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1.  Increased expression of the receptor for advanced glycation end-products in human peripheral neuropathies 
Brain and Behavior  2013;3(6):701-709.
Background
Diabetic neuropathy and idiopathic neuropathy are among the most prevalent neuropathies in human patients. The molecular mechanism underlying pathological changes observed in the affected nerve remains unclear but one candidate molecule, the receptor for advanced glycation end-products (RAGE), has recently gained attention as a potential contributor to neuropathy. Our previous studies revealed that RAGE expression is higher in porcine and murine diabetic nerve, contributing to the inflammatory mechanisms leading to diabetic neuropathy. Here, for the first time, we focused on the expression of RAGE in human peripheral nerve.
Methods
Our study utilized de-identified human sural nerve surplus obtained from 5 non-neuropathic patients (control group), 6 patients with long-term mild-to-moderate diabetic neuropathy (diabetic group) and 5 patients with mild-to-moderate peripheral neuropathy of unknown etiology (idiopathic group). By using immunofluorescent staining and protein immunoblotting we studied the expression and colocalization patterns of RAGE and its ligands: carboxymethyllysine (CML), high mobility group box 1 (HMBG1) and mammalian Diaphanous 1 (mDia1) in control and neuropathic nerves.
Results
We found that in a normal, healthy human nerve, RAGE is expressed in almost 30% of all nerve fibers and that number is higher in pathological states such as peripheral neuropathy. We established that the levels of RAGE and its pro-inflammatory ligands, CML and HMBG1, are higher in both idiopathic and diabetic nerve, while the expression of the RAGE cytoplasmic domain-binding partner, mDia1 is similar among control, diabetic, and idiopathic nerve. The highest number of double stained nerve fibers was noted for RAGE and CML: ∼76% (control), ∼91% (idiopathic) and ∼82% (diabetic) respectively.
Conclusions
Our data suggest roles for RAGE and its inflammatory ligands in human peripheral neuropathies and lay the foundation for further, more detailed and clinically oriented investigation involving these proteins and their roles in disorders of the human peripheral nerve.
doi:10.1002/brb3.176
PMCID: PMC3868174  PMID: 24363972
Diabetes; human; peripheral neuropathy; RAGE; RAGE ligands
2.  Role of nitrosative and oxidative stress in neuropathy in patients with type 2 diabetes mellitus 
Objectives:
Evidences of oxidative and/or nitrosative stress in type 2 diabetes mellitus were demonstrated in experimental and human studies. This study is aimed to assess the serum peroxynitrite and oxidized lipoproteins in patients with type 2 diabetes mellitus presented with clinical and laboratory evidences of peripheral neuropathy.
Materials and Methods:
Eighty four patients with type 2 diabetes mellitus (51 of them had neuropathy) and 31 apparent healthy subjects were studied in the unit of neurophysiology at the University Hospital of Medical College, Al-Nahrin University in Baghdad, Iraq. Neuropathy total symptom score (NTSS), neuropathy impairment score in the lower leg (NIS-LL), and nerve conduction velocity of sensory (ulnar and sural) and motor (ulnar and common peroneal) nerves were used to assess the neuropathy. Fasting venous blood was obtained from each participant for the determination of serum glucose and oxidized lipoproteins.
Results:
The electrophysiology study revealed significant decrease in conduction velocity of ulnar (sensory and motor components), sural, and common peroneal nerves in diabetic neuropathy compared to diabetics without neuropathy and healthy subjects. Significant high level of serum peroxynitrite was found in diabetic patients with or without neuropathy compared with non-diabetics. The changes in serum-oxidized lipoproteins in patients with diabetics with or without neuropathy were non-significantly differed from healthy subjects. Neither nitrosative stress nor oxidative stress indices correlated with the variables that are related to the neuropathy.
Conclusion:
It concludes that evidence of nitrosative and to less extent the oxidative stress is associated with neuropathy in type 2 diabetes mellitus and their indices not correlated with variables related to neuropathy.
doi:10.4103/0976-3147.91932
PMCID: PMC3271613  PMID: 22346190
Neuropathy; peroxynitrite; type 2 diabetes
3.  Up-Regulation of the Receptor for Advanced Glycation End Products in the Skin Biopsy Specimens of Patients with Severe Diabetic Neuropathy 
Background and Purpose
The receptor for advanced glycation end products (RAGE) may contribute to the development of diabetic neuropathy. To assess its relevance in humans, this study examined the expression of RAGE in the skin biopsy samples of patients with diabetes mellitus, and investigated its correlation with intraepidermal nerve-fiber density (IENFD) and clinical measures of neuropathy severity.
Methods
Forty-four patients who either had type 2 diabetes or were prediabetes underwent clinical evaluation and a 3-mm skin punch biopsy. The clinical severity of their neuropathy was assessed using the Michigan Diabetic Neuropathy Score. IENFD was measured along with immunohistochemical staining for RAGE in 29 skin biopsy samples. The expression of RAGE was also quantified by real-time reverse-transcription PCR in the remaining 15 patients.
Results
RAGE was localized mostly in the dermal and subcutaneous vascular endothelia. The staining was more intense in patients with a lower IENFD (p=0.004). The quantity of RAGE mRNA was significantly higher in patients with severe neuropathy than in those with no or mild neuropathy (p=0.003). The up-regulation of RAGE was related to dyslipidemia and diabetic nephropathy. There was a trend toward decreased sural nerve action-potential amplitude and slowed peroneal motor-nerve conduction with increasing RAGE expression.
