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Pathogenesis and Molecular Treatment Strategies of Diabetic Neuropathy 2.0
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Pathogenesis and Molecular Treatment Strategies of Diabetic Neuropathy 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 October 2022) | Viewed by 31421

Special Issue Editor

Dr. Kazunori Sango

E-Mail Website
Guest Editor
Department of Diseases and Infection, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
Interests: diabetic neuropathy; drug-induced neuropathies; dorsal root ganglia; axon-Schwann cell interplay; demyelination
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Diabetic peripheral neuropathy (DPN), one of the major chronic complications of diabetes mellitus, is characterized by nerve-length-dependent depletion of peripheral sensory, motor, and autonomic nerve fibers, and its progression can result in serious consequences such as lower limb amputation and lethal arrhythmia. It is recognized that both metabolic and microvascular abnormalities are involved in the development of DPN, but no effective therapies have yet been established. The aim of this Special Issue is to introduce molecular mechanisms of how hyperglycemia and impaired insulin actions lead to DPN, as well as therapeutic strategies based on those mechanisms.

Topics of this Special Issue include, but are not limited to:

  • Collateral glucose-utilizing pathways (polyol pathway, hexosamine pathway, protein kinase C pathway, and AGEs pathway);
  • Oxidative stress and ER stress;
  • Impaired actions of neurotrophic molecules;
  • Microinflammation;
  • Microvasculature and blood–nerve barrier;
  • Genomic, proteomic, and metabolomic databases and applications;
  • Therapeutic approaches utilizing cell transplantation.

Dr. Kazunori Sango
Guest Editor

Manuscript Submission Information

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Keywords

  • diabetic neuropathy
  • pathogenetic factors
  • therapeutic approaches
  • collateral glucose-utilizing pathways
  • oxidative stress
  • neurotrophic factors
  • microinflammation
  • microvasculature
  • metabolomics
  • cell transplantation

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Published Papers (6 papers)

