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Nature Reviews. Neurology Mar 2017The prevalence of diabetes worldwide is at pandemic levels, with the number of patients increasing by 5% annually. The most common complication of diabetes is peripheral... (Review)
Review
The prevalence of diabetes worldwide is at pandemic levels, with the number of patients increasing by 5% annually. The most common complication of diabetes is peripheral neuropathy, which has a prevalence as high as 50% and is characterized by damage to neurons, Schwann cells and blood vessels within the nerve. The pathogenic mechanisms of diabetic neuropathy remain poorly understood, impeding the development of targeted therapies to treat nerve degeneration and its most disruptive consequences of sensory loss and neuropathic pain. Involvement of Schwann cells has long been proposed, and new research techniques are beginning to unravel a complex interplay between these cells, axons and microvessels that is compromised during the development of diabetic neuropathy. In this Review, we discuss the evolving concept of Schwannopathy as an integral factor in the pathogenesis of diabetic neuropathy, and how disruption of the interactions between Schwann cells, axons and microvessels contribute to the disease.
Topics: Axons; Diabetic Neuropathies; Humans; Microvessels; Schwann Cells
PubMed: 28134254
DOI: 10.1038/nrneurol.2016.201 -
F1000Research 2019Diabetic peripheral neuropathy (DPN) is the most common chronic complication of diabetes. It poses a significant challenge for clinicians as it is often diagnosed late... (Review)
Review
Diabetic peripheral neuropathy (DPN) is the most common chronic complication of diabetes. It poses a significant challenge for clinicians as it is often diagnosed late when patients present with advanced consequences such as foot ulceration. Autonomic neuropathy (AN) is also a frequent and under-diagnosed complication unless it is overtly symptomatic. Both somatic and autonomic neuropathy are associated with increased mortality. Multiple clinical trials have failed because of limited efficacy in advanced disease, inadequate trial duration, lack of effective surrogate end-points and a lack of deterioration in the placebo arm in clinical trials of DPN. Multifactorial risk factor reduction, targeting glycaemia, blood pressure and lipids can reduce the progression of DPN and AN. Treatment of painful DPN reduces painful symptoms by about 50% at best, but there is limited efficacy with any single agent. This reflects the complex aetiology of painful DPN and argues for improved clinical phenotyping with the use of targeted therapy, taking into account co-morbid conditions such as anxiety, depression and sleep disturbance.
Topics: Diabetes Mellitus; Diabetic Neuropathies; Humans; Pain; Risk Factors; Sleep Wake Disorders
PubMed: 30828432
DOI: 10.12688/f1000research.17118.1 -
BMC Medical Informatics and Decision... Aug 2023Diabetic peripheral neuropathy (DPN) is a common complication of diabetes. Predicting the risk of developing DPN is important for clinical decision-making and designing...
BACKGROUND
Diabetic peripheral neuropathy (DPN) is a common complication of diabetes. Predicting the risk of developing DPN is important for clinical decision-making and designing clinical trials.
METHODS
We retrospectively reviewed the data of 1278 patients with diabetes treated in two central hospitals from 2020 to 2022. The data included medical history, physical examination, and biochemical index test results. After feature selection and data balancing, the cohort was divided into training and internal validation datasets at a 7:3 ratio. Training was made in logistic regression, k-nearest neighbor, decision tree, naive bayes, random forest, and extreme gradient boosting (XGBoost) based on machine learning. The k-fold cross-validation was used for model assessment, and the accuracy, precision, recall, F1-score, and the area under the receiver operating characteristic curve (AUC) were adopted to validate the models' discrimination and clinical practicality. The SHapley Additive exPlanation (SHAP) was used to interpret the best-performing model.
RESULTS
The XGBoost model outperformed other models, which had an accuracy of 0·746, precision of 0·765, recall of 0·711, F1-score of 0·736, and AUC of 0·813. The SHAP results indicated that age, disease duration, glycated hemoglobin, insulin resistance index, 24-h urine protein quantification, and urine protein concentration were risk factors for DPN, while the ratio between 2-h postprandial C-peptide and fasting C-peptide(C2/C0), total cholesterol, activated partial thromboplastin time, and creatinine were protective factors.
CONCLUSIONS
The machine learning approach helped established a DPN risk prediction model with good performance. The model identified the factors most closely related to DPN.