Conclusions
The findings of this study demonstrate up-regulation of RAGE in skin biopsy samples from patients with diabetic neuropathy, supporting a pathogenic role of RAGE in the development of diabetic neuropathy.
doi:10.3988/jcn.2014.10.4.334
PMCID: PMC4198715  PMID: 25324883
receptor for advanced glycation end products; diabetes mellitus; diabetic neuropathy
4.  Hereditary sensory neuropathy type I 
Hereditary sensory neuropathy type I (HSN I) is a slowly progressive neurological disorder characterised by prominent predominantly distal sensory loss, autonomic disturbances, autosomal dominant inheritance, and juvenile or adulthood disease onset. The exact prevalence is unknown, but is estimated as very low. Disease onset varies between the 2nd and 5th decade of life. The main clinical feature of HSN I is the reduction of sensation sense mainly distributed to the distal parts of the upper and lower limbs. Variable distal muscle weakness and wasting, and chronic skin ulcers are characteristic. Autonomic features (usually sweating disturbances) are invariably observed. Serious and common complications are spontaneous fractures, osteomyelitis and necrosis, as well as neuropathic arthropathy which may even necessitate amputations. Some patients suffer from severe pain attacks. Hypacusis or deafness, or cough and gastrooesophageal reflux have been observed in rare cases. HSN I is a genetically heterogenous condition with three loci and mutations in two genes (SPTLC1 and RAB7) identified so far. Diagnosis is based on the clinical observation and is supported by a family history. Nerve conduction studies confirm a sensory and motor neuropathy predominantly affecting the lower limbs. Radiological studies, including magnetic resonance imaging, are useful when bone infections or necrosis are suspected. Definitive diagnosis is based on the detection of mutations by direct sequencing of the SPTLC1 and RAB7 genes. Correct clinical assessment and genetic confirmation of the diagnosis are important for appropriate genetic counselling and prognosis. Differential diagnosis includes the other hereditary sensory and autonomic neuropathies (HSAN), especially HSAN II, as well as diabetic foot syndrome, alcoholic neuropathy, neuropathies caused by other neurotoxins/drugs, immune mediated neuropathy, amyloidosis, spinal cord diseases, tabes dorsalis, lepra neuropathy, or decaying skin tumours like amelanotic melanoma. Management of HSN I follows the guidelines given for diabetic foot care (removal of pressure to the ulcer and eradication of infection, followed by the use of specific protective footwear) and starts with early and accurate counselling of patients about risk factors for developing foot ulcerations. The disorder is slowly progressive and does not influence life expectancy but is often severely disabling after a long duration of the disease.
doi:10.1186/1750-1172-3-7
PMCID: PMC2311280  PMID: 18348718
5.  Chewing the Fat: Genetic Approaches to Model Dyslipidemia-Induced Diabetic Neuropathy in Mice 
Experimental neurology  2013;248:504-508.
Emerging clinical evidence now suggests dyslipidemia may be strongly linked with the development and progression of neuropathy in diabetic patients, and dyslipidemia is considered an important risk factor for the development of diabetic neuropathy. However, because of important species differences, current animal models fall short of accurately replicating human diabetic dyslipidemia. Rodents resist expansion in low-density lipoprotein cholesterol (LDL-C) and typically maintain or increase high-density lipoprotein cholesterol (HDL-C), despite prolonged high-fat feeding. Here, we discuss the findings of Hinder et al., in which they utilized novel genetic experimental approaches to develop a diabetic mouse model with human-like dyslipidemia. The authors created a mouse with an apolipoprotein E (ApoE) knockout in conjunction with a leptin receptor mutation. A triple mutant mouse with both ApoE and apolipoprotein B48 knockout and leptin deficiency was also created in an effort to generate a model of diabetic dyslipidemia that better mimics the human condition. The long-term goal of these studies is to develop more faithful models to address how hyperglycemia and hyperlipidemia may drive the development and progression of neuropathy. Hinder and colleagues were successful at creating a diabetic mouse model with severe hypertriglyceridemia, hypercholesterolemia, and a significant increase in the total cholesterol to HDL-C ratio. This work was successful in establishing a model of diabetic dyslipidemia that more closely emulates the poor lipid profile observed in human diabetic patients with neuropathy. This commentary will also review current models used to study the effects of dyslipidemia on diabetic neuropathy and highlight a proposed mechanism for the role of dyslipidemia in the pathogenesis of diabetic neuropathy.
doi:10.1016/j.expneurol.2013.07.016
PMCID: PMC3919132  PMID: 23933575
6.  Histopathological heterogeneity of neuropathy in insulin-dependent and non-insulin-dependent diabetes, and demonstration of axo-glial dysjunction in human diabetic neuropathy. 
Journal of Clinical Investigation  1988;81(2):349-364.
Altered sorbitol and myo-inositol metabolism, (Na,K)-ATPase function, electrochemical sodium gradients, axonal swelling, and distortion and disruption of the node of Ranvier ("axo-glial dysjunction") directly implicate hyperglycemia in the pathogenesis of neuropathy in diabetic rats, but the relevance of this sequence to clinical neuropathy in heterogeneous groups of diabetic patients remains to be established. Fascicular sural nerve morphometry in 11 patients with neuropathy complicating insulin-dependent diabetes revealed a pattern of interrelated structural changes strikingly similar to that of the diabetic rat when compared to age-matched controls. 17 older non-insulin-dependent diabetic patients with comparable duration and severity of hyperglycemia and severity of neuropathy, displayed similar nerve fiber loss, paranodal demyelination, paranodal remyelination and segmental demyelination compared to age-matched controls, but axo-glial dysjunction was replaced by Wallerian degeneration as the primary manifestation of fiber damage, and fiber loss occurred in a spatial pattern consistent with an ischemic component. The mechanistic model developed from the diabetic rat does indeed appear to apply to human diabetic neuropathy, but superimposed hormonal, metabolic, vascular, and/or age-related effects alter the morphologic expression of the neuropathy in non-insulin dependent diabetes.
Images
PMCID: PMC329577  PMID: 3339124
7.  The sural sensory/radial motor amplitude ratio for the diagnosis of peripheral neuropathy in type 2 diabetic patients 
Hippokratia  2010;14(3):198-202.
Background and aim: The diagnosis of peripheral diabetic neuropathy is based on clinical examination. Nerve conduction study (NCS) enables earlier diagnosis, but it is demanding and requires specialised personnel. In an attempt to simplify the procedure, this study aimed to identify a new electrophysiological index, which might correlate with results obtained on standardised NCS in patients with long-standing type 2 diabetes.