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Research

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12 pages, 2098 KiB  
Article
SMTP-44D Exerts Antioxidant and Anti-Inflammatory Effects through Its Soluble Epoxide Hydrolase Inhibitory Action in Immortalized Mouse Schwann Cells upon High Glucose Treatment
by Ryosuke Shinouchi, Keita Shibata, Shiori Jono, Keiji Hasumi and Koji Nobe
Int. J. Mol. Sci. 2022, 23(9), 5187; https://doi.org/10.3390/ijms23095187 - 6 May 2022
Cited by 4 | Viewed by 2092
Abstract
Diabetic neuropathy (DN) is a major complication of diabetes mellitus. We have previously reported the efficacy of Stachybotrys microspora triprenyl phenol-44D (SMTP-44D) for DN through its potential antioxidant and anti-inflammatory activities. However, the mechanisms underlying the antioxidant and anti-inflammatory activities of SMTP-44D remain [...] Read more.
Diabetic neuropathy (DN) is a major complication of diabetes mellitus. We have previously reported the efficacy of Stachybotrys microspora triprenyl phenol-44D (SMTP-44D) for DN through its potential antioxidant and anti-inflammatory activities. However, the mechanisms underlying the antioxidant and anti-inflammatory activities of SMTP-44D remain unclear. The present study aimed to explore the mechanism of these effects of SMTP-44D in regard to its inhibition of soluble epoxide hydrolase (sEH) in immortalized mouse Schwann cells (IMS32) following high glucose treatment. IMS32 cells were incubated in a high glucose medium for 48 h and then treated with SMTP-44D for 48 h. After incubation, the ratio of epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), oxidative stress markers, such as NADPH oxidase-1 and malondialdehyde, inflammatory factors, such as the ratio of nuclear to cytosolic levels of NF-κB and the levels of IL-6, MCP-1, MMP-9, the receptor for the advanced glycation end product (RAGE), and apoptosis, were evaluated. SMTP-44D treatment considerably increased the ratio of EETs to DHETs and mitigated oxidative stress, inflammation, RAGE induction, and apoptosis after high glucose treatment. In conclusion, SMTP-44D can suppress the induction of apoptosis by exerting antioxidant and anti-inflammatory effects, possibly through sEH inhibition. SMTP-44D can be a potential therapeutic agent against DN. Full article
(This article belongs to the Special Issue Pathogenesis and Molecular Treatment Strategies of Diabetic Neuropathy 2.0)
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13 pages, 3160 KiB  
Article
Docosahexaenoic Acid Suppresses Oxidative Stress-Induced Autophagy and Cell Death via the AMPK-Dependent Signaling Pathway in Immortalized Fischer Rat Schwann Cells 1
by Yasuaki Tatsumi, Ayako Kato, Naoko Niimi, Hideji Yako, Tatsuhito Himeno, Masaki Kondo, Shin Tsunekawa, Yoshiro Kato, Hideki Kamiya, Jiro Nakamura, Koji Higai, Kazunori Sango and Koichi Kato
Int. J. Mol. Sci. 2022, 23(8), 4405; https://doi.org/10.3390/ijms23084405 - 15 Apr 2022
Cited by 8 | Viewed by 3090
Abstract
Autophagy is the process by which intracellular components are degraded by lysosomes. It is also activated by oxidative stress; hence, autophagy is thought to be closely related to oxidative stress, one of the major causes of diabetic neuropathy. We previously reported that docosahexaenoic [...] Read more.
Autophagy is the process by which intracellular components are degraded by lysosomes. It is also activated by oxidative stress; hence, autophagy is thought to be closely related to oxidative stress, one of the major causes of diabetic neuropathy. We previously reported that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) induced antioxidant enzymes and protected Schwann cells from oxidative stress. However, the relationship between autophagy and oxidative stress-induced cell death in diabetic neuropathy has not been elucidated. Treatment with tert-butyl hydroperoxide (tBHP) decreased the cell survival rate, as measured by an MTT assay in immortalized Fischer rat Schwann cells 1 (IFRS1). A DHA pretreatment significantly prevented tBHP-induced cytotoxicity. tBHP increased autophagy, which was revealed by the ratio of the initiation markers, AMP-activated protein kinase, and UNC51-like kinase phosphorylation. Conversely, the DHA pretreatment suppressed excessive tBHP-induced autophagy signaling. Autophagosomes induced by tBHP in IFRS1 cells were decreased to control levels by the DHA pretreatment whereas autolysosomes were only partially decreased. These results suggest that DHA attenuated excessive autophagy induced by oxidative stress in Schwann cells and may be useful to prevent or reduce cell death in vitro. However, its potentiality to treat diabetic neuropathy must be validated in in vivo studies. Full article
(This article belongs to the Special Issue Pathogenesis and Molecular Treatment Strategies of Diabetic Neuropathy 2.0)
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11 pages, 2150 KiB  
Article
Functional and Structural Changes in the Corticospinal Tract of Streptozotocin-Induced Diabetic Rats
by Ken Muramatsu, Satoshi Shimo, Toru Tamaki, Masako Ikutomo and Masatoshi Niwa
Int. J. Mol. Sci. 2021, 22(18), 10123; https://doi.org/10.3390/ijms221810123 - 19 Sep 2021
Cited by 4 | Viewed by 2738
Abstract
This study aimed to reveal functional and morphological changes in the corticospinal tract, a pathway shown to be susceptible to diabetes. Type 1 diabetes was induced in 13-week-old male Wistar rats administered streptozotocin. Twenty-three weeks after streptozotocin injection, diabetic animals and age-matched control [...] Read more.
This study aimed to reveal functional and morphological changes in the corticospinal tract, a pathway shown to be susceptible to diabetes. Type 1 diabetes was induced in 13-week-old male Wistar rats administered streptozotocin. Twenty-three weeks after streptozotocin injection, diabetic animals and age-matched control animals were used to demonstrate the conduction velocity of the corticospinal tract. Other animals were used for morphometric analyses of the base of the dorsal funiculus of the corticospinal tract in the spinal cord using both optical and electron microscopy. The conduction velocity of the corticospinal tract decreased in the lumbar spinal cord in the diabetic animal, although it did not decrease in the cervical spinal cord. Furthermore, atrophy of the fibers of the base of the dorsal funiculus was observed along their entire length, with an increase in the g-ratio in the lumbar spinal cord in the diabetic animal. This study indicates that the corticospinal tract fibers projecting to the lumbar spinal cord experience a decrease in conduction velocity at the lumbar spinal cord of these axons in diabetic animals, likely caused by a combination of axonal atrophy and an increased g-ratio due to thinning of the myelin sheath. Full article
(This article belongs to the Special Issue Pathogenesis and Molecular Treatment Strategies of Diabetic Neuropathy 2.0)
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Review

