Pathogenesis Of Diabetic Peripheral Neuropathy Research Articles

Mitochondrial uncoupling has no effect on microvascular complications in type 2 diabetes

Diabetic peripheral neuropathy (DPN), diabetic kidney disease (DKD), and diabetic retinopathy (DR) contribute to significant morbidity and mortality in diabetes patients. The incidence of these complications is increasing with the diabetes epidemic, and current therapies minimally impact their pathogenesis in type 2 diabetes (T2D). Improved mechanistic understanding of each of the diabetic complications is needed in order to develop disease-modifying treatments for patients. We recently identified fundamental differences in mitochondrial responses of peripheral nerve, kidney, and retinal tissues to T2D in BKS-db/db mice. However, whether these mitochondrial adaptations are the cause or consequence of tissue dysfunction remains unclear. In the current study BKS-db/db mice were treated with the mitochondrial uncoupler, niclosamide ethanolamine (NEN), to determine the effects of mitochondrial uncoupling therapy on T2D, and the pathogenesis of DPN, DKD and DR. Here we report that NEN treatment from 6–24 wk of age had little effect on the development of T2D and diabetic complications. Our data suggest that globally targeting mitochondria with an uncoupling agent is unlikely to provide therapeutic benefit for DPN, DKD, or DR in T2D. These data also highlight the need for further insights into the role of tissue-specific metabolic reprogramming in the pathogenesis of diabetic complications.

Efficacy of autologous bone marrow mononuclear cell transplantation therapy in patients with refractory diabetic peripheral neuropathy.

Background:Owing to the multifactorial nature of the pathogenesis of diabetic peripheral neuropathy (DPN), conventional drug therapies have not been effective. The application of stem cells transplantation may be useful for the treatment of DPN. This study was designed to assess the safety and therapeutic effects of autologous bone marrow mononuclear cells (BMMNCs) transplantation on the treatment of refractory DPN.Methods:One hundred and sixty-eight patients with refractory DPN were recruited and enrolled in the study. They received intramuscular injection of BMMNCs and followed at 1, 3, 6, 12, 18, 24, and 36 months after the transplantation. Clinical data, Toronto Clinical Scoring System (TCSS), and nerve conduction studies (NCSs) were compared before and after the transplantation.Results:The signs and symptoms of neuropathy were significantly improved after BMMNCs transplantation. The values of the TCSS scores at 1 month (9.68 ± 2.49 vs. 12.55 ± 2.19, P < 0.001) and 3 months (8.47 ± 2.39 vs. 12.55 ± 2.19, P < 0.001) after the treatment reduced significantly compared with the baseline value. This decrement remained persistent until the end of the study. The conduction velocity and action potential and sensory nerves were significantly improved after transplantation (3 and 12 months after the treatment vs. the baseline: motor nerve conduction velocity, 40.24 ± 2.80 and 41.00 ± 2.22 m/s vs. 38.21 ± 2.28 m/s, P < 0.001; sensory nerve conduction velocity, 36.96 ± 2.26 and 39.15 ± 2.61 m/s vs. 40.41 ± 2.22 m/s, P < 0.001; compound muscle action potential, 4.67 ± 1.05 and 5.50 ± 1.20 μV vs. 5.68 ± 1.08 μV, P < 0.001; sensory nerve action potential, 4.29 ± 0.99 and 5.14 ± 1.26 μV vs. 5.41 ± 1.14 μV, P < 0.001). No adverse event associated with the treatment was observed during the follow-up period.Conclusions:Autologous transplantation of BMMNCs may be an effective and promising therapeutic strategy for the treatment of refractory DPN.

The Role of Extracellular Superoxide Dismutase (Ec-SOD) Gene Polymorphism in Motor Neuron Damage of Type 2 Diabetic Peripheral Neuropathy Patients of Babylon Province-Iraq

