Diabetic Neuropathy: Models, Mechanisms and Mayhem

ABSTRACT:Rational treatment of diabetic polyneuropathy depends upon establishing its cause, which is at present unknown. A number of animal models of diabetes have been examined and although abnormalities are detectable in the peripheral nervous system they do not duplicate the degenerative neuropathy encountered in the human. The relevance of these abnormalities is therefore uncertain, although they may reflect the earlier changes in man. For human neuropathy, it is likely that vascular lesions or an abnormal susceptibility to mechanical injury are responsible for focal neuropathies. The evidence that ischaemia and hypoxia are responsible for the diffuse sensory neuropathy and autonomic polyneuropathy is still equivocal and it is often difficult to establish whether the vascular changes are primary or secondary. Metabolic explanations, such as sorbitol accumulation in nerve, have not so far been adequately validated by responses to treatment. The manifestations of diabetic neuropathy are complex and a single explanation should not be sought.

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Sympathetic Blocks Provided Sustained Pain Relief in a Patient with Refractory Painful Diabetic Neuropathy

Case Reports in Anesthesiology ◽

10.1155/2012/285328 ◽

2012 ◽

Vol 2012 ◽

pp. 1-5 ◽

Cited By ~ 3

Author(s):

Jianguo Cheng ◽

Anuj Daftari ◽

Lan Zhou

Keyword(s):

Nervous System ◽

Pain Relief ◽

Sympathetic Nervous System ◽

Diabetic Neuropathy ◽

Critical Role ◽

Sensory Neuropathy ◽

Painful Diabetic Neuropathy ◽

Nerve Blocks ◽

Sympathetic Nervous ◽

Sympathetic Blocks

The sympathetic nervous system has been implicated in pain associated with painful diabetic neuropathy. However, therapeutic intervention targeted at the sympathetic nervous system has not been established. We thus tested the hypothesis that sympathetic nerve blocks significantly reduce pain in a patient with painful diabetic neuropathy who has failed multiple pharmacological treatments. The diagnosis of small fiber sensory neuropathy was based on clinical presentations and confirmed by skin biopsies. A series of 9 lumbar sympathetic blocks over a 26-month period provided sustained pain relief in his legs. Additional thoracic paravertebral blocks further provided control of the pain in the trunk which can occasionally be seen in severe diabetic neuropathy cases, consequent to extensive involvement of the intercostal nerves. These blocks provided sustained and significant pain relief and improvement of quality of life over a period of more than two years. We thus provided the first clinical evidence supporting the notion that sympathetic nervous system plays a critical role in painful diabetic neuropathy and sympathetic blocks can be an effective management modality of painful diabetic neuropathy. We concluded that the sympathetic nervous system is a valuable therapeutic target of pharmacological and interventional modalities of treatments in painful diabetic neuropathy patients.

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Clinical and functional status of the peripheral nervous system in patients with diabetic polyneuropathy

East European Journal of Neurology ◽

10.33444/2411-5797.2015.1(1).13-17 ◽

2015 ◽

pp. 13-17

Author(s):

N.K. Svyrydova ◽

Y.V. Ponomarenko ◽

N.V. Terentyeva

Keyword(s):

Type 2 Diabetes ◽

Nervous System ◽

Early Detection ◽

Functional Status ◽

Peripheral Nervous System ◽

Diabetic Polyneuropathy ◽

Patients With Diabetes ◽

Clinical And Functional Status ◽

The Moment

It seems impossible at the moment to stem the incidence of diabetes despite the enormous efforts to address this global problem. We have examined 30 patients with type 2 diabetes to study the clinical and functional status of the peripheral nervous system in patients with diabetic distal polyneuropathy. Our works showed the importance of both clinical and electroneuroneuromiographic examination of patients with diabetes who have or do not have objective manifestations of polyneuropathy. This allows for early detection of the initial effects of polyneuropathy. In patients with symptomatic stage of diabetic polyneuropathy, this method allows to establish the pattern, nature, and severity of lesions of fibers of peripheral nerve trunks.

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High-Fat Diet-Induced Neuropathy of Prediabetes and Obesity: Effect of PMI-5011, an Ethanolic Extract ofArtemisia dracunculusL.

Mediators of Inflammation ◽

10.1155/2010/268547 ◽

2010 ◽

Vol 2010 ◽

pp. 1-10 ◽

Cited By ~ 24

Author(s):

Pierre Watcho ◽

Roman Stavniichuk ◽

David M. Ribnicky ◽

Ilya Raskin ◽

Irina G. Obrosova

Keyword(s):