Patients and methods: Medical records of type 2 diabetic patients evaluated for neuropathy by NCS were reviewed retrospectively. This analysis included 104 patients (50 men, 54 women) with a mean age of 67.1±5.5 years and mean diabetes duration of 13.1±2.7 years. NCS was performed on radial, ulnar, sural, and peroneal nerves. Neuropathy was defined as impaired NCS. Ratios of neurophysiological parameters from these nerves were calculated and each of them was compared with diagnosis of neuropathy.
Results: The sural sensory/radial motor amplitude ratio had the best combination of sensitivity (85%) and specificity (71%) for neuropathy. It also remained the strongest independent predictor of neuropathy in multivariate regression analysis: low levels of this ratio yielded an odds ratio of 7.7 for neuropathy.
Conclusions: The sural sensory/radial motor amplitude ratio has a high sensitivity and a moderately high specificity for the diagnosis of neuropathy, low levels being associated with a nearly eightfold increase in the risk for neuropathy. These results encourage further evaluation of this and other electrophysiological indices to enable wider availability of NCS.
PMCID: PMC2943359  PMID: 20981170
diabetes mellitus; diabetic peripheral neuropathy; nerve conduction study
8.  Apolipoprotein E Knockout as the Basis for Mouse Models of Dyslipidemia-Induced Neuropathy 
Experimental neurology  2012;239:102-110.
Dyslipidemia has been identified as an important pathogenic risk factor for diabetic neuropathy, but current animal models do not adequately reproduce the lipid profile observed in human diabetics (increased triglycerides with an elevated LDL-cholesterol and reduced HDL-cholesterol). High fat feeding of mice produces hyperlipidemia, but mice are resistant to increases in the LDL to HDL ratio, reducing the potential for peripheral lipid deposits to impact neuropathy, as is postulated to occur in human subjects. Genetic manipulations provide an alternative approach to reproducing a neuropathic plasma lipid profile. Based on findings from the atherosclerosis literature, we began with knockout of ApoE. Since knockout of ApoE alone only partially mimics the human diabetic lipid profile, we examined the impact of its combination with a well-characterized model of type 2 diabetes exhibiting neuropathy, the db/db mouse. We added further gene manipulations to increase hyperlipidemia by using mice with both ApoE and ApoB48 knockout on the ob/+ (leptin mutation) mice. In all of these models, we found that either the db/db or ob/ob genotypes had increased body weight, hyperlipidemia, hyperglycemia, and evidence of neuropathy compared with the control groups (db/+ or ob/+, respectively). We found that ApoE knockout combined with leptin receptor knockout produced a lipid profile most closely modeling human dyslipidemia that promotes neuropathy. ApoE knockout combined with additional ApoB48 and leptin knockout produced similar changes of smaller magnitude, but, notably, an increase in HDL-cholesterol. Our data suggest that the overall effects of ApoE knockout, either directly upon nerve structure and function or indirectly on lipid metabolism, are insufficient to significantly alter the course of diabetic neuropathy. Although these models ultimately do not deliver optimal lipid profiles for translational diabetic neuropathy research, they do present glycemic and lipid profile properties of value for future therapeutic investigations.
doi:10.1016/j.expneurol.2012.10.002
PMCID: PMC3534788  PMID: 23059459
peripheral neuropathy; dyslipidemia; diabetes; apolipoprotein E; apolipoprotein B48; lipid profile; mouse
9.  Mitochondrial dysfunction driven by the LRRK2-mediated pathway is associated with loss of Purkinje cells and motor coordination deficits in diabetic rat model 
Yang, S | Xia, C | Li, S | Du, L | Zhang, L | Hu, Y
Cell Death & Disease  2014;5(5):e1217-.
Diabetic neuropathy develops on a background of hyperglycemia and an entangled metabolic imbalance. There is increasing evidence of central nervous system involvement in diabetic neuropathy and no satisfactory treatment except maintenance of good glycemic control, thereby highlighting the importance of identifying novel therapeutic targets. Purkinje cells are a class of metabolically specialized active neurons, and degeneration of Purkinje cells is a common feature of inherited ataxias in humans and mice. However, whether Purkinje cells are implicated in diabetic neuropathy development under metabolic stress remains poorly defined. Here, we revealed a novel leucine-rich repeat kinase 2 (LRRK2)-mediated pathway in Purkinje cells that is involved in the pathogenesis of diabetic neuropathy from a 24-week long study of streptozotocin (STZ)-diabetic rats. We found that hyperglycemia, cerebellum proinflammatory cytokines, and chemokines increased markedly in 24-week STZ-diabetic rats. Furthermore, we demonstrated that degeneration of Purkinje cells is characterized by progressive swellings of axon terminals, no autophagosome formation, the reduction of LC3II/LC3I and Lamp2, and accumulation of p62 puncta in 24-week STZ-diabetic rats. Importantly, a higher expression level of LRRK2-mediated hyperphosphorylation of tau along with increased mitochondrial dynamin-like protein (mito-DLP1) was demonstrated in 24-week STZ-diabetic rats. This effect of LRRK2 overexpression induced mitochondrial fragmentation, and reduced mitochondrial protein degradation rates were confirmed in vitro. As a consequence, 24-week STZ-diabetic rats showed mitochondrial dysfunction in cerebellar Purkinje neurons and coordinated motor deficits evaluated by rotarod test. Our findings are to our knowledge the first to suggest that the LRRK2-mediated pathway induces mitochondrial dysfunction and loss of cerebellar Purkinje neurons and, subsequently, may be associated with motor coordination deficits in STZ-diabetic rats. These data may indicate a novel cellular therapeutic target for diabetic neuropathy.
doi:10.1038/cddis.2014.184
PMCID: PMC4047887  PMID: 24810053
Purkinje cell; motor coordination deficit; mitochondria; LRRK2; streptozotocin-diabetic rat model
10.  Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily 
Journal of Clinical Investigation  2004;114(12):1741-1751.
