Diabetic Peripheral Neuropathy: Diagnosis and Treatment.
Røikjer Johan,Mørch Carsten Dahl,Ejskjaer Niels
Current drug safety
BACKGROUND:Diabetic peripheral neuropathy (DPN) is traditionally divided into large and small fibre neuropathy (SFN). Damage to the large fibres can be detected using nerve conduction studies (NCS) and often results in a significant reduction in sensitivity and loss of protective sensation, while damage to the small fibres is hard to reliably detect and can be either asymptomatic, associated with insensitivity to noxious stimuli, or often manifests itself as intractable neuropathic pain. OBJECTIVE:To describe the recent advances in both detection, grading, and treatment of DPN as well as the accompanying neuropathic pain. METHODS:A review of relevant, peer-reviewed, English literature from MEDLINE, EMBASE and Cochrane Library between January 1st 1967 and January 1st 2020 was used. RESULTS:We identified more than three hundred studies on methods for detecting and grading DPN, and more than eighty randomised-controlled trials for treating painful diabetic neuropathy. CONCLUSION:NCS remains the method of choice for detecting LFN in people with diabetes, while a gold standard for the detection of SFN is yet to be internationally accepted. In the recent years, several methods with huge potential for detecting and grading this condition have become available including skin biopsies and corneal confocal microscopy, which in the future could represent reliable endpoints for clinical studies. While several newer methods for detecting SFN have been developed, no new drugs have been accepted for treating neuropathic pain in people with diabetes. Tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors and anticonvulsants remain first line treatment, while newer agents targeting the proposed pathophysiology of DPN are being developed.
10.2174/1574886315666200731173113
Low-Dose Pulsatile Interleukin-6 As a Treatment Option for Diabetic Peripheral Neuropathy.
Cox April Ann,Sagot Yves,Hedou Gael,Grek Christina,Wilkes Travis,Vinik Aaron I,Ghatnekar Gautam
Frontiers in endocrinology
Diabetic peripheral neuropathy (DPN) remains one of the most common and serious complications of diabetes. Currently, pharmacological agents are limited to treating the pain associated with DPN, and do not address the underlying pathological mechanisms driving nerve damage, thus leaving a significant unmet medical need. Interestingly, research conducted using exercise as a treatment for DPN has revealed interleukin-6 (IL-6) signaling to be associated with many positive benefits such as enhanced blood flow and lipid metabolism, decreased chronic inflammation, and peripheral nerve fiber regeneration. IL-6, once known solely as a pro-inflammatory cytokine, is now understood to signal as a multifunctional cytokine, capable of eliciting both pro- and anti-inflammatory responses in a context-dependent fashion. IL-6 released from muscle in response to exercise signals as a myokine and as such has a unique kinetic profile, whereby levels are transiently elevated up to 100-fold and return to baseline levels within 4 h. Importantly, this kinetic profile is in stark contrast to long-term IL-6 elevation that is associated with pro-inflammatory states. Given exercise induces IL-6 myokine signaling, and exercise has been shown to elicit numerous beneficial effects for the treatment of DPN, a causal link has been suggested. Here, we discuss both the clinical and preclinical literature related to the application of IL-6 as a treatment strategy for DPN. In addition, we discuss how IL-6 may directly modulate Schwann and nerve cells to explore a mechanistic understanding of how this treatment elicits a neuroprotective and/or regenerative response. Collectively, studies suggest that IL-6, when administered in a low-dose pulsatile strategy to mimic the body's natural response to exercise, may prove to be an effective treatment for the protection and/or restoration of peripheral nerve function in DPN. This review highlights the studies supporting this assertion and provides rationale for continued investigation of IL-6 for the treatment of DPN.
10.3389/fendo.2017.00089
Expression of Nrf2 Promotes Schwann Cell-Mediated Sciatic Nerve Recovery in Diabetic Peripheral Neuropathy.