Background: Extracellular superoxide dismutase (EC-SOD) gene polymorphism play an essential role in the progression of diabetic complications. Reactive oxygen species (ROS) were known to damage neurons by enhancing nerve lipid peroxidation, the damaging mitochondrial DNA, break-down the respiratory chain, and the cross-linking of neuron proteins. Aim: the aim of this study was to investigate the relationship between (Ec-SOD) gene polymorphism and the pathogenesis of diabetic peripheral neuropathy in type2 diabetic patients. Arg(213)Gly polymorphism of Ec-SOD gene polymorphism were studied in type2 diabetic patients with (n=30) and without DPN (n=30). Results: Polymerase chain reaction (PCR) technique were used for detection Ec-SOD polymorphisms. This technique included the use of PCR primers (Forward and Reverse) to produce a restriction site in the amplified EC-SOD gene product just with the polymorphic base. Then, the product of (PCR) was digested with Eco52I restriction enzyme to detect Arg(-213)Gly polymorphic position. The results of Arg(-213)Gly polymorphism showed that the frequency of Arg/Arg, Arg/Gly, and Gly/Gly were 70%, 13.3%, and 16.6% in healthy control subject and 53.3%, 16.6%, and 30% in diabetic without neuropathy countered by 23.3%, 26.6%, and 50% in diabetic with neuropathy. This proposed that the Arg (-213)Gly polymorphism in the EcSOD gene is significantly associated with a risk for progression of diabetic peripheral neuropathy. Conclusions: Arg(-213)Gly polymorphism of Ec-SOD gene was associated with diabetic peripheral neuropathy in type2 diabetic patients of Babylon Province

Conserved Transcriptional Signatures in Human and Murine Diabetic Peripheral Neuropathy

Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes. In this study, we employed a systems biology approach to identify DPN-related transcriptional pathways conserved across human and various murine models. Eight microarray datasets on peripheral nerve samples from murine models of type 1 (streptozotocin-treated) and type 2 (db/db and ob/ob) diabetes of various ages and human subjects with non-progressive and progressive DPN were collected. Differentially expressed genes (DEGs) were identified between non-diabetic and diabetic samples in murine models, and non-progressive and progressive human samples using a unified analysis pipeline. A transcriptional network for each DEG set was constructed based on literature-derived gene-gene interaction information. Seven pairwise human-vs-murine comparisons using a network-comparison program resulted in shared sub-networks including 46 to 396 genes, which were further merged into a single network of 688 genes. Pathway and centrality analyses revealed highly connected genes and pathways including LXR/RXR activation, adipogenesis, glucocorticoid receptor signalling, and multiple cytokine and chemokine pathways. Our systems biology approach identified highly conserved pathways across human and murine models that are likely to play a role in DPN pathogenesis and provide new possible mechanism-based targets for DPN therapy.

Prolonged high‐glucose exposure decreased SREBP‐1/FASN/ACC in Schwann cells of diabetic mice via blocking PI3K/Akt pathway

Abnormal lipid metabolism and SREBP-1 downregulation are reported to be involved in the pathogenesis of diabetic peripheral neuropathy (DPN). In the current study, the relationship between PI3K/Akt signaling pathway and SREBP-1 expression was explored in Schwann cells of DPN. The phospho-Akt (Ser 473), phospho-Akt (Thr 308), and SREBP-1 expression were inhibited in the sciatic nerves of diabetic mice versus those of normal mice, accompanied with the atrophy of nerve fiber and the irregular myelin sheath. High concentration glucose suppressed phospho-Akt (Ser 473), phospho-Akt (Thr 308), and SREBP-1 expression in cultured Schwann cell (RSC96 cell) in vitro, and 25 mmol/L glucose was enough to lead to the maximum inhibitory effect. The time-course effect of high glucose showed that Akt phosphorylation gradually decreased with the extension of stimulation time. Somewhat differently, short-term high-glucose exposure enhanced SREBP-1 expression and prolonged high-glucose stimulation reduced the SREBP-1 expression in RSC96 cells. Similarly, prolonged high-glucose stimulation also downregulated FASN messenger RNA (mRNA), ACC mRNA, intracellular triglyceride, and cholesterol. LY294002 suppressed Akt activation followed by the decreased SREBP-1, FASN, ACC, triglyceride, and cholesterol. Contrarily, the PI3K/Akt signaling pathway agonist insulin pretreatment avoided prolonged high-glucose stimulation-blocked Akt activation and increased SREBP-1, FASN, and ACC expression in the levels of protein and mRNA in RSC96 cells. The knockdown of SREBP-1 by shRNA prevented insulin-induced enhanced FASN, ACC mRNA expression, triglyceride, and cholesterol in high-glucose-treated RSC96 cells. In conclusion, prolonged high-glucose exposure inhibits the SREBP-1/FASN/ACC expression in the Schwann cells of DPN via the blockage of the PI3K/Akt signaling pathway.