Molecular events that result in loss of pain perception are poorly understood in diabetic neuropathy. Our results show that the receptor for advanced glycation end products (RAGE), a receptor associated with sustained NF-κB activation in the diabetic microenvironment, has a central role in sensory neuronal dysfunction. In sural nerve biopsies, ligands of RAGE, the receptor itself, activated NF-κBp65, and IL-6 colocalized in the microvasculature of patients with diabetic neuropathy. Activation of NF-κB and NF-κB–dependent gene expression was upregulated in peripheral nerves of diabetic mice, induced by advanced glycation end products, and prevented by RAGE blockade. NF-κB activation was blunted in RAGE-null (RAGE–/–) mice compared with robust enhancement in strain-matched controls, even 6 months after diabetes induction. Loss of pain perception, indicative of long-standing diabetic neuropathy, was reversed in WT mice treated with soluble RAGE. Most importantly, loss of pain perception was largely prevented in RAGE–/– mice, although they were not protected from diabetes-induced loss of PGP9.5-positive plantar nerve fibers. These data demonstrate, for the first time to our knowledge, that the RAGE–NF-κB axis operates in diabetic neuropathy, by mediating functional sensory deficits, and that its inhibition may provide new therapeutic approaches.
doi:10.1172/JCI200418058
PMCID: PMC535062  PMID: 15599399
11.  Differential expression of neuregulin-1 isoforms and downregulation of erbin are associated with Erb B2 receptor activation in diabetic peripheral neuropathy 
Background
Aberrant neuron/glia interactions can contribute to a variety of neurodegenerative diseases and we have previously demonstrated that enhanced activation of Erb B2, which is a member of the epidermal growth factor receptor (EGFR) family, can contribute to the development of diabetic peripheral neuropathy (DPN). In peripheral nerves, Erb B receptors are activated by various members of the neuregulin-1 (NRG1) family including NRG1 Type I, NRG1 Type II and NRG1 Type III to regulate Schwann cell (SC) growth, migration, differentiation and dedifferentiation. Alternatively, Erb B2 activity can be negatively regulated by association with the Erb B2-interacting protein, erbin. Since the effect of diabetes on the expression of NRG1 isoforms and erbin in peripheral nerve are unknown, the current study determined whether changes in NRG1 isoforms and erbin may be associated with altered Erb B2 signaling in DPN.
Results
Swiss Webster mice were rendered diabetic with streptozotocin (STZ) and after 12 weeks of diabetes, treated with erlotinib, an inhibitor of Erb B2 activation. Inhibition of Erb B2 signaling partially reversed several pathophysiologic aspects of DPN including a pronounced sensory hypoalgesia, nerve conduction velocity deficits and the decrease in epidermal nerve fiber innervation. We also observed a decrease of NRG1 Type III but an increase of NRG1 Type I level in diabetic sural nerves at early stage of diabetes. With disease progression, we detected reduced erbin expression and enhanced MAPK pathway activity in diabetic mice. Inhibition of Erb B2 receptor suppressed MAPK pathway activity in treated-diabetic sural nerves.
Conclusions
These results support that hyperglycemia may impair NRG1/Erb B2 signaling by disrupting the balance between NRG1 isoforms, decreasing the expression of erbin and correspondingly activating the MAPK pathway. Together, imbalanced NRG1 isoforms and downregulated erbin may contribute to the dysregulation of Erb B2 signaling in the development of DPN.
doi:10.1186/2051-5960-1-39
PMCID: PMC3893607  PMID: 24252174
Nerve conduction velocity; Erlotinib; Sensory hypoalgesia; Intra epidermal nerve fibers; Sural nerve
12.  Validation of the nerve axon reflex for the assessment of small nerve fibre dysfunction 
Objective
To validate nerve–axon reflex‐related vasodilatation as an objective method to evaluate C‐nociceptive fibre function by comparing it with the standard diagnostic criteria.
Methods
Neuropathy was evaluated in 41 patients with diabetes (26 men and 15 women) without peripheral vascular disease by assessing the Neuropathy Symptom Score, the Neuropathy Disability Score (NDS), the vibration perception threshold (VPT), the heat detection threshold (HDT), nerve conduction parameters and standard cardiovascular tests. The neurovascular response to 1% acetylcholine (Ach) iontophoresis was measured at the forearm and at both feet by laser flowmetry. An age‐matched and sex‐matched control group of 10 healthy people was also included.
Results
Significant correlations were observed between the neurovascular response at the foot and HDT (rs = −0.658; p<0.0001), NDS (rs = −0.665; p<0.0001), VPT (rs = −0.548; p = 0.0005), tibial nerve conduction velocity (rs = 0.631; p = 0.0002), sural nerve amplitude (rs = 0.581; p = 0.0002) and autonomic function tests. According to the NDS, in patients with diabetes who had mild, moderate or severe neuropathy, a significantly lower neurovascular response was seen at the foot than in patients without neuropathy and controls. A neurovascular response <50% was found to be highly sensitive (90%), with a good specificity (74%), in identifying patients with diabetic neuropathy.
Conclusion
Small‐fibre dysfunction can be diagnosed reliably with neurovascular response assessment. This response is already reduced in the early stages of peripheral neuropathy, supporting the hypothesis that small‐fibre impairment is an early event in the natural history of diabetic neuropathy.
doi:10.1136/jnnp.2005.069609
PMCID: PMC2077635  PMID: 16624842
13.  Potential risk factors for diabetic neuropathy: a case control study 
BMC Neurology  2005;5:24.
Background
Diabetes mellitus type II afflicts at least 2 million people in Iran. Neuropathy is one of the most common complications of diabetes and lowers the patient's quality of life. Since neuropathy often leads to ulceration and amputation, we have tried to elucidate the factors that can affect its progression.