Tang Wei,Chen Xiangfang,Liu Haoqi,Lv Qian,Zou Junjie,Shi Yongquan,Liu Zhimin
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
BACKGROUND/AIMS:High glucose-induced oxidative stress and inflammatory responses play an important role in painful diabetic neuropathy by activating the TLR4/NFκB signal pathway. Schwann cells (SCs) are integral to peripheral nerve biology, contributing to saltatory conduction along axons, nerve and axon development, and axonal regeneration. SCs provide a microenvironment favoring vascular regeneration but their low survival ratio in hyperglycemic conditions suppress the function to promote nerve growth. Nuclear factor erythroid 2-related factor 2 (Nrf2) promotes remyelination after peripheral nerve injury. The aim of this study was to identify the role of Nrf2 in SC-mediated functional recovery after sciatic nerve injury. METHODS:We compared plasma inflammatory factors in diabetic patients (DN) with/without diabetic peripheral neuropathy (DPN) and assessed whether Nrf2 expression in SCs could repair peripheral nerve injury in a rat model. Nrf2, TLR4/NFκB signal pathway and apoptosis relative protein expression were detected by western blot. Apoptosis and angiogenesis were determined by immunofluorescence and tubule formation assay, respectively. Regenerated nerves were determined by transmission electron microscope. RESULTS:Higher levels of inflammatory factors and VEGF expression were found in DPN patients. Cellular experiments indicate that Nrf2 expression inhibits hyperglycemia-induced apoptosis and promotes angiogenesis by regulating the TLR4/NFκB signal pathway. Animal experiments show that nerve conduction velocity, myelin sheath thickness, and sciatic vasa nervorum are restored with transplantation of SCs overexpressing Nrf2. CONCLUSIONS:Taken together, the high survival ratio of SCs in a DPN rat model indicates that overexpression of Nrf2 restores nerve injury.
10.1159/000489373
[Research Advances in Autophagy and Diabetic Neuropathy].
Xie Jun,Qu Ling,Liang Xiao Chun
Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae
Recent studies have found that autophagy is involved in the development of many chronic complications of diabetes. However,the specific mechanism between autophagy and diabetic neuropathy(DN)remains unclear. This article reviews the latest research on the pathogenesis of autophagy and DN,with an attempt to find new targets and ideas for the treatment of DN.
10.3881/j.issn.1000-503X.10394
MEDICAL BASIS OF DIABETIC NEUROPATHY FORMATION (REVIEW).
Archvadze A,Kistauri A,Gongadze N,Makharadze T,Chirakadze K
Georgian medical news
Nowadays, chronic diseases are leading cause of death worldwide. One of popular chronic disease of 21 century is Diabetes Mellitus (DM) that affected 422 million people around the world in 2014; its prevalence is expected to increase to 592 million by the year 2035. Diabetic neuropathy (DN) seems to be the most common and least understood complication being present in over 50% of chronic diabetics. As the latest date explain the pathogenesis of DN is not fully understood. Therefore, considering the widespread of DN, severity of its consequences, it is vital to investigate details of its pathophysiology and find therapeutic strategies to improve patients' condition. Generally two mechanisms have been suggested to be involved in the pathogenesis of diabetic neuropathy. The first mechanism is the activation of the Renin Angiotensin Aldosterone System (RAAS) in the presence of hyperglycemia with increased tissue level of Angiotenzin II (Ang II). Ang II stimulates Nicotin Adenine Dinucleotide (Phosphate) (NAD (P)) oxidase which enhances oxidative stress and vascular damage and leading to DN. The other mechanism is linked with disturbance in the metabolism and vasculature of nerve tissue in the presence of excessive uptake of glucose. Conclusion: In our review we have discussed different mechanisms involved in formation of DM and DN. Based on the latest research studies the main component in the big picture of DN formation is hyperglycemia.The list of mechanisms are associated with high glucose level leading inflammation, oxidative stress, hypoxia and apoptosis through the activation of several pathogenic pathways induced by Tumor Necrosis Factor alfa (TNFa), AgII, (pro)renin, Protein Kinase C (PKC), glycolysis intermediated products, Cyclooxygenase 2 (COX2) and reactive nitrogen species (RNS). Therefore to use drugs linked with above discussed pathological processes would be effective solution in the treatment of DM and its complications.
Diabetic Neuropathy: Update on Pathophysiological Mechanism and the Possible Involvement of Glutamate Pathways.
