Pathogenesis Of Diabetic Peripheral Neuropathy Research Articles

Oxidative stress in diabetic peripheral neuropathy

Oxidative stress play a key role in the pathogenesis of diabetic peripheral neuropathy. Reactive oxidative species(ROS), derived from hyperglycemia through abnormal mitochondrial electron chain and NADPH oxidase et al, may damage lipids, DNA, and proteins by oxidation. ROS can also promote other classical mechanisms of diabetic peripheral neuropathy, and further cause apoptosis of neurons and Schwann cells, or inflammation of nerve tissue, and finally lead to nerve injury. The relationship between oxidative stress and mechanisms of diabetic peripheral neuropathy was reviewed in this article, in order to get a clue for more effective treatment strategies. (Chin J Endocrinol Metab, 2015, 31: 1000-1003) Key words: Diabetic peripheral neuropathy; Oxidative stress; Reactive oxidative species

Jinmaitong alleviates the diabetic peripheral neuropathy by inducing autophagy.

To observe the deregulation of autophagy in diabetic peripheral neuropathy (DPN) and investigate whether Jinmaitong ( JMT) alleviates DPN by inducing autophagy. DPN models were established by streptozotocin-induced diabetic rats and Schwann cells (SCs) cultured in high glucose medium. The pathological morphology was observed by the improved Bielschowsky's nerve fiber axonal staining and the Luxol fast blue-neutral red myelin staining. The ultrastructure was observed by the transmission electron microscopy. Beclin1 level was detected by immunohistochemistry and Western blot. The proliferation of cultured SCs was detected by methylthiazolyldiphenyl-tetrazolium bromide. Diabetic peripheral nerve tissues demonstrated pathological morphology and reduced autophagic structure, accompanied with down-regulation of Beclin1. JMT apparently alleviated the pathological morphology change and increased the autophagy [in vivo, Beclin1 integral optical density (IOD) value of the control group 86.6±17.7, DM 43.9±8.8, JMT 73.3 ±17.8, P<0.01 or P<0.05, in vitro Beclin1 IOD value of the glucose group 0.47±0.25 vs the control group 0.88±0.29, P<0.05]. Consequently, inhibition of autophagy by 3-methyladenine resulted in a time- and concentration-dependent decrease of the proliferation of SCs (P<0.05, P<0.01). Down-regulation of autophagy in SCs might contribute to the pathogenesis of DPN. JMT alleviates diabetic peripheral nerve injury at least in part by inducing autophagy.

Peroxynitrite and protein nitration in the pathogenesis of diabetic peripheral neuropathy

Peroxynitrite, a product of the reaction of superoxide with nitric oxide, causes oxidative stress with concomitant inactivation of enzymes, poly(ADP-ribosylation), mitochondrial dysfunction and impaired stress signalling, as well as protein nitration. In this study, we sought to determine the effect of preventing protein nitration or increasing peroxynitrite decomposition on diabetic neuropathy in mice after an extended period of untreated diabetes. C57Bl6/J male control and diabetic mice were treated with the peroxynitrite decomposition catalyst Fe(III) tetramesitylporphyrin octasulfonate (FeTMPS, 10 mg/kg/day) or protein nitration inhibitor (-)-epicatechin gallate (20 mg/kg/day) for 4 weeks, after an initial 28 weeks of hyperglycaemia. Untreated diabetic mice developed motor and sensory nerve conduction velocity deficits, thermal and mechanical hypoalgesia, tactile allodynia and loss of intraepidermal nerve fibres. Both FeTMPS and epicatechin gallate partially corrected sensory nerve conduction slowing and small sensory nerve fibre dysfunction without alleviation of hyperglycaemia. Correction of motor nerve conduction deficit and increase in intraepidermal nerve fibre density were found with FeTMPS treatment only. Peroxynitrite injury and protein nitration are implicated in the development of diabetic peripheral neuropathy. The findings indicate that both structural and functional changes of chronic diabetic peripheral neuropathy can be reversed and provide rationale for the development of a new generation of antioxidants and peroxynitrite decomposition catalysts for treatment of diabetic peripheral neuropathy.

