, the neuropathy tended to improve. There was significant improvement in the motor and sensory indexes 12 months after transplantation and in the sensory index 24 months after transplantation. The other measures improved slightly but not significantly at these times, as did all four measures in the patients studied 42 months after transplantation. We conclude that the progression of diabetic polyneuropathy may be halted through the restoration of a euglycemic state by successful pancreatic transplantation.