Evaluation of Apelin Level in Type 2 Diabetic Patients with Peripheral Neuropathy and Nephropathy

AbstractBackground: Diabetic Peripheral Neuropathy (DPN) and Diabetic Nephropathy (DN) are serious complications of diabetes mellitus. Their pathogenesis is associated with dura-tion of diabetes, hyperglycemia and increased pro-inflammatory response that cause endothelial dysfunction and impaired angiogenesis. Apelin is an endogenous peptide which is expressed in the kidney, adipose tissue, liver, endothelium, and plasma. It contributes to endothelial dysfunction, angio-genesis, and inflammation that lead to pathogenesis of DPN and DN.Aim of Work: To assess serum apelin level in type 2 diabetic patients with peripheral neuropathy and nephropathy.Patients and Methods: 80 subjects were selected from Nasser Institute for Research and divided into four groups: Group 1 included 20 healthy controls, group 2 included 20 diabetic patients without complications, group 3 included 20 patients with DPN and group 4 included 20 patients with DN. They were subjected to monofilament test, fasting blood glucose, kidney function tests, HbA1c, lipid profile, liver profile, urine analysis, urinary albumin/creatinine ratio and serum apelin.Results: Apelin levels are significantly higher in diabetic patients in the presence of neuropathy and nephropathy compared to other groups. There was a positive correlation between serum apelin and HbA1c in group 2 and 3. Further, there was a positive correlation between apelin level and HbA1c, serum creatinine and urine albumin/creatinine ratio in group 4. There was no correlation between serum apelin and other parameters in all studied groups.Conclusion: Serum apelin may play an important role in pathogenesis of DPN and DN.

Differential gene expression profiling of the sciatic nerve in type 1 and type 2 diabetic mice.

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus (DM). The pathogenic mechanisms of DPN and the therapeutic interventions required may be distinct between type 1 (T1) and type 2 (T2) DM. However, the molecular mechanisms underlying the pathogenesis of DPN in both types of diabetes remain unclear. The aim of the current study was to identify the changes in genes and pathways associated with DPN in sciatic nerves of T1- and T2DM mice using bioinformatics analysis. The microarray profiles of sciatic nerves of T1DM (GSE11343) and T2DM (GSE27382) mouse models were downloaded from the Gene Expression Omnibus database to identify differentially expressed genes (DEGs) in each. DEGs in the two types of DM (with fold change ≥2 and P<0.05) were identified with BRB-ArrayTools. Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the Database for Annotation, Visualization and Integrated Discovery. A protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins and visualized using Cytoscape. Compared with control samples, 623 and 1,890 DEGs were identified in sciatic nerves of T1- and T2DM mice, respectively. Of these, 75 genes were coordinately dysregulated in the sciatic nerves of both models. Many DEGs unique to T1DM mice were localized to the nucleoplasm and were associated with regulation of transcription processes, while many unique to T2DM mice were localized at cell junctions and were associated with ion transport. In addition, certain DEGs may be associated with the different treatment strategies used for the two types of DM. This analysis provides insight into the functional gene sets and pathways operating in sciatic nerves in T1- and T2DM. The results should improve understanding of the molecular mechanisms underlying the pathophysiology of DPN, and provide information for the development of therapeutic strategies for DPN specific to each type of DM.

Activation of the intracellular Ca++-AMPK pathway ameliorates apoptosis and improves autophagy in diabetic peripheral neuropathy