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16 pages, 3289 KiB  
Review
Diabetic Polyneuropathy: New Strategies to Target Sensory Neurons in Dorsal Root Ganglia
by Akiko Miyashita, Masaki Kobayashi, Takanori Yokota and Douglas W. Zochodne
Int. J. Mol. Sci. 2023, 24(6), 5977; https://doi.org/10.3390/ijms24065977 - 22 Mar 2023
Cited by 9 | Viewed by 3587
Abstract
Diabetic polyneuropathy (DPN) is the most common type of diabetic neuropathy, rendering a slowly progressive, symmetrical, and length-dependent dying-back axonopathy with preferential sensory involvement. Although the pathogenesis of DPN is complex, this review emphasizes the concept that hyperglycemia and metabolic stressors directly target [...] Read more.
Diabetic polyneuropathy (DPN) is the most common type of diabetic neuropathy, rendering a slowly progressive, symmetrical, and length-dependent dying-back axonopathy with preferential sensory involvement. Although the pathogenesis of DPN is complex, this review emphasizes the concept that hyperglycemia and metabolic stressors directly target sensory neurons in the dorsal root ganglia (DRG), leading to distal axonal degeneration. In this context, we discuss the role for DRG-targeting gene delivery, specifically oligonucleotide therapeutics for DPN. Molecules including insulin, GLP-1, PTEN, HSP27, RAGE, CWC22, and DUSP1 that impact neurotrophic signal transduction (for example, phosphatidylinositol-3 kinase/phosphorylated protein kinase B [PI3/pAkt] signaling) and other cellular networks may promote regeneration. Regenerative strategies may be essential in maintaining axon integrity during ongoing degeneration in diabetes mellitus (DM). We discuss specific new findings that relate to sensory neuron function in DM associated with abnormal dynamics of nuclear bodies such as Cajal bodies and nuclear speckles in which mRNA transcription and post-transcriptional processing occur. Manipulating noncoding RNAs such as microRNA and long-noncoding RNA (specifically MALAT1) that regulate gene expression through post-transcriptional modification are interesting avenues to consider in supporting neurons during DM. Finally, we present therapeutic possibilities around the use of a novel DNA/RNA heteroduplex oligonucleotide that provides more efficient gene knockdown in DRG than the single-stranded antisense oligonucleotide. Full article
(This article belongs to the Special Issue Pathogenesis and Molecular Treatment Strategies of Diabetic Neuropathy 2.0)
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11 pages, 3442 KiB  
Review
Inflammatory Mechanisms in the Pathophysiology of Diabetic Peripheral Neuropathy (DN)—New Aspects
by Petra Baum, Klaus V. Toyka, Matthias Blüher, Joanna Kosacka and Marcin Nowicki
Int. J. Mol. Sci. 2021, 22(19), 10835; https://doi.org/10.3390/ijms221910835 - 7 Oct 2021
Cited by 54 | Viewed by 10231
Abstract
The pathogenesis of diabetic neuropathy is complex, and various pathogenic pathways have been proposed. A better understanding of the pathophysiology is warranted for developing novel therapeutic strategies. Here, we summarize recent evidence from experiments using animal models of type 1 and type 2 [...] Read more.
The pathogenesis of diabetic neuropathy is complex, and various pathogenic pathways have been proposed. A better understanding of the pathophysiology is warranted for developing novel therapeutic strategies. Here, we summarize recent evidence from experiments using animal models of type 1 and type 2 diabetes showing that low-grade intraneural inflammation is a facet of diabetic neuropathy. Our experimental data suggest that these mild inflammatory processes are a likely common terminal pathway in diabetic neuropathy associated with the degeneration of intraepidermal nerve fibers. In contrast to earlier reports claiming toxic effects of high-iron content, we found the opposite, i.e., nutritional iron deficiency caused low-grade inflammation and fiber degeneration while in normal or high non-heme iron nutrition no or only extremely mild inflammatory signs were identified in nerve tissue. Obesity and dyslipidemia also appear to trigger mild inflammation of peripheral nerves, associated with neuropathy even in the absence of overt diabetes mellitus. Our finding may be the experimental analog of recent observations identifying systemic proinflammatory activity in human sensorimotor diabetic neuropathy. In a rat model of type 1 diabetes, a mild neuropathy with inflammatory components could be induced by insulin treatment causing an abrupt reduction in HbA1c. This is in line with observations in patients with severe diabetes developing a small fiber neuropathy upon treatment-induced rapid HbA1c reduction. If the inflammatory pathogenesis could be further substantiated by data from human tissues and intervention studies, anti-inflammatory compounds with different modes of action may become candidates for the treatment or prevention of diabetic neuropathy. Full article
(This article belongs to the Special Issue Pathogenesis and Molecular Treatment Strategies of Diabetic Neuropathy 2.0)
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21 pages, 760 KiB  
Review
Effect of Acupuncture on Diabetic Neuropathy: A Narrative Review
by Eunwoo Cho and Woojin Kim
Int. J. Mol. Sci. 2021, 22(16), 8575; https://doi.org/10.3390/ijms22168575 - 9 Aug 2021
Cited by 24 | Viewed by 8437
Abstract
Diabetic neuropathy, a major complication of diabetes mellitus, refers to a collection of clinically diverse disorders affecting the nervous system that may present with pain. Although the number of patients suffering from severe neuropathy is increasing, no optimal treatment method has been developed [...] Read more.
Diabetic neuropathy, a major complication of diabetes mellitus, refers to a collection of clinically diverse disorders affecting the nervous system that may present with pain. Although the number of patients suffering from severe neuropathy is increasing, no optimal treatment method has been developed yet. Acupuncture is well known for its ability to reduce various kinds of pain, and a number of studies have also reported its effect on diabetes mellitus; however, its effect and underlying mechanism against diabetic neuropathy are not yet clearly understood. In this review, ten and five studies performed in humans and animals, respectively, were analyzed. All studies reported that acupuncture significantly relieved diabetic neuropathy. ST36, BL13, BL20, SP6, and SP9 were the most widely used acupoints. Five studies used electro-acupuncture, whereas other studies used manual acupuncture. Furthermore, the effect of acupuncture was shown to be mediated through the various molecules present in the peripheral nerves and spinal cord, such as P65, GPR78, and TRPV1. Five studies reported side effects, such as swelling, numbness, and nausea, but none were reported to be serious. Based on these results, we suggest that acupuncture should be considered as a treatment option for diabetic neuropathy. Full article
(This article belongs to the Special Issue Pathogenesis and Molecular Treatment Strategies of Diabetic Neuropathy 2.0)
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