Nervous System ◽

Peripheral Nervous System ◽

Nerve Conduction ◽

High Fat Diet ◽

Nitrosative Stress ◽

Ethanolic Extract ◽

Sensory Neuropathy ◽

Herbal Remedies ◽

High Fat ◽

Botanical Extract

Artemisiaspecies are a rich source of herbal remedies with antioxidant and anti-inflammatory properties. We evaluated PMI-5011, an ethanolic extract ofArtemisia dracunculusL., on neuropathy in high-sfat diet-fed mice, a model of prediabetes and obesity developing oxidative stress and proinflammatory changes in peripheral nervous system. C57Bl6/J mice fed high-fat diet for 16 weeks developed obesity, moderate nonfasting hyperglycemia, nerve conduction deficit, thermal and mechanical hypoalgesia, and tactile allodynia. They displayed 12/15-lipoxygenase overexpression, 12(S)-hydroxyeicosatetraenoic acid accumulation, and nitrosative stress in peripheral nerve and spinal cord. PMI-5011 (500 mgkg-1d-1, 7 weeks) normalized glycemia, alleviated nerve conduction slowing and sensory neuropathy, and reduced 12/15-lipoxygenase upregulation and nitrated protein expression in peripheral nervous system. PMI-5011, a safe and nontoxic botanical extract, may find use in treatment of neuropathic changes at the earliest stage of disease.

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Large animal models contribute to the development of therapies for central and peripheral nervous system dysfunction in patients with lysosomal storage diseases

Human Molecular Genetics ◽

10.1093/hmg/ddz127 ◽

2019 ◽

Vol 28 (R1) ◽

pp. R119-R131 ◽

Cited By ~ 3

Author(s):

Brittney L Gurda ◽

Charles H Vite

Keyword(s):

Nervous System ◽

Animal Models ◽

Peripheral Nervous System ◽

Neuronal Ceroid Lipofuscinosis ◽

Lysosomal Storage Diseases ◽

Large Animal ◽

Lysosomal Storage ◽

Storage Diseases ◽

Large Animal Models ◽

Biomedical Field

Abstract Lysosomal storage diseases (LSDs) are a group of 70 monogenic disorders characterized by the lysosomal accumulation of a substrate. As a group, LSDs affect ~1 in 5000 live births; however, each individual storage disease is rare, limiting the ability to perform natural history studies or to perform clinical trials. Perhaps in no other biomedical field have naturally occurring large animal (canine, feline, ovine, caprine, and bovine) models been so essential for understanding the fundamentals of disease pathogenesis and for developing safe and effective therapies. These models were critical for the development of hematopoietic stem cell transplantation in α- and β- mannosidosis, fucosidosis, and the mucopolysaccharidoses; enzyme replacement therapy for fucosidosis, the mucopolysaccharidoses, and neuronal ceroid lipofuscinosis; and small molecule therapy in Niemann–Pick type C disease. However, their most notable contributions to the biomedical field are in the development of gene therapy for LSDs. Adeno-associated viral vectors to treat nervous system disease have been evaluated in the large animal models of α-mannosidosis, globoid cell leukodystrophy, GM1 and GM2 gangliosidosis, the mucopolysaccharidoses, and neuronal ceroid lipofuscinosis. This review article will summarize the large animal models available for study as well as their contributions to the development of central and peripheral nervous system dysfunction in LSDs.

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Held Up in Traffic—Defects in the Trafficking Machinery in Charcot-Marie-Tooth Disease

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.695294 ◽

2021 ◽

Vol 14 ◽

Author(s):

Ronja Markworth ◽

Mathias Bähr ◽

Katja Burk

Keyword(s):

Nervous System ◽

Peripheral Nervous System ◽

Intracellular Transport ◽

Early Adulthood ◽

Sensory Neuropathy ◽

Common Denominator ◽

Charcot Marie Tooth ◽

Charcot Marie Tooth Disease ◽

Trafficking Defects ◽

Tooth Disease

Charcot-Marie-Tooth disease (CMT), also known as motor and sensory neuropathy, describes a clinically and genetically heterogenous group of disorders affecting the peripheral nervous system. CMT typically arises in early adulthood and is manifested by progressive loss of motor and sensory functions; however, the mechanisms leading to the pathogenesis are not fully understood. In this review, we discuss disrupted intracellular transport as a common denominator in the pathogenesis of different CMT subtypes. Intracellular transport via the endosomal system is essential for the delivery of lipids, proteins, and organelles bidirectionally to synapses and the soma. As neurons of the peripheral nervous system are amongst the longest neurons in the human body, they are particularly susceptible to damage of the intracellular transport system, leading to a loss in axonal integrity and neuronal death. Interestingly, defects in intracellular transport, both in neurons and Schwann cells, have been found to provoke disease. This review explains the mechanisms of trafficking and subsequently summarizes and discusses the latest findings on how defects in trafficking lead to CMT. A deeper understanding of intracellular trafficking defects in CMT will expand our understanding of CMT pathogenesis and will provide novel approaches for therapeutic treatments.