Methods
In this case-control study, 110 diabetic patients were selected from the Shariati Hospital diabetes clinic. Michigan Neuropathic Diabetic Scoring (MNDS) was used to differentiate cases from controls. The diagnosis of neuropathy was confirmed by nerve conduction studies (nerve conduction velocity and electromyography). The multiple factors compared between the two groups included consumption of angiotensin converting enzyme inhibitors (ACEI), blood pressure, serum lipid level, sex, smoking, method of diabetes control and its quality.
Results
Statistically significant relationships were found between neuropathy and age, gender, quality of diabetes control and duration of disease (P values in the order: 0.04, 0.04, < 0.001 and 0.005). No correlation was found with any atherosclerosis risk factor (high BP, hyperlipidemia, cigarette smoking).
Conclusion
In this study, hyperglycemia was the only modifiable risk factor for diabetic neuropathy. Glycemic control reduces the incidence of neuropathy, slows its progression and improves the diabetic patient's quality of life. More attention must be paid to elderly male diabetic patients with poor diabetes control with regard to regular foot examinations and more practical education.
doi:10.1186/1471-2377-5-24
PMCID: PMC1343576  PMID: 16336693
14.  Recent advances in the management of diabetic distal symmetrical polyneuropathy 
Abstract
There is now little doubt that poor blood glucose control is an important risk factor for the development of diabetic peripheral neuropathy (DPN). Furthermore, traditional cardiovascular risk factors for macrovascular disease appear to be associated with an increased risk of DPN. The recently established International Expert Group on Diabetic Neuropathy has recommended new criteria for the diagnosis of DPN in the context of clinical and research settings. Studies in experimental diabetes examining the pathogenesis of DPN have identified a number of metabolic abnormalities including polyol pathway hyperactivity, increased advanced glycation end‐point formation, alterations in the protein kinase C beta pathway through diacylglycerol and oxidative stress. There is now strong evidence implicating nerve ischemia as the cause of DPN. Studies in human and animal models have shown reduced nerve perfusion and endoneurial hypoxia. These endoneurial microvascular changes strongly correlate with clinical severity and the degree of nerve‐fiber pathology. Unfortunately, many compounds that have been effective in animal models of neuropathy have not been successful in human diabetic neuropathy. The only compounds found to be efficacious in human diabetic neuropathy, and are in clinical use, are the anti‐oxidant, α‐lipoic acid and the aldose reductase inhibitor, epalrestat. Overall, the evidence emphasizes the importance of vascular dysfunction, driven by metabolic change, in the etiology of DPN, and highlights potential therapeutic approaches. Epidemiological data on diabetic painful neuropathic pain (DPNP) are limited. In one population‐based study, the prevalence of DPNP, as assessed by a structured questionnaire and examination, was estimated at 16%. It was notable that, of these patients, 12.5% had never reported symptoms to their doctor and 39% had never received treatment for their pain. Thus, despite being common, DPNP continues to be underdiagnosed and undertreated. Pharmacological treatment of DPNP include tricyclic compounds, serotonin noradrenalin reuptake inhibitors, the anti‐oxidant α‐lipoic acid, anticonvulsants, opiates, membrane stabilizers, topical capsaicin and so on. Management of the patient with DPNP must be tailored to individual requirements and will depend on the presence of other comorbidities. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00083.x)
doi:10.1111/j.2040-1124.2010.00083.x
PMCID: PMC4008012  PMID: 24843458
Diabetic peripheral neuropathy; Diabetic neuropathy; Painful diabetic neuropathy
15.  Transcriptional Profiling of Diabetic Neuropathy in the BKS db/db Mouse 
Diabetes  2011;60(7):1981-1989.
OBJECTIVE
A better understanding of the molecular mechanisms underlying the development and progression of diabetic neuropathy (DN) is essential for the design of mechanism-based therapies. We examined changes in global gene expression to define pathways regulated by diabetes in peripheral nerve.
RESEARCH DESIGN AND METHODS
Microarray data for 24-week-old BKS db/db and db/+ mouse sciatic nerve were analyzed to define significantly differentially expressed genes (DEGs); DEGs were further analyzed to identify regulated biological processes and pathways. Expression profile clustering was performed to identify coexpressed DEGs. A set of coexpressed lipid metabolism genes was used for promoter sequence analysis.
RESULTS
Gene expression changes are consistent with structural changes of axonal degeneration. Pathways regulated in the db/db nerve include lipid metabolism, carbohydrate metabolism, energy metabolism, peroxisome proliferator–activated receptor signaling, apoptosis, and axon guidance. Promoter sequences of lipid metabolism–related genes exhibit evidence of coregulation of lipid metabolism and nervous system development genes.
CONCLUSIONS
Our data support existing hypotheses regarding hyperglycemia-mediated nerve damage in DN. Moreover, our analyses revealed a possible coregulation mechanism connecting hyperlipidemia and axonal degeneration.
doi:10.2337/db10-1541
PMCID: PMC3121428  PMID: 21617178
16.  Elevated Triglycerides Correlate With Progression of Diabetic Neuropathy 
Diabetes  2009;58(7):1634-1640.
OBJECTIVE
To evaluate mechanisms underlying diabetic neuropathy progression using indexes of sural nerve morphometry obtained from two identical randomized, placebo-controlled clinical trials.
RESEARCH DESIGN AND METHODS
Sural nerve myelinated fiber density (MFD), nerve conduction velocities (NCVs), vibration perception thresholds, clinical symptom scores, and a visual analog scale for pain were analyzed in participants with diabetic neuropathy. A loss of ≥500 fibers/mm2 in sural nerve MFD over 52 weeks was defined as progressing diabetic neuropathy, and a MFD loss of ≤100 fibers/mm2 during the same time interval as nonprogressing diabetic neuropathy. The progressing and nonprogressing cohorts were matched for baseline characteristics using an O'Brien rank-sum and baseline MFD.
RESULTS
At 52 weeks, the progressing cohort demonstrated a 25% decrease (P < 0.0001) from baseline in MFD, while the nonprogressing cohort remained unchanged. MFD was not affected by active drug treatment (P = 0.87), diabetes duration (P = 0.48), age (P = 0.11), or BMI (P = 0.30). Among all variables tested, elevated triglycerides and decreased peroneal motor NCV at baseline significantly correlated with loss of MFD at 52 weeks (P = 0.04).