Association of peripheral neuropathy with circulating advanced glycation end products, soluble receptor for advanced glycation end products and other risk factors in patients with type 2 diabetes

The pathogenesis of diabetic peripheral neuropathy remains uncertain and nonenzymatic glycoxidation is one of the contributing mechanisms. The aim of this study was to assess the respective relationship of diabetic peripheral neuropathy with glycoxidation, compared with other identified risk factors, in patients with type 2 diabetes. We included 198 patients with type 2 diabetes and high risk for vascular complications. Circulating concentrations of three advanced glycation end products (carboxymethyllysine, methyl-glyoxal-hydroimidazolone-1, pentosidine) and of their soluble receptor (sRAGE) were measured. Peripheral neuropathy was assessed by the neuropathy disability score and by the monofilament test and defined as either an abnormal monofilament test and/or a neuropathy disability score ≥6. Multivariate regression analyses were performed adjusting for potential confounding factors for neuropathy: age, gender, diabetes duration, current smoking, systolic blood pressure, waist circumference, height, peripheral arterial occlusive disease, glycated haemoglobin, estimated glomerular filtration rate and lipid profile. Prevalence of peripheral neuropathy was 20.7%. sRAGE and carboxymethyllysine were independently and positively associated with the presence of peripheral neuropathy. No significant association was found between peripheral neuropathy and methyl-glyoxal-hydroimidazolone-1 or pentosidine. Waist circumference, height and peripheral arterial occlusive disease were independently associated with peripheral neuropathy. Carboxymethyllysine and sRAGE were independently associated with peripheral neuropathy in patients with type 2 diabetes. Although the conclusions are limited by the absence of a healthy control population, this study confirms the relationship between advanced glycoxidation and diabetic peripheral neuropathy, independently of other risk factors.

Hyperglycemia- and neuropathy-induced changes in mitochondria within sensory nerves.

ObjectiveThis study focused on altered mitochondrial dynamics as a potential mechanism for diabetic peripheral neuropathy (DPN). We employed both an in vitro sensory neuron model and an in situ analysis of human intraepidermal nerve fibers (IENFs) from cutaneous biopsies to measure alterations in the size distribution of mitochondria as a result of hyperglycemia and diabetes, respectively.MethodsNeurite- and nerve-specific mitochondrial signals within cultured rodent sensory neurons and human IENFs were measured by employing a three-dimensional visualization and quantification technique. Skin biopsies from distal thigh (DT) and distal leg (DL) were analyzed from three groups of patients; patients with diabetes and no DPN, patients with diabetes and confirmed DPN, and healthy controls.ResultsThis analysis demonstrated an increase in mitochondria distributed within the neurites of cultured sensory neurons exposed to hyperglycemic conditions. Similar changes were observed within IENFs of the DT in DPN patients compared to controls. This change was represented by a significant shift in the size frequency distribution of mitochondria toward larger mitochondria volumes within DT nerves of DPN patients. There was a length-dependent difference in mitochondria within IENFs. Distal leg IENFs from control patients had a significant shift toward larger volumes of mitochondrial signal compared to DT IENFs.InterpretationThe results of this study support the hypothesis that altered mitochondrial dynamics may contribute to DPN pathogenesis. Future studies will examine the potential mechanisms that are responsible for mitochondrial changes within IENFs and its effect on DPN pathogenesis.