Hussain Nadia,Adrian Thomas E
Current diabetes reviews
INTRODUCTION:Diabetic neuropathy is a common complication of diabetes. It adversely affects the lives of most diabetics. It is the leading cause of non-traumatic limb amputation. Diabetic autonomic neuropathy can target any system and increases morbidity and mortality. Treatment begins with adequate glycemic control but despite this, many patients go on to develop neuropathy which suggests there are additional and unidentified, as yet, pathological mechanisms in place. Although several theories exist, the exact mechanisms are not yet established. Disease modifying treatment requires a more complete understanding of the mechanisms of disease. Pathways Involved: This review discusses the potential pathological mechanisms of diabetic neuropathy, including the polyol pathway, hexosamine pathway, protein kinase C, advanced glycation end product formation, polyADP ribose polymerase, and the role of oxidative stress, inflammation, growth factors and lipid abnormalities. Finally it focuses on how possible changes in glutamate signaling pathways fit into the current theories. CONCLUSION:Insights into the mechanisms involving gene expression in diabetic neuropathy can help pinpoint genes with altered expression. This will help in the development of novel alternative therapeutic strategies to significantly slow the progression of neuropathy in susceptible individuals and perhaps even prevention.
10.2174/1573399812666160624122605
Increased ATP and ADO Overflow From Sympathetic Nerve Endings and Mesentery Endothelial Cells Plus Reduced Nitric Oxide Are Involved in Diabetic Neurovascular Dysfunction.
Frontiers in pharmacology
Since the mechanism of human diabetic peripheral neuropathy and vascular disease in type 1 diabetes mellitus remains unknown, we assessed whether sympathetic transmitter overflow is altered by this disease and associated to vascular dysfunction. Diabetes was induced by streptozotocin (STZ)-treatment and compared to vehicle-treated rats. Aliquots of the perfused rat arterial mesenteric preparation, denuded of the endothelial layer, were collected to quantify analytically sympathetic nerve co-transmitters overflow secreted by the isolated mesenteries of both groups of rats. Noradrenaline (NA), neuropeptide tyrosine (NPY), and ATP/metabolites were detected before, during, and after electrical field stimulation (EFS, 20 Hz) of the nerve terminals surrounding the mesenteric artery. NA overflow was comparable in both groups; however, basal or EFS-secreted ir-NPY was 26% reduced ( < 0.05) in diabetics. Basal and EFS-evoked ATP and adenosine (ADO) overflow to the arterial mesentery perfusate increased twofold and was longer lasting in diabetics; purine tissue content was 37.8% increased ( < 0.05) in the mesenteries from STZ-treated group of rats. Perfusion of the arterial mesentery vascular territory with 100 μM ATP, 100 nM 2-MeSADP, or 1 μM UTP elicited vasodilator responses of the same magnitude in controls or diabetics, but the increase in luminally accessible NO was 60-70% lower in diabetics ( < 0.05). Moreover, the concentration-response curve elicited by two NO donors was displaced downwards ( < 0.01) in diabetic rats. Parallel studies using primary cultures of endothelial cells from the arterial mesentery vasculature revealed that mechanical stimulation induced a rise in extracellular nucleotides, which in the cells from diabetic rats was larger and longer-lasting when comparing the extracellular release of ATP and ADO values to those of vehicle-treated controls. A 5 min challenge with purinergic agonists elicited a cell media NO rise, which was reduced in the endothelial cells from diabetic rats. Present findings provide neurochemical support for the diabetes-induced neuropathy and show that mesenteric endothelial cells alterations in response to mechanical stimulation are compatible with the endothelial dysfunction related to vascular disease progress.
10.3389/fphar.2018.00546
Molecular mechanism of diabetic neuropathy and its pharmacotherapeutic targets.
