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Antioxidants & Redox Signaling May 2023Diabetic peripheral neuropathy (DPN), a complication of metabolic syndrome, type I and type II diabetes, leads to sensory changes that include slow nerve conduction,... (Review)
Review
Diabetic peripheral neuropathy (DPN), a complication of metabolic syndrome, type I and type II diabetes, leads to sensory changes that include slow nerve conduction, nerve degeneration, loss of sensation, pain, and gate disturbances. These complications remain largely untreatable, although tight glycemic control can prevent neuropathy progression. Nonpharmacologic approaches remain the most impactful to date, but additional advances in treatment approaches are needed. This review highlights several emerging interventions, including a focus on dietary interventions and physical activity, that continue to show promise for treating DPN. We provide an overview of our current understanding of how exercise can improve aspects of DPN. We also highlight new studies in which a ketogenic diet has been used as an intervention to prevent and reverse DPN. Both exercise and consuming a ketogenic diet induce systemic and cellular changes that collectively improve complications associated with DPN. Both interventions may involve similar signaling pathways and benefits but also impact DPN through unique mechanisms. These lifestyle interventions are critically important as personalized medicine approaches will likely be needed to identify specific subsets of neuropathy symptoms and deficits in patients, and determine the most impactful treatment. Overall, these two interventions have the potential to provide meaningful relief for patients with DPN and provide new avenues to identify new therapeutic targets.
Topics: Humans; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Metabolic Syndrome; Signal Transduction; Pain
PubMed: 36503268
DOI: 10.1089/ars.2022.0158 -
Proceedings of the National Academy of... Apr 2022SignificanceDiabetic neuropathy is a commonly occurring complication of diabetes that affects hundreds of millions of patients worldwide. Patients suffering from...
SignificanceDiabetic neuropathy is a commonly occurring complication of diabetes that affects hundreds of millions of patients worldwide. Patients suffering from diabetic neuropathy experience abnormal sensations and have damage in their peripheral nerve axons as well as myelin, a tightly packed Schwann cell sheath that wraps around axons to provide insulation and increases electrical conductivity along the nerve fibers. The molecular events underlying myelin damage in diabetic neuropathy are largely unknown, and there is no efficacious treatment for the disease. The current study, using a diabetic mouse model and human patient nerve samples, uncovered a molecular mechanism underlying myelin sheath damage in diabetic neuropathy and provides a potential treatment strategy for the disease.
Topics: Animals; Axons; Diabetes Mellitus; Diabetic Neuropathies; Humans; Mice; Myelin Sheath; Peripheral Nerves; Protein Kinases; Schwann Cells
PubMed: 35344427
DOI: 10.1073/pnas.2121552119 -
Journal of Diabetes Investigation Sep 2019Diabetic neuropathy (DN) is a common complication of diabetes and can be either painful or non-painful. It is challenging to diagnose this complication, as no biomarker... (Review)
Review
Diabetic neuropathy (DN) is a common complication of diabetes and can be either painful or non-painful. It is challenging to diagnose this complication, as no biomarker or clear consensus on the clinical definition of either painful or non-painful DN exists. Hence, a hierarchical classification has been developed categorizing the probability of the diagnosis into: possible, probable or definite, based on the clinical presentation of symptoms and signs. Pain is a warning signal of tissue damage, and non-painful DN therefore represents a clinical and diagnostic challenge because it often goes unnoticed until irreversible nerve damage has occurred. Simple clinical tests seem to be the best for evaluation of DN in the general care for diabetes. Screening programs at regular intervals might be the most optimal strategy for early detection and interventions to possibly prevent further neuronal damage and to lower the economic burden of this complication.
Topics: Diabetic Neuropathies; Humans; Mass Screening; Pain; Severity of Illness Index
PubMed: 31222961
DOI: 10.1111/jdi.13105 -
Frontiers in Endocrinology 2022Diabetic neuropathy is regarded as one of the most debilitating outcomes of diabetes. It can affect both the peripheral and central nervous systems, leading to pain,...
Diabetic neuropathy is regarded as one of the most debilitating outcomes of diabetes. It can affect both the peripheral and central nervous systems, leading to pain, decreased motility, cognitive decline, and dementia. S-palmitoylation is a reversible posttranslational lipid modification, and its dysregulation has been implicated in metabolic syndrome, cancers, neurological disorders, and infections. However, the role of S-palmitoylation in diabetic neuropathy remains unclear. Here we demonstrate a potential association between activating protein palmitoylation and diabetic neuropathy. We compared the proteomic data of lumbar dorsal root ganglia (DRG) of diabetes mice and palmitoylome profiling data of the HUVEC cell line. The mapping results identified peroxiredoxin-6 (PRDX6) as a novel target in diabetic neuropathy, whose biological mechanism was associated with S-palmitoylation. Bioinformatic prediction revealed that PRDX6 had two palmitoylation sites, Cys47 and Cys91. Immunofluorescence results indicated PRDX6 translocating between the cytoplasm and cell membrane. Protein function analysis proposed that increased palmitoylation could competitively inhibit the formation of disulfide-bond between Cys47 and Cys91 and change the spatial topology of PRDX6 protein. ClHCO3 anion exchanger 3 (AE3) was one of the AE family members, which was proved to express in DRG. AE3 activity evoked Cl influx in neurons which was generally associated with increased excitability and susceptibility to pain. We demonstrated that the S-palmitoylation status of Cys47 could affect the interaction between PRDX6 and the C-terminal domain of AE3, thereby regulating the activity of AE3 anion exchanger enzyme in the nervous system. The results highlight a central role for PRDX6 palmitoylation in protection against diabetic neuropathy.