Erythropoietin attenuates oxidative stress and apoptosis in Schwann cells isolated from streptozotocin-induced diabetic rats

High glucose-evoked oxidative stress and apoptosis within Schwann cells (SCs) are mechanisms facilitating the procession of diabetic peripheral neuropathy (DPN). Although erythropoietin (EPO) was demonstrated to have neuroprotective effects in neurodegenerative diseases, the effects of EPO on glucose-evoked oxidative stress and apoptosis of SCs remain unknown. Primary cultured SCs isolated from streptozotocin (STZ)-induced diabetic peripheral neuropathic rats and normal control rats were exposed to high or normal glucose condition with or without EPO incubation for 72 h. Cell viability, apoptotic rate, cellular reactive oxygen species (ROS) level, total glutathione (GSH) level, EPO mRNA and erythropoietin receptor (EPOR) mRNA levels were assayed. SCs from diabetic rats showed a lower cell viability and a higher apoptotic rate. High glucose culture condition elevated ROS level and diminished total GSH level of SCs. EPO improved cell viability and decreased cell apoptotic rate of SCs. EPO also elevated total GSH level and decreased intracellular ROS level. SCs from diabetic rats exhibited higher EPO mRNA and EPOR mRNA levels than SCs from normal control rats. The data of this study offered fresh viewpoints for interpreting the pathogenesis of DPN and novel pharmacological principles implicit in the therapeutic effect of EPO.

ER Stress in Diabetic Peripheral Neuropathy: A New Therapeutic Target

Diabetes and other diseases that comprise the metabolic syndrome have reached epidemic proportions. Diabetic peripheral neuropathy (DPN) is the most prevalent complication of diabetes, affecting ~50% of diabetic patients. Characterized by chronic pain or loss of sensation, recurrent foot ulcerations, and risk for amputation, DPN is associated with significant morbidity and mortality. Mechanisms underlying DPN pathogenesis are complex and not well understood, and no effective treatments are available. Thus, an improved understanding of DPN pathogenesis is critical for the development of successful therapeutic options. Recent research implicates endoplasmic reticulum (ER) stress as a novel mechanism in the onset and progression of DPN. ER stress activates the unfolded protein response (UPR), a well-orchestrated signaling cascade responsible for relieving stress and restoring normal ER function. During times of extreme or chronic stress, such as that associated with diabetes, the UPR may be insufficient to alleviate ER stress, resulting in apoptosis. Here, we discuss the potential role of ER stress in DPN, as well as evidence demonstrating how ER stress intersects with pathways involved in DPN development and progression. An improved understanding of how ER stress contributes to peripheral nerve dysfunction in diabetes will provide important insight into DPN pathogenesis. Future studies aimed at gaining the necessary insight into ER stress in DPN pathogenesis will ultimately facilitate the development of novel therapies.

Mouse Models of Diabetic Neuropathy

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes and is associated with significant morbidity and mortality. DPN is characterized by progressive, distal-to-proximal degeneration of peripheral nerves that leads to pain, weakness, and eventual loss of sensation. The mechanisms underlying DPN pathogenesis are uncertain, and other than tight glycemic control in type 1 patients, there is no effective treatment. Mouse models of type 1 (T1DM) and type 2 diabetes (T2DM) are critical to improving our understanding of DPN pathophysiology and developing novel treatment strategies. In this review, we discuss the most widely used T1DM and T2DM mouse models for DPN research, with emphasis on the main neurologic phenotype of each model. We also discuss important considerations for selecting appropriate models for T1DM and T2DM DPN studies and describe the promise of novel emerging diabetic mouse models for DPN research. The development, characterization, and comprehensive neurologic phenotyping of clinically relevant mouse models for T1DM and T2DM will provide valuable resources for future studies examining DPN pathogenesis and novel therapeutic strategies.

Angiogenin gene polymorphism: A risk factor for diabetic peripheral neuropathy in the northern Chinese Han population.

Angiogenin is associated with the pathogenesis of diabetic peripheral neuropathy. Here, we quenced the coding region of the angiogenin gene in genomic DNA from 207 patients with type 2 diabetes mellitus (129 diabetic peripheral neuropathy patients and 78 diabetic non-neuropathy patients) and 268 healthy controls. All subjects were from the Han population of northern China. No mutations were found. We then compared the genotype and allele frequencies of the angiogenin synonymous single nucleotide polymorphism rs11701 between the diabetic peripheral neuropathy patients and controls, and between the diabetic neuropathy and non-neuropathy patients, using a case-control design. We detected no statistically significant genetic associations. Angiogenin may not be associated with genetic susceptibility to diabetic peripheral neuropathy in the Han population of northern China.