A decrement of AMP-activated protein kinase-eNOS bioavailability is critical for the pathogenesis of diabetic peripheral neuropathy. We evaluated the neuro-protective effect of cinacalcet on DPN by activating the AMPK-eNOS pathway using db/db mice. The db/db mice and db/m controls at 8 weeks of age were divided to receive either a regular diet or a diet containing cinacalcet. Mice were evaluated sciatic motor nerve conduction and tactile response. We performed Mason's trichrome staining and immunohistochemistry for type IV collagen and 8-hydroxy-deoxyguanosine, an oxidative DNA damage marker. For immunofluorescence double staining, apoptosis was detected by ApopTag Fluorescein In Situ Apoptosis Detection Kit. The sciatic nerve specimens were double stained and we measured unmyelinated fiber areas and axonal areas using NIH Image J under a transmission electron microscope. Western blot assay was performed total protein of sciatic nerve with specific antibodies for CaSR, CaMKK, total LKB1, phospho-Ser428 LKB1, total AMPK, phospho-Thr172 AMPK, total eNOS, phospho-Ser1177 eNOS, PGC-1. The db/db mice showed sensorimotor impairment, nerve fibrosis and inflammation, apoptosis, disorganized myelin with axonal shrinkage and degeneration, and fewer unmyelinated fibers in the sciatic nerve compared to db/m mice. Cinacalcet administration, without causing any changes in blood glucose and Ca++ concentrations, significantly increased the paw withdrawal mechanical threshold and decreased the motor conduction latency, and ameliorated the deterioration of sciatic nerve pathology, accompanied by increases in the expressions of calcium-sensing receptor-CaMKK and phosphorylation of AMPK-eNOS in diabetic mice. Cinacalcet may play an important role in the prevention and amelioration of DPN by amplifying AMPK signaling.

Large-Scale DNA Methylation Profiling of Human Diabetic Peripheral Neuropathy in Subjects with Type 2 Diabetes Mellitus

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes. Emerging evidence suggests that aberrant DNA methylation may play a critical role in the pathogenesis of diabetic complications. Yet, its involvement in DPN is not fully characterized. In this study, we performed a large-scale genome-wide methylation profiling of sural nerve samples obtained from subjects with type 2 diabetes mellitus (T2DM) using Reduced Representation Bisulfite Sequencing (RRBS). A total of 78 samples were sequenced and mapped to the human reference genome. Differential analysis was performed on two groups, identified by our previous transcriptomic analysis of the same samples, which showed significantly different HbA1c levels: Group 1 (=8.5%±1.6%) and Group 2 (&amp;lt;7.0%±1.4%). Using MethylKit R package, with an adjusted p-value &amp;lt; 0.01 and 15% methylation change as significance cutoffs, we identified 2,066 differentially methylated CpG sites and 440 regions, corresponding to 1,519 and 429 unique differentially methylated genes (DMGs). These genes were highly enriched in biological processes related to nervous system development, neuron fate specification and neuron differentiation. KEGG pathway enrichment analysis demonstrated that genes involved in cancer, ECM-receptor interaction and axon guidance pathways were significantly differentially methylated between the two groups, highlighting the importance of DNA methylation in DPN pathogenesis. In summary, we demonstrate that type 2 diabetic patients with peripheral neuropathy and high HbA1c show distinct variations in sural nerve methylome, suggesting that DNA methylation and DPN are associated and that these associations are at least in part HbA1c-dependent. Our results provide new insights into the role of HbA1c in epigenetic variation, and identify candidate genes relevant to the pathogenesis of DPN in human sural nerves of subjects with T2DM. Disclosure K. Guo: None. S. Elzinga: None. S. Eid: None. C. Figueroa-Romero: None. B.A. McGregor: None. G. de Anda-Jáuregui: None. C. Pacut: None. E.L. Feldman: None. J. Hur: None.

Antioxidant therapy of type 2 diabetic peripheral neuropathy

Diabetic peripheral neuropathy (DPN) is a nerve damage caused by chronically high blood glucose and dia-betes. It leads to loss of sensation and sometimes pain in feet, legs and hands. More than 50% of type 2 diabetic patients will develop this complication. To date, the pathogenesis of DPN remains unclear. However, hyperglycemia, metabolic imbal-ance, and oxidative stress appear in the neurons of DPN patients. In addition, oxidative stress results in the change of poly-ADP-ribose polymerase, advanced glycation end products, polyol, protein kinase C, and hexosamine and causes endothelial cell damage and vascular dysfunction, consequently causing peripheral nerve ischemia and hypoxia. According to the oxi-dative stress and related pathways of DPN, some drugs are used in clinical treatment, such as taurine, acetyl-L-carnitine, aldose reductase inhibitors (epalrestat, ranirestat), α-lipoic acid (ALA), protein kinase C inhibitor (ruboxistaurin), inhibitor of poly ADPribose polymerase (nicotinamide), angiotensin-converting enzyme inhibitor (trandolapril), and advanced gly-cation end product inhibitors (aspirin, benfotiamine). However, no drugs can completely cure it. In this review, we sum-marize the pathogenesis of DPN and suggest that amifostine, which is clinically used as an antioxidant, might be used for the treatment of DPN.