CONCLUSIONS
In this cohort of participants with mild to moderate diabetic neuropathy, elevated triglycerides correlated with MFD loss independent of disease duration, age, diabetes control, or other variables. These data support the evolving concept that hyperlipidemia is instrumental in the progression of diabetic neuropathy.
doi:10.2337/db08-1771
PMCID: PMC2699859  PMID: 19411614
17.  Enhanced glucose control for preventing and treating diabetic neuropathy 
Background
There are two types of diabetes. Type 1 diabetes affects younger people and needs treatment with insulin injections. Type 2 diabetes affects older people and can usually be treated by diet and oral drugs. Diabetic neuropathy affects 10% of patients with diabetes mellitus at diagnosis and 40% to 50% after 10 years. Enhanced glucose control is the best studied intervention for the prevention of this disabling condition but there have been no systematic reviews of the evidence.
Objectives
To examine the evidence for enhanced glucose control in the prevention of distal symmetric polyneuropathy in people with type 1 and type 2 diabetes.
Search methods
We searched the Cochrane Neuromuscular Disease Group Specialized Register (30 January 2012), CENTRAL (2012, Issue 1), MED-LINE (1966 to January 2012) and EMBASE (1980 to January 2012) for randomized controlled trials of enhanced glucose control in diabetes mellitus.
Selection criteria
We included all randomized, controlled studies investigating enhanced glycemic control that reported neuropathy outcomes after at least one year of intervention. Our primary outcome measure was annual development of clinical neuropathy defined by a clinical scale. Secondary outcomes included motor nerve conduction velocity and quantitative vibration testing.
Data collection and analysis
Two authors independently reviewed all titles and abstracts identified by the database searches for inclusion. Two authors abstracted data from all included studies with a standardized form. A third author mediated conflicts. We analyzed the presence of clinical neuropathy with annualized risk differences (RDs), and conduction velocity and quantitative velocity measurements with mean differences per year.
Main results
This review identified 17 randomized studies that addressed whether enhanced glucose control prevents the development of neuropathy. Seven of these studies were conducted in people with type 1 diabetes, eight in type 2 diabetes, and two in both types. A meta-analysis of the two studies that reported the primary outcome (incidence of clinical neuropathy) with a total of 1228 participants with type 1 diabetes revealed a significantly reduced risk of developing clinical neuropathy in those with enhanced glucose control, an annualized RD of −1.84% (95% confidence interval (CI) −1.11 to −2.56). In a similar analysis of four studies that reported the primary outcome, involving 6669 participants with type 2 diabetes, the annualized RD of developing clinical neuropathy was −0.58% (95% CI 0.01 to −1.17). Most secondary outcomes were significantly in favor of intensive treatment in both populations. However, both types of diabetic participants also had a significant increase in severe adverse events including hypoglycemic events.
Authors’ conclusions
According to high-quality evidence, enhanced glucose control significantly prevents the development of clinical neuropathy and reduces nerve conduction and vibration threshold abnormalities in type 1 diabetes mellitus. In type 2 diabetes mellitus, enhanced glucose control reduces the incidence of clinical neuropathy, although this was not formally statistically significant (P = 0.06). However, enhanced glucose control does significantly reduce nerve conduction and vibration threshold abnormalities. Importantly, enhanced glucose control significantly increases the risk of severe hypoglycemic episodes, which needs to be taken into account when evaluating its risk/benefit ratio.
doi:10.1002/14651858.CD007543.pub2
PMCID: PMC4048127  PMID: 22696371
Medical Subject Headings (MeSH): Diabetes Mellitus; Type 1 [*complications]; Diabetes Mellitus; Type 2 [*complications]; Diabetic Neuropathies [*prevention & control]; Hyperglycemia [*prevention & control]; Hypoglycemic Agents [*therapeutic use]; Insulin [*therapeutic use]; Humans
18.  The Characteristics of Chronic Inflammatory Demyelinating Polyneuropathy in Patients with and without Diabetes – An Observational Study 
PLoS ONE  2014;9(2):e89344.
Introduction
We aimed to determine whether the clinical characteristics and electrodiagnostic classification of nerve injury, and response to treatment differed in patients diagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP) with and without diabetes.
Methods
CIDP patients with diabetes (CIDP+DM) (n = 67) and without diabetes (CIDP-DM) (n = 67) underwent clinical examination and nerve conduction studies (NCS). CIDP-DM patients were selected using age and gender matching with the existing CIDP+DM cohort. Patients treated with immunotherapies were classified as responders (R) (n = 46) or non-responders (NR) (n = 54) based on clinical response to treatment. The groups were compared using analysis of variance, contingency tables and Kruskal-Wallis analyses.
Results
CIDP+DM subjects had more severe neuropathy based on higher lower limb vibration potential thresholds (VPT)(p = 0.004), higher Toronto Clinical Neuropathy Score (TCNS) (p = 0.0009), more proximal weakness (p = 0.03), more gait abnormality (p = 0.03) and more abnormal NCS. CIDP+DM subjects had more abnormal sural NCS with lower sural sensory nerve action potential amplitudes (2.4±3.0 µV, 6.6±6.0 µV, p<0.0001) and slower sural nerve conduction velocities (38.6±5.4 m/s, 41.0±5.3 m/s, p = 0.04). CIDP-DM subjects were more likely to receive immune therapies (93% vs 57%, p = <0.0001), despite no significant differences in treatment responder rates (p = 0.71). Patients who responded to therapy had shorter duration of CIDP than non-responders (8.0±6.0 y vs 11.9±7.6 y, p = 0.004).