Diabetic Schwann cells suffer from nerve growth factor and neurotrophin-3 underproduction and poor associability with axons

Schwann cells (SCs) are integral to peripheral nerve biology, contributing to saltatory conduction along axons, nerve and axon development, and axonal regeneration. SCs also provide a microenvironment favoring neural regeneration partially due to production of several neurotrophic factors. Dysfunction of SCs may also play an important role in the pathogenesis of peripheral nerve diseases such as diabetic peripheral neuropathy where hyperglycemia is often considered pathogenic. In order to study the impact of diabetes mellitus (DM) upon the regenerative capacity of adult SCs, we investigated the differential production of the neurotrophic factors nerve growth factor (NGF) and neurotrophin-3 (NT3) by SCs harvested from the sciatic nerves of murine models of type 1 DM (streptozotocin treated C57BL/6J mice) and type 2 DM (LepR(-/-) or db/db mice) or non-diabetic cohorts. In vitro, SCs from diabetic and control mice were maintained under similar hyperglycemic and euglycemic conditions respectively. Mature SCs from diabetic mice produced lower levels of NGF and NT3 under hyperglycemic conditions when compared to SCs in euglycemia. In addition, SCs from both DM and non-DM mice appear to be incapable of insulin production, but responded to exogenous insulin with greater proliferation and heightened myelination potentiation. Moreover, SCs from diabetic animals showed poorer association with co-cultured axons. Hyperglycemia had significant impact upon SCs, potentially contributing to the pathogenesis of diabetic peripheral neuropathy.

Impaired slow axonal transport in diabetic peripheral nerve is independent of RAGE

Diabetic peripheral nerve dysfunction is a common complication occurring in 30-50% of long-term diabetic patients. The pathogenesis of this dysfunction remains unclear but growing evidence suggests that it might be attributed, in part, to alteration in axonal transport. Our previous studies demonstrated that RAGE (Receptor for Advanced Glycation Endproducts) contributes to the pathogenesis of diabetic peripheral neuropathy and impairs nerve regeneration consequent to sciatic nerve crush, particularly in diabetes. We hypothesize that RAGE plays a role in axonal transport impairment via the interaction of its cytoplasmic domain with mammalian Diaphanous 1 (mDia1) - actin interacting molecule. Studies showed that mDia1-RAGE interaction is necessary for RAGE-ligand-dependent cellular migration, AKT phosphorylation, macrophage inflammatory response and smooth muscle migration. Here, we studied RAGE, mDia1 and markers of axonal transport rates in the peripheral nerves of wild-type C57BL/6 and RAGE null control and streptozotocin-injected diabetic mice at 1, 3 and 6h after sciatic nerve crush. The results show that in both control and diabetic nerves, the amount of RAGE accumulated at the proximal and distal side of the crush area is similar, indicating that the recycling rate for RAGE is very high and that it is evenly transported from and towards the neuronal cell body. Furthermore, we show that slow axonal transport of proteins such as Neurofilament is affected by diabetes in a RAGE-independent manner. Finally, our study demonstrates that mDia1 axonal transport is impaired in diabetes, suggesting that diabetes-related changes affecting actin binding proteins occur early in the course of the disease.