Topics: Humans; Bayes Theorem; C-Peptide; Diabetic Neuropathies; Retrospective Studies; Risk Factors; Machine Learning; Diabetes Mellitus
PubMed: 37533059
DOI: 10.1186/s12911-023-02232-1 -
Journal of Diabetes Research 2021Despite the high prevalence of diabetic neuropathy, its early start, and its impact on quality of life and mortality, unresolved clinical issues persist in the field... (Review)
Review
Despite the high prevalence of diabetic neuropathy, its early start, and its impact on quality of life and mortality, unresolved clinical issues persist in the field regarding its screening implementation, the understanding of its mechanisms, and the search for valid biomarkers, as well as disease-modifying treatment. Genetics may address these needs by providing genetic biomarkers of susceptibility, giving insights into pathogenesis, and shedding light on how to select possible responders to treatment. After a brief summary of recent studies on the genetics of diabetic neuropathy, the current review focused mainly on microRNAs (miRNAs), including the authors' results in this field. It summarized the findings of animal and human studies that associate miRNAs with diabetic neuropathy and explored the possible pathogenetic meanings of these associations, in particular regarding miR-128a, miR-155a, and miR-499a, as well as their application for diabetic neuropathy screening. Moreover, from a genetic perspective, it examined new findings of polymorphisms of miRNA genes in diabetic neuropathy. It considered in more depth the pathogenetic implications for diabetic neuropathy of the polymorphism of MIR499A and the related changes in the downstream action of miR-499a, showing how epigenetic and genetic studies may provide insight into pathogenetic mechanisms like mitochondrial dysfunction. Finally, the concept and the data of genotype-phenotype association for polymorphism of miRNA genes were described. In conclusion, although at a very preliminary stage, the findings linking the genetics and epigenetics of miRNAs might contribute to the identification of exploratory risk biomarkers, a comprehensive definition of susceptibility to specific pathogenetic mechanisms, and the development of mechanism-based treatment of diabetic neuropathy, thus addressing the goals of genetic studies.
Topics: Animals; Diabetic Neuropathies; Epigenesis, Genetic; Genetic Predisposition to Disease; Humans; MicroRNAs; Phenotype; Polymorphism, Genetic; Predictive Value of Tests; Prognosis; Risk Assessment; Risk Factors
PubMed: 34660810
DOI: 10.1155/2021/5593608 -
International Journal of Molecular... Sep 2019Diabetic neuropathy is a serious complication of chronic hyperglycemia in diabetes patients. This complication can involve both peripheral sensorimotor and autonomic... (Review)
Review
Diabetic neuropathy is a serious complication of chronic hyperglycemia in diabetes patients. This complication can involve both peripheral sensorimotor and autonomic nervous system. The precise nature of injury to the peripheral nerves mediated by chronic hyperglycemia is unknown; however, several mechanisms have been proposed including polyol pathway activation, enhanced glycation of proteins and lipids, increased oxidative stress, and cytokine release in the site of injury. MicroRNAs (miRNAs) are small non-coding RNAs that mediate RNA interference by post-transcriptionally modulating gene expression and protein synthesis. Therefore, they have been implicated in several developmental, physiological, and pathophysiological processes where they modulate the expression of different proteins. Recently, miRNAs gained an increasing attention also for their role as diagnostic test in many diseases due to their stability in serum and their easy detection. Furthermore, recent studies suggest that miRNAs may be involved in diabetic neuropathy although their role in the onset and the development of this complication is not fully understood. In this review, we discuss the most recent literature providing evidence for miRNAs role in diabetic neuropathy opening new pathways to improve both early diagnosis and treatment of this complication.