Topics: Animals; Chloride-Bicarbonate Antiporters; Diabetes Mellitus; Diabetic Neuropathies; Disulfides; Lipids; Lipoylation; Mice; Pain; Peroxiredoxin VI; Proteins; Proteomics
PubMed: 36120430
DOI: 10.3389/fendo.2022.992875 -
Acta Neurologica Belgica Jun 2023Research suggests that diabetic peripheral neuropathy (DPN) is related to high serum uric acid (SUA) level, although its correlation with low SUA level has not been... (Observational Study)
Observational Study
BACKGROUND AND OBJECTIVES
Research suggests that diabetic peripheral neuropathy (DPN) is related to high serum uric acid (SUA) level, although its correlation with low SUA level has not been reported. Here, diabetic patients with hyperuricemia were excluded, and the correlation between low SUA level and DPN was explored.
SUBJECTS AND METHODS
This prospective observational clinical study enrolled 525 type 2 diabetes mellitus (T2DM) patients without hyperuricemia, who were divided into the diabetes with symptomatic neuropathy (150 cases), diabetes with asymptomatic neuropathy (125 cases) and diabetes with no neuropathy (250 cases) groups.
RESULTS
The SUA slightly decreased in subjects with asymptomatic DPN compared with those with no neuropathy and greatly decreased in subjects with symptomatic DPN compared with those without (P < 0.001). The association of the SUA with diabetic neuropathy was independent of the hyperglycemic state and other potential confounders (odds ratio 0.985 [0.981-0.988], P < 0.001). The SUA was closely correlated with the means of motor/sensory nerve amplitude and CV (all P < 0.001). The optimal cut-off point for SUA to distinguish patients with diabetic neuropathy from those without was 324 umol/L, with a sensitivity of 76.0% and a specificity of 79.2% (AUC = 0.806).
CONCLUSIONS
The low SUA level is closely associated with DPN. Future studies are warranted to clarify the relationship.
Topics: Humans; Diabetes Mellitus, Type 2; Uric Acid; Diabetic Neuropathies; Hyperuricemia; Risk Factors
PubMed: 35643885
DOI: 10.1007/s13760-022-01978-1 -
Hand (New York, N.Y.) Jan 2023Diabetes mellitus (DM) increases the risk for carpal tunnel syndrome (CTS) and is associated with its own neuropathic complications. Diabetic peripheral neuropathy (DPN)...
BACKGROUND
Diabetes mellitus (DM) increases the risk for carpal tunnel syndrome (CTS) and is associated with its own neuropathic complications. Diabetic peripheral neuropathy (DPN) is a common complication seen in diabetic patients. In this study, we examine the relationship between the severity of DPN and CTS.
METHODS
Type 2 diabetic and control patients (n = 292) were recruited at a clinic visit. The Michigan Neuropathy Screening Instrument (MNSI) questionnaire was used to collect data related to peripheral neuropathy. The MNSI scores were compared for patients with CTS with and without DM in univariable and multivariable analyses. χ analyses were performed to quantitatively measure the associations between peripheral neuropathy and the presence of CTS.
RESULTS
Of the 292 patients, 41 had CTS, and 19 of these had both CTS and DM. Of the 138 diabetic patients, 85 had peripheral neuropathy. There was no association between a diagnosis of CTS and an MNSI score indicative of peripheral neuropathy. In the diabetic population, CTS was inversely associated with DPN ( = .017). The MNSI scores between diabetic and control patients with CTS were comparable.
CONCLUSION
The severity of peripheral neuropathy in diabetic patients with and without CTS is comparable. Diabetic patients without peripheral neuropathy have an association with higher incidence of CTS in this study, suggesting that there are disparate mechanisms causing DPN and CTS. Nevertheless, diabetes and CTS are risk factors for developing the other, and future studies should further explore how DPN and CTS differ to tailor patient interventions based on their comorbidities.
Topics: Humans; Carpal Tunnel Syndrome; Diabetic Neuropathies; Comorbidity; Risk Factors; Diabetes Mellitus
PubMed: 34032176
DOI: 10.1177/15589447211014607 -
International Journal of Molecular... Feb 2021Diabetic neuropathy is one of the most common complications of diabetes. This complication is peripheral neuropathy with predominant sensory impairment, and its symptoms... (Review)
Review
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.