Beneficial effect of TNF-α inhibition on diabetic peripheral neuropathy

BackgroundTumor necrosis factor-α (TNF-α) is an important inflammatory factor produced by activated macrophages and monocytes and plays an important role in the pathogenesis of diabetic peripheral neuropathy (DPN). To evaluate the effect of TNF-α signaling suppression and the potential of TNF-α in the treatment of DPN, a recombinant human TNF-α receptor-antibody fusion protein (rhTNFR:Fc) was used. We focused on the pathophysiology of the sciatic nerve and examined the expression of myelin basic protein (MBP) under DPN status with or without TNF-α inhibition.MethodsThe DPN rat model was generated by intraperitoneal injection of streptozotocin and by feeding with a high-fat, high-sugar diet. The nerve conduction velocity (NCV) in sciatic nerve of rat was monitored over a period of four weeks. The histopathological changes in nerve tissue were examined through traditional tissue histology and ultrastructure transmission electron microscopy (TEM). The expression of MBP was examined through western blot analysis.ResultsThe DPN induced rats showed significant signs of nerve damage including lower NCV, demyelination of nerve fibers, disorganization of lamellar and axonal structures, and decreased expression of MBP in the nerve tissue. The inhibition of TNF-α in the DPN rats resulted in a significant recovery from those symptoms compared to the DPN rats.ConclusionsOur study demonstrates that TNF-α plays a key role in the pathogenesis of DPN and its inhibition by rhTNFR:Fc can prove to be a useful therapeutic strategy for the treatment of and/or prevention from DPN symptoms.

Diabetic Peripheral Neuropathy in Youth

Neuropathy is a common long-term complication of diabetes recognized almost entirely in adults (Moser et al., 2013). It is a precursor to foot ulcers and lower limb amputations, both of which are preventable (Fletcher, 2006; Zangaro & Margaret, 1999). The pathogenesis of diabetic peripheral neuropathy (DPN) is not completely understood. Evidence suggests that hyperglycemia and other metabolic factors contribute to nerve damage, at least in part by degrading the function of small blood vessels supplying the nerves, resulting in progressive structural deterioration of nerve pathways (Trotta, Verrotti, Salladini, & Chiarelli, 2004).

Endoplasmic Reticulum Stress Plays a Key Role in the Pathogenesis of Diabetic Peripheral Neuropathy

Endoplasmic reticulum stress resulting from abnormal folding of newly synthesized proteins impairs metabolism, transcriptional regulation, and gene expression, and it is a key mechanism of cell injury. Endoplasmic reticulum stress plays an important role in cardiovascular and neurodegenerative diseases, cancer, and diabetes. We evaluated the role for this phenomenon in diabetic peripheral neuropathy. Endoplasmic reticulum stress manifest in upregulation of multiple components of unfolded protein response was identified in neural tissues (sciatic nerve, spinal cord) of streptozotocin diabetic rats and mice. A chemical chaperone, trimethylamine oxide, administered for 12 weeks after induction of diabetes (110 mg⋅kg−1⋅d−1, a prevention paradigm) attenuated endoplasmic reticulum stress, peripheral nerve dysfunction, intraepidermal nerve fiber loss, and sciatic nerve and spinal cord oxidative-nitrative stress in streptozotocin diabetic rats. Similar effects on diabetes-induced endoplasmic reticulum stress and peripheral nerve dysfunction were observed with a structurally unrelated chemical chaperone, 4-phenylbutyric acid (100 mg⋅kg−1⋅d−1, intraperitoneal). CCAAT/enhancer-binding protein homologous protein (CHOP)−/− mice made diabetic with streptozotocin displayed less severe sciatic nerve oxidative-nitrative stress and peripheral neuropathy than the wild-type (C57Bl6/J) mice. Neither chemical chaperones nor CHOP gene deficiency reduced diabetic hyperglycemia. Our findings reveal an important role of endoplasmic reticulum stress in the development of diabetic peripheral neuropathy and identify a potential new therapeutic target.

Interactions between sorbitol pathway of glucose metabolism and 12/15‐lipoxygenase activation in diabetic peripheral neuropathy