Discussion
The clinical phenotype and electrophysiological profile of CIDP patients differs according to the presence or absence of diabetes. Despite CIDP+DM patients having more severe clinical and electrophysiological neuropathy, they are less likely to receive disease-modifying/specific therapy, yet have similar response rates to treatment as those without diabetes. Specifically, the duration of neuropathy - not diabetes status - was associated with treatment response.
doi:10.1371/journal.pone.0089344
PMCID: PMC3929752  PMID: 24586703
19.  Genome-Wide Screen Identifies Drug-Induced Regulation of the Gene Giant Axonal Neuropathy (Gan) in a Mouse Model of Antiretroviral-Induced Painful Peripheral Neuropathy 
Painful peripheral neuropathy is a debilitating complication of the treatment of HIV with nucleoside reverse transcriptase inhibitors (NRTIs). Patients are living longer with these drugs; however many develop excruciating, unremitting, and often treatment-limiting neuropathy that is resistant to conventional pain management therapies. Improving patient comfort and quality of life is paramount and depends on a clearer understanding of this devastating side effect. The mechanisms underlying the development of NRTI-induced neuropathy, however, remain unclear. Using a mouse model of NRTI-induced neuropathy, the authors conducted an unbiased whole-genome microarray screen to identify molecular targets in the spinal dorsal horn, which is the location where integration of ascending sensory transmission and descending modulatory effects occur. Analysis of the microarray data identified a change in the gene giant axonal neuropathy 1 (Gan1). Mutation of this gene has been linked to the development of giant axonal neuropathy (GAN), a rare autosomal recessive condition characterized by a progressive sensorimotor neuropathy. Gan1 has not been previously linked to nerve pathologies in other populations. In this study, downregulation of the Gan1 gene and the gene protein product, gigaxonin, was validated via quantitative polymerase chain reaction ([qPCR] gene expression) and Western blot analyses (protein level). Our report is the first to suggest that Gan1 might be a novel molecular target in the development of NRTI-induced peripheral neuropathy with implications for new therapeutic approaches to preventing or reducing a significant side effect of HIV treatment.
doi:10.1177/1099800409332726
PMCID: PMC3513273  PMID: 19398414
microarray; painful peripheral neuropathy; chronic pain; gigaxonin; giant axonal neuropathy; HIV/AIDS; HAART; NRTI
20.  Multifocal Visual Evoked Potentials (mfVEP) in Diabetic Patients with and without Polyneuropathy 
Previously not shown this study support that mfVEP is an indicator of optic nerve neuropathy in diabetic patients and there could be a correlation between the optic nerve dysfunction and diabetic poly neuropathy. The early optic nerve involvement might explain some of the visual complain in this group of diabetic patients.
Purpose:
To investigate the function of the visual pathway measured by mfVEP (multifocal Visual Evoked Potentials) in patients with diabetic retinopathy and neurophysiologically verified polyneuropathy
Subjects and Methods:
Thirty-two diabetic patients with the same degree of diabetic retinopathy were classified with neurography regarding polyneuropathy and further examined with mfVEP. The mfVEPs of eighteen patients with polyneuropathy were compared to those of fourteen diabetic patients without polyneuropathy and to those of ten nondiabetic subjects.
Results:
Diabetic duration, and the number of patients who had undergone panretinal photocoagulation for proliferative diabetic retinopathy were similar in the two patient groups, 29±13 vs 25±7 years, p=0.3.
Both groups of patients with diabetic retinopathy had significantly lower amplitudes in the mfVEP than the healthy subjects.
In addition the mfVEP amplitudes, which reflect selected areas of the visual function, were significantly reduced in the lower nasal quadrant in patients with neuropathy compared to patients without neuropathy.
Conclusion:
The results indicate that mfVEP could be an indicator of optic nerve neuropathy in patients with diabetic retinopathy. The early optic nerve involvement might explain some of the visual complaints in this group of diabetic patients.
doi:10.2174/1874364101206010098
PMCID: PMC3504721  PMID: 23198007
Diabetic retinopathy; neuropathy; multifocal VEP (mfVEP).
21.  Mendenhall's syndrome: clues to the aetiology of human diabetic neuropathy. 
The pathogenesis of human diabetic neuropathy remains unclear. Mendenhall's syndrome is characterised by a mutation in the insulin receptor gene with consequent lifelong uncontrolled hyperglycaemia. The sural nerve biopsy from a patient with Mendenhall's syndrome showed a gross loss of myelinated fibres that was comparable with the degree of fibre loss in a case matched diabetic patient with established neuropathy. The biopsy from the patient with Mendenhall's syndrome showed only a very mild degree of microangiopathy, however, which failed to relate to the degree of nerve fibre loss and also did not compare with the advanced degree of microangiopathy seen in the diabetic patient. Thus hyperglycaemia itself did not result in appreciable microangiopathy. Furthermore the presence of severe neuropathy without advanced microangiopathy suggests an important and independent role for metabolic factors in the pathogenesis of neuropathy.
Images
PMCID: PMC1073444  PMID: 7738565
22.  HIV Associated Sensory Neuropathy 
Background: In the era of highly active antiretroviral therapy, sensory neuropathies have increased in prevalence. We have documented the frequency and profile of the two most common forms of sensory neuropathies associated with Human Immunodeficiency Virus (HIV) infection and looked into clinicoelectrophysiological correlates to differentiate the two entities.
Methods: The study population comprised of all consecutive patients detected to be HIV positive and attending the Neurology outpatient department (from March 2011 to March 2012) who were aged ≥ 18 years and were able to give informed consent. The data were collected from the patient records (including CD4 counts and treatment details) and questionnaire based interview with each patient. All patients underwent detailed clinical examination and nerve conduction studies (NCSs).
