Inflammatory Mechanisms in the Pathophysiology of Diabetic Peripheral Neuropathy (DN)—New Aspects

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.

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Lesions of the nervous system in children with type 1 diabetes mellitus (literature review)

Russian Journal of Child Neurology ◽

10.17650/2073-8803-2019-14-1-36-39 ◽

2019 ◽

Vol 14 (1) ◽

pp. 36-39

Author(s):

E. V. Mukhina ◽

A. S. Kotov

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Nervous System ◽

Literature Review ◽

Diabetic Neuropathy ◽

Nerve Fibers ◽

Common Complication ◽

Criteria For Diagnosis ◽

Immune Changes

This article provides an overview of the current literature on the most common complication of type 1 diabetes in children – diabetic neuropathy (DN). Diabetic neuropathy is a consequence of the widespread defeat of neurons and their processes in the central and peripheral nervous system due to metabolic, vascular and immune changes in diabetes and manifested in most children and adolescents with distal polyneuropathy and autonomic neuropathy. The mechanisms of the pathogenesis of the development of DN are discussed in the article, and it is noted that the clinical picture of DN is diverse and depends on the severity, nature of the lesion and the type of nerve fibers. The article deals with diagnostics, the criteria for diagnosis and treatment of DN.

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Human C-peptide Dose Dependently Prevents Early Neuropathy in the BB/Wor-rat

International Journal of Experimental Diabetes Research ◽

10.1155/edr.2001.187 ◽

2001 ◽

Vol 2 (3) ◽

pp. 187-193 ◽

Cited By ~ 42

Author(s):

W. Zhang ◽

M. Yorek ◽

C. R. Pierson ◽

Y. Murakawa ◽

A. Breidenbach ◽

...

Keyword(s):

Diabetic Neuropathy ◽

Axonal Degeneration ◽

Diabetic Rats ◽

Nerve Fibers ◽

C Peptide ◽

Conserved Sequence ◽

Structural Abnormalities ◽

Onset Of Diabetes ◽

Dose Dependent

In order to explore the neuroprotective and crossspecies activities of.C-peptide on type 1 diabetic neuropathy, spontaneously diabetic BB/W-rats were given increasing doses of human recombinant Cpeptide (hrC-peptide). Diabetic rats received 10, 100, 500, or 1000 μg of hrC-peptide/kg body weight/ day from onset of diabetes. After 2 months of hrC-peptide administration, 100 μg and greater doses completely prevented the nerve conduction defect, which was associated with a significant but incomplete prevention of neuralNa+/K+-ATPase activity in diabetic rats with 500 μg or greater C-peptide replacement. Increasing doses of hrC-peptide showed increasing prevention of early structural abnormalities such as paranodal swelling and axonal degeneration and an increasing frequency of regenerating sural nerve fibers. We conclude that hrC-peptide exerts a dose dependent protection on type 1 diabetic neuropathy in rats and that this effect is probably mediated by the partially conserved sequence of the active C-terminal pentapeptide

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Acquired and progressive myelinated retinal nerve fibers in neurofibromatosis type 1

Journal of American Association for Pediatric Ophthalmology and Strabismus ◽

10.1016/j.jaapos.2019.01.012 ◽

2019 ◽

Vol 23 (3) ◽

pp. 178-179

Author(s):

Filipa Teixeira ◽

Ana Cláudia Fonseca ◽

Filomena Pinto

Keyword(s):

Neurofibromatosis Type 1 ◽

Neurofibromatosis Type ◽

Nerve Fibers

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NEUROPROTECTION OF ABELMOSCHUS ESCULENTUS L. AGAINST DIABETIC NEUROPATHY

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2018.v11s3.30023 ◽

2018 ◽

Vol 11 (15) ◽

pp. 28

Author(s):

Lee Wei Yang ◽

Santosh Fattepur ◽

Kiran Chanabasappa Nilugal ◽

Fadli Asmani ◽

Eddy Yusuf ◽

...