Both sorbitol pathway of glucose metabolism and, recently, 12/15‐lipoxygenase (12/15‐LO) activation have been implicated in the pathogenesis of diabetic peripheral neuropathy (DPN). Activation of the key enzyme of the sorbitol pathway, aldose reductase, is known to lead to NF‐κB activation and accumulation of cytosolic Ca++ i.e., two events implicated in 12/15‐LO overexpression and activation. We, therefore, evaluated the relationship between the two mechanisms using a pharmacological approach. Male C57Bl6/J mice were made diabetic with streptozotocin, after which non‐diabetic and diabetic mice were treated with the aldose reductase inhibitor fidarestat, at 16 mgkg−1d−1, in the drinking water, for 12 weeks. Diabetic mice displayed accumulation of glucose, sorbitol pathway intermediates, as well as 12/15‐LO overexpression and 12(S)‐HETE accumulation (a sign of increased 12/15‐LO activity) in two tissue‐targets for DPN, sciatic nerve and spinal cord. Fidarestat treatment did not affect diabetes‐induced glucose accumulation and completely corrected sorbitol and fructose accumulation in both tissues. It did not affect sciatic nerve or spinal cord 12/15‐LO overexpression; however, 12(S)‐HETE concentrations were either completely (sciatic nerve) or partially (spinal cord) corrected. In conclusion, increased sorbitol pathway activity is responsible for activation, but not overexpression, of 12/15‐LO in the pathogenesis of DPN. Studies in dorsal root ganglia are in progress.

Evaluation of oxidative stress markers and vascular risk factors in patients with diabetic peripheral neuropathy

Diabetic peripheral neuropathy (DPN) is one of the most common diabetic chronic complications. The pathogenesis of DPN is complex and involves an intertwined array of mechanisms. The purposes of this study were to evaluate the association of oxidative stress and vascular risk factors with the prevalence of DPN and to determine the role of these biochemical parameters in the prognosis of DPN. One hundred patients with type 2 diabetes mellitus and 40 clinically healthy individuals were evaluated. The patients were divided into two groups. Group 1 included 40 diabetic patients without peripheral neuropathy, and group 2 consisted of 60 patients with DPN. Erythrocytes glutathione (GSH) level, plasma malondialdehyde (MDA), nitrite/nitrate (NOx) and homocysteine (Hcy) levels as well as serum ceruloplasmin (Cp), total antioxidants (TAO), endothelin-1 (ET-1) levels and γ-glutamyl transferase (GGT) activity were estimated. A significant decrease of erythrocyte GSH was observed in groups 1 and 2 relative to the controls. An increase in glycosylated haemoglobin (HbA1c), MDA, NOx, GGT, Cp, TAO, Hcy and ET-1 was noted in patients with DPN. In conclusion, oxidative stress biomarkers and vascular risk factors could be important in the pathogenesis of DPN. The measurement of serum GGT and Hcy in addition to HbA1c and disease duration could facilitate the early detection of neuropathy in diabetic patients.

Advances in the epidemiology, pathogenesis and management of diabetic peripheral neuropathy

Diabetic peripheral neuropathy (DPN) affects up to 50% of patients with diabetes and is a major cause of morbidity and increased mortality. Its clinical manifestations include painful neuropathic symptoms and insensitivity, which increases the risk for burns, injuries and foot ulceration. Several recent studies have implicated poor glycaemic control, duration of diabetes, hyperlipidaemia (particularly hypertryglyceridaemia), elevated albumin excretion rates and obesity as risk factors for the development of DPN. Although there is now strong evidence for the importance of nerve microvascular disease in the pathogenesis of DPN, the risk factors for painful DPN are not known. However, emerging evidence regarding the central correlates of painful DPN is now afforded by brain imaging. The diagnosis of DPN begins with a careful history of sensory and motor symptoms. The quality and severity of neuropathic pain if present should be assessed using a suitable scale. Clinical examination should include inspection of the feet and evaluation of reflexes and sensory responses to vibration, light touch, pinprick and the 10-g monofilament. Glycaemic control and addressing cardiovascular risk is now considered important in the overall management of the neuropathic patient. Pharmacological treatment of painful DPN includes tricyclic compounds, serotonin-norepinephrine reuptake inhibitors (e.g. duloxetine), anticonvulsants (e.g. pregabalin), opiates, membrane stabilizers, the antioxidant alpha lipoic acid and others. Over the past 7 years, new agents with perhaps less side effect profiles have immerged. Management of patients with painful neuropathy must be tailored to individual requirements and will depend on the presence of other co-morbidities. There is limited literature with regard to combination treatment.