Topics: Animals; Biomarkers; Cytokines; Diabetic Neuropathies; Exosomes; Glyoxal; Humans; Inflammation; Lactoylglutathione Lyase; MicroRNAs; Nerve Fibers; Neurons; Polymorphism, Genetic; Pyruvaldehyde; Regenerative Medicine; Toll-Like Receptors
PubMed: 33669048
DOI: 10.3390/ijms22052301 -
Diabetes & Vascular Disease Research 2023Diabetes patients frequently experience diabetic neuropathy (DN), a microvascular complication that significantly reduces patients' quality of life. Memantine has... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Diabetes patients frequently experience diabetic neuropathy (DN), a microvascular complication that significantly reduces patients' quality of life. Memantine has demonstrated potential benefits for neuropathic pains in preclinical studies. This study aimed to assess the efficacy of memantine in the management of peripheral neuropathy in patients with type 2 diabetes mellitus (T2DM).
METHOD
This randomized clinical trial includes 143 diabetic patients (aged between 18 and 75 years) with a confirmed diagnosis of diabetic neuropathy. Patients were randomly assigned to receive memantine 5 mg twice daily for 1 week, followed by 10 mg twice daily plus gabapentin 300 mg daily ( = 72) or just gabapentin 300 mg daily ( = 71) for 8 weeks. The DN4 questionnaire, monofilament, tuning fork, and Tip-therm tests were used to measure neuropathy at baseline and after the 8-week intervention.
RESULTS
The mean score of the DN4 questionnaire in the memantine group was significantly lower than the control group (. value: .001). The number of patients with diabetic neuropathy remarkably decreased in the memantine group at the end of the study based on the performed tests (. value: .001).
CONCLUSION
Memantine functions as a beneficial agent in the management of diabetic neuropathy, which would significantly improve the quality of life in diabetic patients.
Topics: Humans; Adolescent; Young Adult; Adult; Middle Aged; Aged; Diabetic Neuropathies; Gabapentin; Memantine; Diabetes Mellitus, Type 2; Quality of Life
PubMed: 37495223
DOI: 10.1177/14791641231191093 -
JPMA. the Journal of the Pakistan... Aug 2022Pruritis is a common symptom of many systemic and cutaneous localized diseases and diabetes mellitus is a common syndrome with multiple long term complications,...
Pruritis is a common symptom of many systemic and cutaneous localized diseases and diabetes mellitus is a common syndrome with multiple long term complications, including diabetic painful neuropathy. The involvement of small fibre neurons, in diabetic neuropathy, is recognized as the main pathophysiology. While the C fibres that mediate the sensation of pain and pruritus may belong to different neuronal circuits, there is evidence of cross talk between them. We therefore posit that pruritus may be a symptom of diabetic neuropathy. It should be viewed as an equivalent of microvascular disease, with its accompanying clinical significance and therapeutic implications.
Topics: Humans; Diabetic Neuropathies; Pruritus; Pain; Diabetes Mellitus
PubMed: 36280941
DOI: 10.47391/JPMA.22-85 -
Current Diabetes Reviews 2022Animal models have been widely used to investigate the etiology and potential treatments for diabetic peripheral neuropathy. What we have learned from these studies and... (Review)
Review
INTRODUCTION
Animal models have been widely used to investigate the etiology and potential treatments for diabetic peripheral neuropathy. What we have learned from these studies and the extent to which this information has been adapted for the human condition will be the subject of this review article.
METHODS
A comprehensive search of the PubMed database was performed, and relevant articles on the topic were included in this review.
RESULTS
Extensive study of diabetic animal models has shown that the etiology of diabetic peripheral neuropathy is complex, with multiple mechanisms affecting neurons, Schwann cells, and the microvasculature, which contribute to the phenotypic nature of this most common complication of diabetes. Moreover, animal studies have demonstrated that the mechanisms related to peripheral neuropathy occurring in type 1 and type 2 diabetes are likely different, with hyperglycemia being the primary factor for neuropathology in type 1 diabetes, which contributes to a lesser extent in type 2 diabetes, whereas insulin resistance, hyperlipidemia, and other factors may have a greater role. Two of the earliest mechanisms described from animal studies as a cause for diabetic peripheral neuropathy were the activation of the aldose reductase pathway and increased non-enzymatic glycation. However, continuing research has identified numerous other potential factors that may contribute to diabetic peripheral neuropathy, including oxidative and inflammatory stress, dysregulation of protein kinase C and hexosamine pathways, and decreased neurotrophic support. In addition, recent studies have demonstrated that peripheral neuropathy-like symptoms are present in animal models, representing pre-diabetes in the absence of hyperglycemia.
CONCLUSION
This complexity complicates the successful treatment of diabetic peripheral neuropathy, and results in the poor outcome of translating successful treatments from animal studies to human clinical trials.
Topics: Animals; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Humans; Hyperglycemia; Models, Animal
PubMed: 33949936
DOI: 10.2174/1573399817666210504101609