Topics: Animals; Diabetic Neuropathies; Humans; MicroRNAs; Oxidative Stress; Peripheral Nerves; RNA Interference
PubMed: 31540445
DOI: 10.3390/ijms20184627 -
Journal of Diabetes Investigation Nov 2018Diabetic polyneuropathy (DPN) continues to be generally considered as a "microvascular" complication of diabetes mellitus alongside nephropathy and retinopathy. The... (Review)
Review
Diabetic polyneuropathy (DPN) continues to be generally considered as a "microvascular" complication of diabetes mellitus alongside nephropathy and retinopathy. The microvascular hypothesis, however, might be tempered by the concept that diabetes directly targets dorsal root ganglion sensory neurons. This neuron-specific concept, supported by accumulating evidence, might account for important features of DPN, such as its early sensory neuron degeneration. Diabetic sensory neurons develop neuronal atrophy alongside a series of messenger ribonucleic acid (RNA) changes related to declines in structural proteins, increases in heat shock protein, increases in the receptor for advanced glycation end-products, declines in growth factor signaling and other changes. Insulin is recognized as a potent neurotrophic factor, and insulin ligation enhances neurite outgrowth through activation of the phosphoinositide 3-kinase-protein kinase B pathway within sensory neurons and attenuates phenotypic features of experimental DPN. Several interventions, including glucagon-like peptide-1 agonism, and phosphatase and tensin homolog inhibition to activate growth signals in sensory neurons, or heat shock protein overexpression, prevent or reverse neuropathic abnormalities in experimental DPN. Diabetic sensory neurons show a unique pattern of microRNA alterations, a key element of messenger RNA silencing. For example, let-7i is widely expressed in sensory neurons, supports their growth and is depleted in experimental DPN; its replenishment improves features of DPN models. Finally, impairment of pre-messenger RNA splicing in diabetic sensory neurons including abnormal nuclear RNA metabolism and structure with loss of survival motor neuron protein, a neuron survival molecule, and overexpression of CWC22, a splicing factor, offer further novel insights. The present review addresses these new aspects of DPN sensory neurodegeneration.
Topics: Animals; Diabetic Neuropathies; Ganglia, Spinal; Humans; Microvessels; Nerve Regeneration; Sensory Receptor Cells; Signal Transduction
PubMed: 29533535
DOI: 10.1111/jdi.12833 -
Journal of Diabetes Investigation Sep 2020Burning and stabbing pain in the feet and lower limbs can have a significant impact on the activities of daily living, including walking, climbing stairs and sleeping.... (Review)
Review
Burning and stabbing pain in the feet and lower limbs can have a significant impact on the activities of daily living, including walking, climbing stairs and sleeping. Peripheral neuropathy in particular is often misdiagnosed or underdiagnosed because of a lack of awareness amongst both patients and physicians. Furthermore, crude screening tools, such as the 10-g monofilament, only detect advanced neuropathy and a normal test will lead to false reassurance of those with small fiber mediated painful neuropathy. The underestimation of peripheral neuropathy is highly prevalent in the South-East Asia region due to a lack of consensus guidance on routine screening and diagnostic pathways. Although neuropathy as a result of diabetes is the most common cause in the region, other causes due to infections (human immunodeficiency virus, hepatitis B or C virus), chronic inflammatory demyelinating polyneuropathy, drug-induced neuropathy (cancer chemotherapy, antiretrovirals and antituberculous drugs) and vitamin deficiencies (vitamin B , B , B , D) should be actively excluded.
Topics: Asia, Southeastern; Diabetic Neuropathies; Humans; Peripheral Nervous System Diseases; Prognosis
PubMed: 32268012
DOI: 10.1111/jdi.13269 -
Clinical Therapeutics Jun 2017The present review highlights current concepts regarding the effects of diabetic peripheral neuropathy (DPN) in skeletal muscle. It discusses the lack of effective... (Review)
Review
PURPOSE
The present review highlights current concepts regarding the effects of diabetic peripheral neuropathy (DPN) in skeletal muscle. It discusses the lack of effective pharmacologic treatments and the role of physical exercise intervention in limb protection and symptom reversal. It also highlights the importance of magnetic resonance imaging (MRI) techniques in providing a mechanistic understanding of the disease and helping develop targeted treatments.
METHODS
This review provides a comprehensive reporting on the effects of DPN in the skeletal muscle of patients with diabetes. It also provides an update on the most recent trials of exercise intervention targeting DPN pathology. Lastly, we report on emerging MRI techniques that have shown promise in providing a mechanistic understanding of DPN and can help improve the design and implementation of clinical trials in the future.