Dewanjee Saikat,Das Sonjit,Das Anup Kumar,Bhattacharjee Niloy,Dihingia Anjum,Dua Tarun K,Kalita Jatin,Manna Prasenjit
European journal of pharmacology
Diabetic neuropathy is regarded as one of the most debilitating outcomes of diabetes mellitus and may cause pain, decreased motility, and even amputation. Diabetic neuropathy includes multiple forms, ranging from discomfort to death. Prognosis of diabetic neuropathy is an uphill task as it remains silent for several years after the onset of diabetes. Hyperglycemia, apart from inducing oxidative stress in neurons, also leads to activation of multiple biochemical pathways which constitute the major source of damage and are potential therapeutic targets in diabetic neuropathy. A vast array of molecular pathways, including polyol pathway, hexosamine pathway, PKCs signaling, oxidative stress, AGEs pathway, PARP pathway, MAPK pathway, NF-κB signaling, hedgehog pathways, TNF-α signaling, cyclooxygenase pathway, interleukins, lipoxygenase pathway, nerve growth factor, Wnt pathway, autophagy, and GSK3 signaling may be accounted for the pathogenesis and progression of diabetic neuropathy. Although symptomatic treatment is available for diabetic neuropathy, few treatment options are available to eliminate the root cause. The immense physical, psychological, and economic burden of diabetic neuropathy highlights the need for cost effective and targeted therapies. The main aim of this review is to highlight the putative role of various mechanisms and pathways involved in the development of diabetic neuropathy and to impart an in-depth insight on new therapeutic approaches aimed at delaying or reversing various modalities of diabetic neuropathy.
10.1016/j.ejphar.2018.06.034
New Horizons in Diabetic Neuropathy: Mechanisms, Bioenergetics, and Pain.
Feldman Eva L,Nave Klaus-Armin,Jensen Troels S,Bennett David L H
Neuron
Pre-diabetes and diabetes are a global epidemic, and the associated neuropathic complications create a substantial burden on both the afflicted patients and society as a whole. Given the enormity of the problem and the lack of effective therapies, there is a pressing need to understand the mechanisms underlying diabetic neuropathy (DN). In this review, we present the structural components of the peripheral nervous system that underlie its susceptibility to metabolic insults and then discuss the pathways that contribute to peripheral nerve injury in DN. We also discuss systems biology insights gleaned from the recent advances in biotechnology and bioinformatics, emerging ideas centered on the axon-Schwann cell relationship and associated bioenergetic crosstalk, and the rapid expansion of our knowledge of the mechanisms contributing to neuropathic pain in diabetes. These recent advances in our understanding of DN pathogenesis are paving the way for critical mechanism-based therapy development.
10.1016/j.neuron.2017.02.005
Gene expression profiling reveals candidate biomarkers and probable molecular mechanism in diabetic peripheral neuropathy.
Diabetes, metabolic syndrome and obesity : targets and therapy
PURPOSE:To investigate the molecular mechanism and search for candidate biomarkers in the gene expression profile of patients with diabetic peripheral neuropathy (DPN). METHODS:Differentially expressed genes (DEGs) of progressive vs non-progressive DPN patients in dataset GSE24290 were screened. Functional enrichment analysis was conducted, and hub genes were extracted from the protein-protein interaction network. The expression level of hub genes in serum samples in another dataset GSE95849 was obtained, followed by the ROC curve analysis. RESULTS:A total of 352 DEGs were obtained from dataset GSE24290. They were involved in 14 gene ontology terms and 10 Kyoto Encyclopedia of Genes and Genomes pathways, mainly related to lipid metabolism. Eight hub genes (LEP, APOE, ADIPOQ, FABP4, CD36, GPAM, CIDEC, and PNPLA4) were revealed, and their expression level was obtained in dataset GSE95849. The receiver operating characteristic curve analysis indicated that CIDEC (AUC=1), APOE (AUC=0.833), CD36 (AUC=0.803), and PNPLA4 (AUC=0.861) might be candidate serum biomarkers of DPN. CONCLUSION:Lipid metabolism of Schwann cells might be inhibited in progressive DPN. CIDEC, APOE, CD36, and PNPLA4 might be potential predictive biomarkers in the early DPN diagnosis of patients with DM.
10.2147/DMSO.S209118
Effects of Mitochondrial Dysfunction via AMPK/PGC-1 α Signal Pathway on Pathogenic Mechanism of Diabetic Peripheral Neuropathy and the Protective Effects of Chinese Medicine.