Results: Among the total study population of 50 patients, there were 31 men and 19 women. Thirty two patients were in age range of 21 - 40 years and rest were above 40 years. 25 were on antiretroviral therapy (18 on regimen containing zidovudine; seven on regimen containing stavudine). The mean duration of antiretroviral therapy was 16.6±8.4 months. Low CD4 counts (<200) were noted in 24 patients (13 of these were on antiretroviral therapy). Clinically, the patients were classified as asymptomatic (n=34) and symptomatic (n=16). Among the symptomatic patients, nine were on antiretroviral therapy since less than one year (seven of these were on regimen containing stavudine). Ten patients aged more than 40-years had symptomatic neuropathy. No significant correlation was found between low CD4 counts and symptomatic neuropathy (p=0.21). Impaired vibration (100%) and absent ankle jerks (75%) were commoner than reduced pin sensitivity (46.6%). Twenty two patients had abnormal NCS results (18 of these were on antiretroviral therapy). Axonal distal symmetrical sensory neuropathy was the commonest pattern noted in 14 patients who were receiving antiretroviral therapy. Subclinical involvement as evidenced by abnormal NCSs was noted in 5 asymptomatic patients who were all on antiretroviral therapy.
Conclusion: Symptomatic neuropathy was seen predominantly in HIV patients who were on antiretroviral therapy. All patients receiving stavudine containing regimen had severe symptomatic neuropathy within 1 year. There was an increase in the likelihood of symptomatic neuropathy among patients aged > 40 years. Subclinical neuropathy was common in those on antiretroviral therapy. Axonal neuropathy was the commonest pattern noted in patients who were receiving antiretroviral therapy and demyelinating neuropathy in patients not on antiretroviral therapy. Surprisingly no significant correlation was found between low CD4 counts and symptomatic neuropathy.
doi:10.7860/JCDR/2014/8143.4531
PMCID: PMC4149093  PMID: 25177587
Anti-retroviral therapy; Antiretroviral toxic neuropathies; Distal sensory peripheral neuropathies; HIV associated sensory neuropathy; Human immune deficiency Virus;  Peripheral neuropathy; Stavudine
23.  Mechanisms of Disease: The Oxidative Stress Theory of Diabetic Neuropathy 
Diabetic neuropathy is the most common complication of diabetes, affecting 50% of diabetic patients. Currently, the only treatment for diabetic neuropathy is glucose control and careful foot care. In this review, we discuss the idea that excess glucose overloads the electron transport chain, leading to the production of superoxides and subsequent mitochondrial and cytosolic oxidative stress. Defects in metabolic and vascular pathways intersect with oxidative stress to produce the onset and progression of nerve injury present in diabetic neuropathy. These pathways include the production of advanced glycation end products, alterations in the sorbitol, hexosamine and protein kinase C pathways and activation of Poly-ADP ribose polymerase. New bioinformatics approaches can augment current research and lead to new discoveries to understand the pathogenesis of diabetic neuropathy and to identify more effective molecular therapeutic targets.
doi:10.1007/s11154-008-9104-2
PMCID: PMC4239697  PMID: 18709457
Diabetes; Neuropathy; Oxidative Stress; Bioinformatics
24.  Neuroprotective effect of herpes simplex virus-mediated gene transfer of erythropoietin in hyperglycemic dorsal root ganglion neurons 
Brain  2009;132(4):879-888.
We examined the efficacy of herpes simplex virus vector-mediated gene transfer of erythropoietin in preventing neuropathy in mouse model of streptozotocin-diabetes. A replication-incompetent herpes simplex virus vector with erythropoietin under the control of the human cytomegalovirus promoter (vector DHEPO) was constructed. DHEPO expressed and released erythropoietin from primary dorsal root ganglion neurons in vitro, and following subcutaneous inoculation in the foot, expressed erythropoietin in dorsal root ganglion neurons in vivo. At 2 weeks after induction of diabetes, subcutaneous inoculation of erythropoietin prevented the reduction in sensory nerve amplitude characteristic of diabetic neuropathy measured 4 weeks later, preserved autonomic function measured by pilocarpine-induced sweating, and prevented the loss of nerve fibres in the skin and reduction of neuropeptide calcitonin gene-related peptide in the dorsal horn of spinal cord of the diabetic mice. We further investigated whether vector-mediated local expression of erythropoietin in dorsal root ganglion neurons can protect in vivo as well as in vitro hyperglycemia-induced axonal degeneration. Our findings show that the AKT/GSK-3β dependent pathway plays an important role in mediating the protection of erythropoietin against diabetic neuropathy. Herpes simplex virus-mediated transfer of erythropoietin to dorsal root ganglia may prove useful in treatment of diabetic neuropathy.
doi:10.1093/brain/awp014
PMCID: PMC2724909  PMID: 19244253
diabetes; gene therapy; herpes simplex virus; erythropoietin
25.  Is the C677T polymorphism in methylenetetrahydrofolate reductase gene or plasma homocysteine a risk factor for diabetic peripheral neuropathy in Chinese individuals?☆ 
Neural Regeneration Research  2012;7(30):2384-2391.
The present study enrolled 251 diabetic patients, including 101 with neuropathy and 150 without neuropathy. Of the 150 patients, 100 had no complications, such as retinopathy, nephropathy, or neuropathy. Polymerase chain reaction-restriction fragment length polymorphism analysis was used to identify methylenetetrahydrofolate reductase gene variants. Plasma homocysteine levels were also measured. Homocysteine levels and the frequency of hyperhomocysteinemia were significantly higher in patients with diabetic peripheral neuropathy compared with diabetic patients without neuropathy (P < 0.05). In logistic regression analysis with neuropathy as the dependent variable, the frequency of C677T in methylenetetrahydrofolate reductase was significantly higher in patients with diabetic peripheral neuropathy compared with patients without diabetic complications. Homocysteine levels were significantly higher in patients with diabetic peripheral neuropathy carrying the 677T allele and low folic acid levels. In conclusion, hyperhomocysteinemia is an independent risk factor for diabetic neuropathy in Chinese patients with diabetes. The C677T polymorphism in methylenetetrahydrofolate reductase and low folic acid levels may be risk factors for diabetic peripheral neuropathy in Chinese patients with diabetes.
doi:10.3969/j.issn.1673-5374.2012.30.009
PMCID: PMC4268745  PMID: 25538764
homocysteine; methylenetetrahydrofolate reductase; type 2 diabetes mellitus; diabetic peripheral neuropathy; neural regeneration

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