Microarray Analysis of Long Noncoding RNAs in Female Diabetic Peripheral Neuropathy Patients

Background/Aims: Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes mellitus (DM). Because of its controversial pathogenesis, DPN is still not diagnosed or managed properly in most patients. Methods: In this study, human lncRNA microarrays were used to identify the differentially expressed lncRNAs in DM and DPN patients, and some of the discovered lncRNAs were further validated in additional 78 samples by quantitative realtime PCR (qRT-PCR). Results: The microarray analysis identified 446 and 1327 differentially expressed lncRNAs in DM and DPN, respectively. The KEGG pathway analysis further revealed that the differentially expressed lncRNA-coexpressed mRNAs between DPN and DM groups were significantly enriched in the MAPK signaling pathway. The lncRNA/mRNA coexpression network indicated that BDNF and TRAF2 correlated with 6 lncRNAs. The qRT-PCR confirmed the initial microarray results. Conclusion: These findings demonstrated that the interplay between lncRNAs and mRNA may be involved in the pathogenesis of DPN, especially the neurotrophin-MAPK signaling pathway, thus providing relevant information for future studies.

Involvement of microRNA-146a in diabetic peripheral neuropathy through the regulation of inflammation.

PurposeRecent evidence has shown the involvement of inflammation in the development of diabetic peripheral neuropathy (DPN). MicroRNA-146a (miR-146a) is closely involved in the inflammatory response. However, the role of miR-146a in the inflammatory reaction in DPN has not been clarified. This study was designed to explore the role of miR-146a in the regulation of inflammatory responses in DPN.MethodsRats were randomly divided into three groups (n=6 per group): control group, type 2 diabetes mellitus (T2DM) group and DPN group. T2DM and DPN rats were intraperitoneally injected with streptozotocin. Sciatic nerve conduction velocity (NCV) was determined at the 6th week and the 12th week in each group. The expression of microRNAs was detected by quantitative real-time polymerase chain reaction in three sciatic nerves for each group of rats. Expression of inflammatory cytokines in nerve tissues and plasma was measured by Western blot and Bio-Plex Pro™ assays.ResultsThe NCV and expression levels of miR-146a in the DPN group were significantly decreased (P<0.01) compared to the other two groups. Expression of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in the DPN group was significantly increased compared with the control and T2DM groups (P<0.01). Pearson’s correlation analysis showed that the expression level of miR-146a was negatively correlated with the levels of IL-1β, TNF-α and NF-κB.ConclusionmiR-146a is involved in the pathogenesis of DPN, and its expression level is closely related to the inflammatory responses that aggravate sciatic nerve injuries.

TRPA1 sensitization during diabetic vascular impairment contributes to cold hypersensitivity in a mouse model of painful diabetic peripheral neuropathy.

BackgroundDiabetic peripheral neuropathy is a common long-term complication of diabetes. Accumulating evidence suggests that vascular impairment plays important roles in the pathogenesis of diabetic peripheral neuropathy, while the mechanism remains unclear. We recently reported that transient receptor potential ankyrin 1 (TRPA1) is sensitized by hypoxia, which can contribute to cold hypersensitivity. In this study, we investigated the involvement of TRPA1 and vascular impairment in painful diabetic peripheral neuropathy using streptozotocin-induced diabetic model mice.ResultsStreptozotocin-induced diabetic model mice showed mechanical and cold hypersensitivity with a peak at two weeks after the streptozotocin administration, which were likely to be paralleled with the decrease in the skin blood flow of the hindpaw. Streptozotocin-induced cold hypersensitivity was significantly inhibited by an antagonist HC-030031 (100 mg/kg) or deficiency for TRPA1, whereas mechanical hypersensitivity was unaltered. Consistent with these results, the nocifensive behaviors evoked by an intraplantar injection of the TRPA1 agonist allyl isothiocyanate (AITC) were enhanced two weeks after the streptozotocin administration. Both streptozotocin-induced cold hypersensitivity and the enhanced AITC-evoked nocifensive behaviors were significantly inhibited by a vasodilator, tadalafil (10 mg/kg), with recovery of the decreased skin blood flow. Similarly, in a mouse model of hindlimb ischemia induced by the ligation of the external iliac artery, AITC-evoked nocifensive behaviors were significantly enhanced three and seven days after the ischemic operation, whereas mechanical hypersensitivity was unaltered in TRPA1-knockout mice. However, no difference was observed between wild-type and TRPA1-knockout mice in the hyposensitivity for current or mechanical stimulation or the deceased density of intraepidermal nerve fibers eight weeks after the streptozotocin administration.ConclusionThese results suggest that TRPA1 sensitization during diabetic vascular impairment causes cold, but not mechanical, hypersensitivity in the early painful phase of diabetic peripheral neuropathy. However, TRPA1 may play little or no role in the progression of diabetic peripheral neuropathy.