Interplay of sorbitol pathway of glucose metabolism, 12/15-lipoxygenase, and mitogen-activated protein kinases in the pathogenesis of diabetic peripheral neuropathy

The interactions among multiple pathogenetic mechanisms of diabetic peripheral neuropathy largely remain unexplored. Increased activity of aldose reductase, the first enzyme of the sorbitol pathway, leads to accumulation of cytosolic Ca2+, essentially required for 12/15-lipoxygenase activation. The latter, in turn, causes oxidative–nitrosative stress, an important trigger of mitogen activated protein kinase (MAPK) phosphorylation. This study therefore evaluated the interplay of aldose reductase, 12/15-lipoxygenase, and MAPKs in diabetic peripheral neuropathy. In experiment 1, male control and streptozotocin-diabetic mice were maintained with or without the aldose reductase inhibitor fidarestat, 16mgkg−1d−1, for 12 weeks. In experiment 2, male control and streptozotocin-diabetic wild-type (C57Bl6/J) and 12/15-lipoxygenase-deficient mice were used. Fidarestat treatment did not affect diabetes-induced increase in glucose concentrations, but normalized sorbitol and fructose concentrations (enzymatic spectrofluorometric assays) as well as 12(S)-hydroxyeicosatetraenoic concentration (ELISA), a measure of 12/15-lipoxygenase activity, in the sciatic nerve and spinal cord. 12/15-lipoxygenase expression in these two tissues (Western blot analysis) as well as dorsal root ganglia (immunohistochemistry) was similarly elevated in untreated and fidarestat-treated diabetic mice. 12/15-Lipoxygenase gene deficiency prevented diabetes-associated p38 MAPK and ERK, but not SAPK/JNK, activation in the sciatic nerve (Western blot analysis) and all three MAPK activation in the dorsal root ganglia (immunohistochemistry). In contrast, spinal cord p38 MAPK, ERK, and SAPK/JNK were similarly activated in diabetic wild-type and 12/15-lipoxygenase−/− mice. These findings identify the nature and tissue specificity of interactions among three major mechanisms of diabetic peripheral neuropathy, and suggest that combination treatments, rather than monotherapies, can sometimes be an optimal choice for its management.

Interactions between the 12/15‐lipoxygenase pathway and MAPK activation in diabetic peripheral neuropathy

Both MAPK activation and, recently, the 12/15-lipoxygenase (12/15-LO) pathway, have been implicated in the pathogenesis of diabetic peripheral neuropathy (DPN). We evaluated the relationship between the two mechanisms using the 12/15-LO inhibitor cinnamyl-3,4-dihydroxy-á-cyanocinnamate (CDC) and 12/15-LO−/− mice. Male wild-type (WT) and 12/15-LO−/− mice were made diabetic with streptozotocin. Wild-type mice with 12–14 wk duration of STZ diabetes displayed motor and sensory nerve conduction velocity deficits, thermal hypoalgesia, tactile allodynia, and intraepidermal nerve fiber loss. They also displayed 12/15-LO overexpression, 12(S)-HETE accumulation (a sign of increased 12/15-LO activity), and increased phosphorylation of p38, ERK, and SAP/JNK in the sciatic nerve. 12/15-LO inhibition with CDC (8 mgkg-1d-1, s.c., for 4 wks after initial 12 wks without treatment) or 12/15-LO gene deficiency alleviated peripheral nerve dysfunction and reduced p38 and ERK phosphorylation, without affecting SAP/JNK phosphorylation or intraepidermal nerve fiber loss, a sign of small sensory nerve fiber degeneration. In conclusion, the findings suggest interaction between the 12/15-LO pathway and p38 and ERK, but not SAP/JNK, in the development of peripheral nerve dysfunction characteristic for DPN. Neither 12/15-LO nor MAPK activation contribute to diabetes-induced intraepidermal nerve fiber loss.

Recent advances in the management of diabetic distal symmetrical polyneuropathy.

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).