Zhang Qian,Liang Xiao-Chun
Chinese journal of integrative medicine
Diabetic peripheral neuropathy (DPN) is a progressive neurodegenerative disease of peripheral nervous system with high energy requirement. The adenosine monophosphate-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor- γ coactivator 1 α (PGC-1 α) axis plays a key role in regulating mitochondrial energy metabolism. Increasing preclinical evidences have shown that inhibition of AMPK/PGC-1 α pathway leading to mitochondrial dysfunction in neurons or Schwann cells contributes to neuron apoptosis, distal axonopathy and nerve demyelination in DPN. Some Chinese medicine formulae or extracts from herbs may have potential neuroprotective effects on DPN via activating AMPK/PGC-1 α pathway and improving mitochondrial function.
10.1007/s11655-018-2579-0
The mechanisms of glycemic variability accelerate diabetic central neuropathy and diabetic peripheral neuropathy in diabetic rats.
Yang Junpeng,Zhao Zhigang,Yuan Huijuan,Ma Xiangxiang,Li Yakun,Wang Huimeng,Ma Xiaojun,Qin Guijun
Biochemical and biophysical research communications
The effect of glycemic variability (GV) on diabetic neuropathy, including diabetic central neuropathy and diabetic peripheral neuropathy (DPN), and the involved mechanism are not fully understood. In this study, a fluctuant hyperglycemia rat model was induced by alternate intraperitoneal injections of glucose and insulin. To assess diabetic central neuropathy, step-down type passive avoidance tests were conducted, and the expression levels of p-Tau, T-Tau, p-GSK3β, GSK3β, p-Akt, and Akt in the hippocampus were measured. To assess DPN, the motor nerve conduction velocity (MNCV) was measured, and the microstructure of the sciatic nerve was observed. Additionally, the expression levels of oxidative stress and inflammation indicators were detected in the sciatic nerve. We observed that both learning and memory abilities were disrupted by GV. GV promoted Tau phosphorylation and inhibited the Akt/GSK3β pathway in the hippocampus. Additionally, GV weakened the MNCV of the sciatic nerve, and the structures of both the myelin sheath and the axons in the sciatic nerve were disrupted. GV also significantly reduced the expression of superoxide dismutase (SOD) and increased the expression levels of malondialdehyde (MDA), of proinflammatory cytokines (TNF-α and IL-6) and of NF-κB. In conclusion, the present study highlighted that GV might induce diabetic central neuropathy through the hyperphosphorylation of Tau in the hippocampus by inhibiting the Akt/GSK3β pathway and that it may cause DPN through oxidative stress and inflammatory responses by activating the NF-κB pathway.
10.1016/j.bbrc.2018.12.179
TRPA1 sensitization during diabetic vascular impairment contributes to cold hypersensitivity in a mouse model of painful diabetic peripheral neuropathy.
Hiyama Haruka,Yano Yuichi,So Kanako,Imai Satoshi,Nagayasu Kazuki,Shirakawa Hisashi,Nakagawa Takayuki,Kaneko Shuji
Molecular pain
Background Diabetic 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. Results Streptozotocin-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. Conclusion These 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.
10.1177/1744806918789812
Gene Expression Profiling Identifies Downregulation of the Neurotrophin-MAPK Signaling Pathway in Female Diabetic Peripheral Neuropathy Patients.
Luo Lin,Zhou Wen-Hua,Cai Jiang-Jia,Feng Mei,Zhou Mi,Hu Su-Pei,Xu Jin,Ji Lin-Dan
Journal of diabetes research
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.
10.1155/2017/8103904
Understanding the Signaling Pathways Related to the Mechanism and Treatment of Diabetic Peripheral Neuropathy.
Tang He-Yong,Jiang Ai-Juan,Ma Jun-Long,Wang Fan-Jing,Shen Guo-Ming
Endocrinology
Worldwide, the most prevalent metabolic disorder is diabetes mellitus (DM), an important condition that has been widely studied. Diabetic peripheral neuropathy (DPN), a complication that can occur with DM, is associated with pain and can result in foot ulcers and even amputation. DPN treatments are limited and mainly focus on pain management. There is a clear need to develop treatments for DPN at all stages. To make this progress, it is necessary to understand the molecular signaling pathways related to DPN. For this review, we aimed to concentrate on the main signaling cascades that contribute to DPN. In addition, we provide information with regard to treatments that are being explored.
10.1210/en.2019-00311