Potential utility of aldose reductase-deficient Schwann cells IKARS1 for the study of axonal degeneration and regeneration.

Potential utility of aldose reductase-deficient Schwann cells IKARS1 for the study of axonal degeneration and regeneration.

Application of electrophysiological test in prediabetic peripheral neuropathy

Early diagnosis of prediabetic peripheral neuropathy depends on the evaluation of small fibers. Traditional nerve conduction tests can only evaluate the function of large myelinated fibers, while lack of sensitivity to small fibrous lesions. These lesions were related to pain and autonomic neuropathy. In recent years, with the progress of neurophysiological diagnosis technology, the early diagnosis of diabetic peripheral neuropathy has been improved. Clinical methods, commonly used in the detection of small fibrous lesions, mainly include skin sympathetic response, quantitative sensory test, contact heat pain evoked potential, and quantitative sudomotor axonal reflex test. In this paper, the pathogenesis of diabetic peripheral neuropathy, neurological pathological changes and applications of electrophysiology technology were reviewed to provide an objective basis for early diagnosis of prediabetic peripheral neuropathy. Key words: Electrophysiological test; Prediabetes; Peripheral neuropathy

Mediators of diabetic neuropathy: is hyperglycemia the only culprit?

Diabetic peripheral neuropathy (DPN) is a disabling, highly prevalent complication of both type 1 and type 2 diabetes mellitus (T1DM and T2DM). Large clinical studies support the concept that, in addition to hyperglycemia, components of the metabolic syndrome (MetS) may underlie the pathogenesis of DPN, especially in T2DM. This review will present the evidence supporting the MetS and its individual components as potential causal factors for the development of neuropathy. In addition to poor glycemic control and duration of diabetes, components of MetS such as dyslipidemia, obesity, and hypertension may have an important impact on the prevalence of DPN. Obesity and prediabetes have the most data to support their role in neuropathy, whereas hypertension and dyslipidemia have more mixed results. Nonmetabolic factors, such as genetic susceptibility, age, height, sex, smoking, and alcohol, have also been highlighted as potential risk factors in peripheral neuropathy, although the exact contribution of these factors to DPN remains unknown. DPN is a chronic and disabling disease, and the accurate identification and modification of DPN risk factors is important for clinical management. Recent data support a role for components of the MetS and other risk factors in the development of DPN, offering novel targets beyond hyperglycemia for therapeutic development.

Discussion of acupuncture for diabetic peripheral neuropathy based on blood stasis theory

Based on the understanding of TCM and western medicine on diabetes mellitus (DM) and diabetic peripheral neuropathy (DPN), the relationship between DPN pathogenesis and blood stasis of TCM is discussed from the perspective of modern medicine. It is indicated blood stasis is the key pathogenesis to DPN, and a two-step acupuncture treatment of DPN from the theory of blood stasis is proposed. The first step is to analyze the pathogenesis of blood stasis, which could block the progress of the disease and diminish the symptoms. The second step is to apply acupuncture for pathological result of blood stasis by following the principle of eliminating exogenous pathogen, as a result, the purpose of treating both symptoms and root cause is achieved.

Gene Expression Profiling Identifies Downregulation of the Neurotrophin-MAPK Signaling Pathway in Female Diabetic Peripheral Neuropathy Patients.

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus (DM). It is not diagnosed or managed properly in the majority of patients because its pathogenesis remains controversial. In this study, human whole genome microarrays identified 2898 and 4493 differentially expressed genes (DEGs) in DM and DPN patients, respectively. A further KEGG pathway analysis indicated that DPN and DM share four pathways, including apoptosis, B cell receptor signaling pathway, endocytosis, and Toll-like receptor signaling pathway. The DEGs identified through comparison of DPN and DM were significantly enriched in MAPK signaling pathway, NOD-like receptor signaling pathway, and neurotrophin signaling pathway, while the “neurotrophin-MAPK signaling pathway” was notably downregulated. Seven DEGs from the neurotrophin-MAPK signaling pathway were validated in additional 78 samples, and the results confirmed the initial microarray findings. These findings demonstrated that downregulation of the neurotrophin-MAPK signaling pathway may be the major mechanism of DPN pathogenesis, thus providing a potential approach for DPN treatment.