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The clinical and functional state of peripheral nervous system during the treatment of patients with diabetic polyneuropathy

East European Journal of Neurology ◽

10.33444/2411-5797.2015.1(1).30-32 ◽

2015 ◽

pp. 30-32

Author(s):

N.V. Terentyeva ◽

N.K. Svyrydova ◽

Y.V. Ponomarenko

Keyword(s):

Type 2 Diabetes ◽

Nervous System ◽

Peripheral Nervous System ◽

Diabetic Polyneuropathy ◽

Improve Treatment ◽

Treat Ment ◽

Objective Evidence ◽

Patients With Diabetes ◽

Clinical And Functional Status

The state of the peripheral nervous system and treat- ment of patients with diabetic polyneuropathy is global problem. To study the clinical and functional status of the peripheral nervous system in patients with diabetic distal polyneuropathy we have examined 30 patients with type 2 diabetes. Our research showed the importance of both clinical and electroneuromyographic examination for patients with diabetes who may have or do not to have objective evidence of polyneuropathy. This allows for early detection of initial effects of polyneuropathy and improve treatment tactics.

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Dynamics of global gene expression and chromatin accessibility of the peripheral nervous system in animal models of persistent pain

10.1101/2021.01.27.427793 ◽

2021 ◽

Author(s):

Kimberly E. Stephens ◽

Weiqiang Zhou ◽

Zachary Renfro ◽

Zhicheng Ji ◽

Hongkai Ji ◽

...

Keyword(s):

Gene Expression ◽

Chronic Pain ◽

Nervous System ◽

Animal Models ◽

Sciatic Nerve ◽

Peripheral Nervous System ◽

Dna Sequences ◽

Chromatin Accessibility ◽

Persistent Pain ◽

Rna Seq

AbstractEfforts to understand genetic variability involved in an individual’s susceptibility to chronic pain support a role for upstream regulation by epigenetic mechanisms. To examine the transcriptomic and epigenetic basis of chronic pain that resides in the peripheral nervous system, we used RNA-seq and ATAC-seq of the rat dorsal root ganglion (DRG) to identify novel molecular pathways associated with pain hypersensitivity in two well-studied persistent pain models induced by Chronic Constriction Injury (CCI) of the sciatic nerve and intra-plantar injection of Complete Freund’s Adjuvant (CFA) in rats. Our RNA-seq studies identify a variety of biological process related to synapse organization, membrane potential, transmembrane transport, and ion binding. Interestingly, genes that encode transcriptional regulators were disproportionately downregulated in both models. Our ATAC-seq data provide a comprehensive map of chromatin accessibility changes in the DRG. A total of 1123 regions showed changes in chromatin accessibility in one or both models when compared to the naïve and 31 shared differentially accessible regions (DAR)s. Functional annotation of the DARs identified disparate molecular functions enriched for each pain model which suggests that chromatin structure may be altered differently following sciatic nerve injury and hind paw inflammation. Motif analysis identified 17 DNA sequences known to bind transcription factors in the CCI DARs and 33 in the CFA DARs. Two motifs were significantly enriched in both models. Our improved understanding of the changes in chromatin accessibility that occur in chronic pain states may identify regulatory genomic elements that play essential roles in modulating gene expression in the DRG.SummaryShared transcriptomic and epigenetic changes in two animal models improves our understanding of how chromatin structural changes alter DRG gene expression under persistent pain conditions.

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Clinical aspects of B vitamin use

Russian Medical Inquiry ◽

10.32364/2587-6821-2021-5-9-579-585 ◽

2021 ◽

Vol 5 (9) ◽

pp. 579-585

Author(s):

E.V. Biryukova ◽

◽

M.V. Shinkin ◽

Keyword(s):

Nervous System ◽

Diabetic Neuropathy ◽

Peripheral Nerve ◽

Peripheral Nervous System ◽

Nerve Fibers ◽

B Vitamins ◽

Clinical Aspects ◽

Vegetative Nervous System ◽

High Blood Glucose ◽

B Vitamin

Polyneuropathy is a common disorder of the peripheral nervous system. Diabetic neuropathy is the most common and most studied variant of polyneuropathies. The duration of carbohydrate metabolism disorders and inadequate glycemic control are risk factors for nervous system damage in diabetes. Distal neuropathy is a common type of neuropathy associated with diabetes. Interconnecting pathological mechanisms initiated by high blood glucose result in the damage of peripheral nerve fibers. Clinical presentations of distal neuropathy depend on the damage of proximal or distal and sensory or motor nerve fibers and the involvement of the vegetative nervous system. Medications improving metabolic processes in nerve fibers and reducing the severity of peripheral nerve damage are beneficial in addressing the harmful effects of hyperglycemia. Neurometabolic therapy includes thiamine, pyridoxine, and cyanocobalamin (B vitamins) which provide neurotropic effects. B vitamins acting as co-factors in many enzymatic reactions significantly affect the normal functioning of nerve fibers. B vitamins are effective and safe agents used to treat peripheral nervous system diseases for many years. This paper discusses the potential use of B vitamins for diabetic neuropathy and the COVID-19 treatment and rehabilitation. KEYWORDS: polyneuropathy, hyperglycemia, diabetes, distal neuropathy, B vitamins, thiamine, pyridoxine, cyanocobalamin, COVID-19. FOR CITATION: Biryukova E.V., Shinkin M.V. Clinical aspects of B vitamin use. Russian Medical Inquiry. 2021;5(9):579–585 (in Russ.). DOI: 10.32364/2587-6821-2021-5-9-579-585.

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