FINDINGS
Impairments in lower limb muscles reduce functional capacity and contribute to altered gait, increased fall risk, and impaired balance in patients with DPN. This finding is an important concern for patients with DPN because their falls are likely to be injurious and lead to bone fractures, poorly healing wounds, and chronic infections that may require amputation. Preliminary studies have shown that moderate-intensity exercise programs are well tolerated by patients with DPN. They can improve their cardiorespiratory function and partially reverse some of the symptoms of DPN. MRI has the potential to bring new mechanistic insights into the effects of DPN as well as to objectively measure small changes in DPN pathology as a result of intervention.
IMPLICATIONS
Noninvasive exercise intervention is particularly valuable in DPN because of its safety, low cost, and potential to augment pharmacologic interventions. As we gain a better mechanistic understanding of the disease, more targeted and effective interventions can be designed.
Topics: Animals; Diabetic Neuropathies; Exercise Therapy; Humans; Magnetic Resonance Imaging; Muscle, Skeletal
PubMed: 28571613
DOI: 10.1016/j.clinthera.2017.05.001 -
Daru : Journal of Faculty of Pharmacy,... Dec 2019Diabetic neuropathy (DNP) is a widespread and debilitating complication with complex pathophysiology that is caused by neuronal dysfunction in diabetic patients.... (Review)
Review
OBJECTIVES
Diabetic neuropathy (DNP) is a widespread and debilitating complication with complex pathophysiology that is caused by neuronal dysfunction in diabetic patients. Conventional therapeutics for DNP are quite challenging due to their serious adverse effects. Hence, there is a need to investigate novel effective and safe options. The novelty of the present study was to provide available therapeutic approaches, emerging molecular mechanisms, signaling pathways and future directions of DNP as well as polyphenols' effect, which accordingly, give new insights for paving the way for novel treatments in DNP.
EVIDENCE ACQUISITION
A comprehensive review was done in electronic databases including Medline, PubMed, Web of Science, Scopus, national database (Irandoc and SID), and related articles regarding metabolic pathways on the pathogenesis of DNP as well as the polyphenols' effect. The keywords "diabetic neuropathy" and "diabetes mellitus" in the title/abstract and "polyphenol" in the whole text were used. Data were collected from inception until May 2019.
RESULTS
DNP complications is mostly related to a poor glycemic control and metabolic imbalances mainly inflammation and oxidative stress. Several signaling and molecular pathways play key roles in the pathogenesis and progression of DNP. Among natural entities, polyphenols are suggested as multi-target alternatives affecting most of these pathogenesis mechanisms in DNP.
CONCLUSION
The findings revealed novel pathogenicity signaling pathways of DNP and affirmed the auspicious role of polyphenols to tackle these destructive pathways in order to prevent, manage, and treat various diseases. Graphical Abstract .
Topics: Diabetic Neuropathies; Humans; Oxidative Stress; Polyphenols; Randomized Controlled Trials as Topic; Signal Transduction; Treatment Outcome
PubMed: 31352568
DOI: 10.1007/s40199-019-00289-w -
Journal of Diabetes Science and... Mar 2022The development of painful diabetic neuropathy (PDN) is a common complication of chronic diabetes that can be associated with significant disability and healthcare... (Review)
Review
The development of painful diabetic neuropathy (PDN) is a common complication of chronic diabetes that can be associated with significant disability and healthcare costs. Prompt symptom identification and aggressive glycemic control is essential in controlling the development of neuropathic complications; however, adequate pain relief remains challenging and there are considerable unmet needs in this patient population. Although guidelines have been established regarding the pharmacological management of PDN, pain control is inadequate or refractory in a high proportion of patients. Pharmacotherapy with anticonvulsants (pregabalin, gabapentin) and antidepressants (duloxetine) are common first-line agents. The use of oral opioids is associated with considerable morbidity and mortality and can also lead to opioid-induced hyperalgesia. Their use is therefore discouraged. There is an emerging role for neuromodulation treatment modalities including intrathecal drug delivery, spinal cord stimulation, and dorsal root ganglion stimulation. Furthermore, consideration of holistic alternative therapies such as yoga and acupuncture may augment a multidisciplinary treatment approach. This aim of this review is to focus on the current management strategies for the treatment of PDN, with a discussion of treatment rationale and practical considerations for their implementation.
Topics: Anticonvulsants; Antidepressive Agents; Diabetes Mellitus; Diabetic Neuropathies; Humans; Pain Management
PubMed: 32856490
DOI: 10.1177/1932296820951829