Altered expression of IRS2 and GRB2 in demyelination of peripheral neurons: Implications in diabetic neuropathy

Demyelination of the peripheral nerves and dysfunction of Schwann cells (SCs) are the chronic complications involved in the development of peripheral neuropathy among diabetic patients. Insulin signaling plays an important role in restoring the myelin proteins in diabetic peripheral neuropathy (DPN). Since insulin levels are altered in diabetes, it becomes of great interest to appreciate the role and regulation of docking and adaptor protein, how these proteins respond to variations in the levels of insulin as experienced in juvenile diabetes. Tyrosine phosphorylation of receptor protein kinases provides a docking site for the activation of adaptor proteins which are the key regulators of insulin signaling pathway. In this report, we studied the long term effect of insulin as a neurotrophic factor and identified the isoform of receptor substrate involved in the propagation of insulin signal in SCs. We also studied the ability of insulin to regulate the expression of different receptor substrates like insulin receptor substrate-1 (IRS1), insulin receptor substrate-2 (IRS2) and growth factor receptor-bound protein-2 (GRB2) that propagate the insulin signaling and also their variation in hyperglycemic SCs and sciatic nerve of the diabetic rats. Results confirmed that IRS2 is the key receptor substrate involved in insulin signal transduction. But, a radical increase in the phosphorylation of IRS2 at serine 731 prevents the recruitment of GRB2 adaptor protein which may fail further to connect the Ras and other pathways required to the cell for its survival and to maintain integrity. These findings prove that SCs and sciatic nerve express IRS proteins that are altered by diabetes and thereby insulin signaling downstream is impaired and that contribute to the pathogenesis of DPN.

Association between small fiber neuropathy and higher skin accumulation of advanced glycation end products in patients with type 1 diabetes.

INTRODUCTION Advanced glycation end products (AGEs) play a crucial role in the pathogenesis of diabetic peripheral neuropathy (DPN). OBJECTIVES The aim of the study was to assess the skin accumulation of AGEs in patients with long‑lasting type 1 diabetes in relation to the presence of DPN. PATIENTS AND METHODS We evaluated 178 patients with type 1 diabetes (99 men; age, 43 years [interquartile range [IQR], 34-54 years]; disease duration, 25 years [IQR, 18-31 years]). DPN was diagnosed if 2 or more of the following 5 abnormalities were present: symptoms of neuropathy, lack of ankle reflexes, and impaired sensation of touch, temperature, and/or vibration. PGP 9.5‑immunoreactive nerve fibers were counted to assess intraepidermal nerve fiber density (IENFD) in skin biopsy. The accumulation of AGEs in the skin was assessed on the basis of skin autofluorescence (AF). RESULTS Patients with DPN (45%), compared with those without neuropathy, had higher skin AF (2.6 AU [IQR, 2.3-3.1 AU] vs 2.1 AU [IQR, 1.8-2.5 AU]; P <0.001) and lower IENFD (10 fibers/mm [IQR, 7-14 fibers/mm] vs 12 fibers/mm [IQR, 8-16 fibers/mm]; P = 0.005). We found a positive correlation between skin AF and patients' age (Rs = 0.44; P <0.001), diabetes duration (Rs = 0.32; P <0.001), and a negative correlation between skin AF and the estimated glomerular filtration rate (Rs = -0.26, P <0.001) and IENFD (Rs = -0.22; P = 0.004). In a multiple linear regression analysis, skin AF was independently associated with age (β = 0.45; P <0.001), glycated hemoglobin level (β = 0.19; P = 0.007), and IENFD (β = - 0.14; P = 0.04) (R2 = 0.27; P <0.001). In multivariate logistic regression, the presence of DPN was independently associated with skin AF (odds ratio, 4.16; 95% confidence interval, 1.88-9.20; P <0.001). CONCLUSIONS The presence of DPN, and particularly small fiber neuropathy, is associated with a higher accumulation of AGEs in the skin of patients with type 1 diabetes.