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International Journal of Molecular... Apr 2023The two-hit model has been proposed to explain the effects of diabetes on mothers who are already in a putative subclinical damaged state and then undergo neuronal... (Review)
Review
The two-hit model has been proposed to explain the effects of diabetes on mothers who are already in a putative subclinical damaged state and then undergo neuronal damage during the delivery process. However, the anatomical and pathophysiological mechanisms are not well understood. Our overarching hypothesis in this review paper is that pregnant women who are diabetic have a damaged peripheral nervous system, constituting the "first hit" hypothesis. The delivery process itself-the "second hit"-can produce neurological damage to the mother. Women with diabetes mellitus (DM) are at risk for neurological damage during both hits, but the cumulative effects of both "hits" pose a greater risk of neurological damage and pathophysiological changes during delivery. In our analysis, we introduce the different steps of our concept paper. Subsequently, we describe each of the topics. First, we outline the mechanisms by which diabetes acts as a detrimental variable in neuropathy by focusing on the most common form of diabetic neuropathy, diabetic distal symmetrical polyneuropathy, also known as distal sensorimotor neuropathy. The possible role of macrosomia in causing diabetic neuropathy and obstetric neurological injury is discussed. Second, we describe how vaginal delivery can cause various obstetrical neurological syndromes and pathophysiological changes. Third, we highlight the risk of obstetric neuropathy and discuss anatomical sites at which lesions may occur, including lesions during delivery. Fourth, we characterize the pathophysiological pathways involved in the causation of diabetic neuropathy. Finally, we highlight diabetic damage to sensory vs. motor nerves, including how hyperglycemia causes different types of damage depending on the location of nerve cell bodies.
Topics: Pregnancy; Humans; Female; Diabetic Neuropathies; Hyperglycemia; Diabetes Mellitus
PubMed: 37047786
DOI: 10.3390/ijms24076812 -
International Journal of Molecular... Nov 2021Ursolic acid (UA) is a pentacyclic triterpenoid frequently found in medicinal herbs and plants, having numerous pharmacological effects. UA and its analogs treat... (Review)
Review
Ursolic acid (UA) is a pentacyclic triterpenoid frequently found in medicinal herbs and plants, having numerous pharmacological effects. UA and its analogs treat multiple diseases, including cancer, diabetic neuropathy, and inflammatory diseases. UA inhibits cancer proliferation, metastasis, angiogenesis, and induced cell death, scavenging free radicals and triggering numerous anti- and pro-apoptotic proteins. The biochemistry of UA has been examined broadly based on the literature, with alterations frequently having been prepared on positions C-3 (hydroxyl), C12-C13 (double bonds), and C-28 (carboxylic acid), leading to several UA derivatives with increased potency, bioavailability and water solubility. UA could be used as a protective agent to counter neural dysfunction via anti-oxidant and anti-inflammatory effects. It is a potential therapeutic drug implicated in the treatment of cancer and diabetic complications diseases provide novel machinery to the anti-inflammatory properties of UA. The pharmacological efficiency of UA is exhibited by the therapeutic theory of one-drug → several targets → one/multiple diseases. Hence, UA shows promising therapeutic potential for cancer and diabetic neuropathy diseases. This review aims to discuss mechanistic insights into promising beneficial effects of UA. We further explained the pharmacological aspects, clinical trials, and potential limitations of UA for the management of cancer and diabetic neuropathy diseases.
Topics: Anti-Inflammatory Agents; Antineoplastic Agents, Phytogenic; Diabetic Neuropathies; Humans; Neoplasms; Plants, Medicinal; Triterpenes; Ursolic Acid
PubMed: 34830043
DOI: 10.3390/ijms222212162 -
Diabetes Research and Clinical Practice Dec 2023Up to 25% of people with diabetes develop painful diabetic neuropathy (PDN). The standard of care pharmacotherapies for PDN have limited efficacy with a considerable... (Review)
Review
Up to 25% of people with diabetes develop painful diabetic neuropathy (PDN). The standard of care pharmacotherapies for PDN have limited efficacy with a considerable side effect profile. Spinal cord stimulation (SCS) is a form of electrical neurostimulation that modulates neural function via electrodes implanted into the spinal epidural space. While low frequency SCS has been shown to be potentially effective for treating pain associated with neuropathies, it masks pain perception by inducing paresthesia. Compared to low frequency SCS, high frequency (10 kHz) SCS delivers paresthesia-free therapy. As was shown in a randomized controlled trial, SENZA-PDN (NCT03228420), 10 kHz SCS is safe and effective for the treatment of painful diabetic neuropathy. 10 kHz SCS offered a comprehensive treatment that improved pain levels, sleep, quality of life, and neurological function. These improvements correlated with a high degree of patient satisfaction. 10 kHz SCS provides a safe, durable and effective treatment for PDN with the unique potential to improve neurological function. In patients for whom durable, effective treatments have been limited thus far, the findings of the SENZA-PDN study are encouraging.
Topics: Humans; Diabetes Mellitus; Diabetic Neuropathies; Pain; Pain Management; Quality of Life; Spinal Cord Stimulation; Treatment Outcome; Randomized Controlled Trials as Topic
PubMed: 38245324
DOI: 10.1016/j.diabres.2023.110760 -
Indian Journal of Ophthalmology Nov 2021To determine the relationship between diabetic retinopathy (DR) and diabetic peripheral neuropathy (DPN), and their associated risk factors.
PURPOSE
To determine the relationship between diabetic retinopathy (DR) and diabetic peripheral neuropathy (DPN), and their associated risk factors.
METHODS
We conducted a cross-sectional analysis on 500 patients who attended the Endocrinology department at a quaternary health care center in Kerala between November 2017 and April 2018. Patients above the age of 30 years with type 2 diabetes mellitus (DM) were included. They underwent a detailed medical history, dilated fundus examination for DR, assessment and grading of DPN, and blood investigations. Among these, 49 randomly selected patients without DR had peripapillary retinal nerve fiber layer (RNFL) and ganglion cell inner plexiform layer (GCIPL) assessed by optical coherence tomogram. RNFL and GCIPL changes in different grades of neuropathy were evaluated.
RESULTS
Out of 500 patients, 303 (60.6%) were males and 197 (39.4%) were females. Prevalence of DR was 48% and DPN 71.8%. Risk factors for the development of DR included duration of DM >15 years, HbA1c (glycated hemoglobin) greater than 6.5%, serum creatinine more than 1.5 mg/dl, and the presence of DPN. There was a statistically significant association between DR and DPN. There was significant thinning of GCIPL in patients with moderate to severe neuropathy without DR.
CONCLUSION
There is a significant association between DR and DPN and their severities. There are early changes in inner retinal layers of diabetic patients without microvascular changes of DR. These neurodegenerative changes parallel DPN in the course of DM. Our study stresses the importance of multidisciplinary approach in the management of diabetes and its complications.
Topics: Adult; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Diabetic Retinopathy; Female; Humans; Male; Tomography, Optical Coherence
PubMed: 34708808
DOI: 10.4103/ijo.IJO_1279_21 -
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 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 -
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