Keyword(s):

Body Weight ◽

Sciatic Nerve ◽

Diabetic Neuropathy ◽

Performance Test ◽

Neuroprotective Effect ◽

Thermal Hyperalgesia ◽

Diabetic Rats ◽

Nerve Fibers ◽

Abelmoschus Esculentus ◽

Rotarod Performance

Objective: The present study was designed to determine the neuroprotective effect of Abelmoschus esculentus L. on alloxan-induced diabetic neuropathy in rats.Methods: Diabetes was induced in rats with a single intraperitoneal injection of alloxan monohydrate (130 mg/kg b.w). The ethanol extract of A. esculentus L. at a dose of 100 and 200 mg/kg of body weight was administered at single dose per day to alloxan-induced diabetic rats for 21 days. The fasting blood glucose was screened in the intermittent on day 0, day 14, and day 21. Behavioral tests such as thermal hyperalgesia test and rotarod performance test were performed to assess the thermal sensitivity and muscle grip strength. At the end of the study period, experimental animals were sacrificed and sciatic nerve tissues were obtained for histopathological investigation.Results: Animals treated with A. esculentus L. extarct at a dose of 200 mg/kg of body weight significantly reduced (p<0.05) in hyperglycemia and thermal hyperalgesia and significantly increased (p<0.05) in rotarod performance. The sciatic nerve fiber of diabetic rats receiving 200 mg/kg of body weight of A. esculentus L. extract also shows no swelling of nerve fibers, and lesser demyelination was observed.Conclusion: These findings demonstrate that A. esculentus L. exhibits significant antidiabetic and neuroprotective effect against alloxan-induced diabetic neuropathy in rats.

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Recent Advances in Biomarkers and Regenerative Medicine for Diabetic Neuropathy

International Journal of Molecular Sciences ◽

10.3390/ijms22052301 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2301

Author(s):

Yoshikai Fujita ◽

Tatsufumi Murakami ◽

Akihiro Nakamura

Keyword(s):

Diabetic Neuropathy ◽

Target Gene ◽

Pathological Condition ◽

Nerve Fibers ◽

Nerve Degeneration ◽

Limb Amputation ◽

Sensory Impairment ◽

Mechanical Stimuli ◽

Pathological Conditions ◽

The Relationship

Diabetic neuropathy is one of the most common complications of diabetes. This complication is peripheral neuropathy with predominant sensory impairment, and its symptoms begin with hyperesthesia and pain and gradually become hypoesthesia with the loss of nerve fibers. In some cases, lower limb amputation occurs when hypoalgesia makes it impossible to be aware of trauma or mechanical stimuli. On the other hand, up to 50% of these complications are asymptomatic and tend to delay early detection. Therefore, sensitive and reliable biomarkers for diabetic neuropathy are needed for an early diagnosis of this condition. This review focuses on systemic biomarkers that may be useful at this time. It also describes research on the relationship between target gene polymorphisms and pathological conditions. Finally, we also introduce current information on regenerative therapy, which is expected to be a therapeutic approach when the pathological condition has progressed and nerve degeneration has been completed.

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Cartilage oligomeric matrix protein is an endogenous β-arrestin-2-selective allosteric modulator of AT1 receptor counteracting vascular injury

Cell Research ◽

10.1038/s41422-020-00464-8 ◽

2021 ◽

Author(s):

Yi Fu ◽

Yaqian Huang ◽

Zhao Yang ◽

Yufei Chen ◽

Jingang Zheng ◽

...

Keyword(s):

Cartilage Oligomeric Matrix Protein ◽

Matrix Protein ◽

Therapeutic Strategies ◽

At1 Receptor ◽

Extracellular Matrix Protein ◽

Binding Motif ◽

Abdominal Aortic ◽

Novel Therapeutic Strategies ◽

G Protein Coupled

AbstractCompelling evidence has revealed that biased activation of G protein-coupled receptor (GPCR) signaling, including angiotensin II (AngII) receptor type 1 (AT1) signaling, plays pivotal roles in vascular homeostasis and injury, but whether a clinically relevant endogenous biased antagonism of AT1 signaling exists under physiological and pathophysiological conditions has not been clearly elucidated. Here, we show that an extracellular matrix protein, cartilage oligomeric matrix protein (COMP), acts as an endogenous allosteric biased modulator of the AT1 receptor and its deficiency is clinically associated with abdominal aortic aneurysm (AAA) development. COMP directly interacts with the extracellular N-terminus of the AT1 via its EGF domain and inhibits AT1-β-arrestin-2 signaling, but not Gq or Gi signaling, in a selective manner through allosteric regulation of AT1 intracellular conformational states. COMP deficiency results in activation of AT1a-β-arrestin-2 signaling and subsequent exclusive AAA formation in response to AngII infusion. AAAs in COMP–/– or ApoE–/– mice are rescued by AT1a or β-arrestin-2 deficiency, or the application of a peptidomimetic mimicking the AT1-binding motif of COMP. Explorations of the endogenous biased antagonism of AT1 receptor or other GPCRs may reveal novel therapeutic strategies for cardiovascular diseases.

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