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International Journal of Molecular... Jan 2024Abnormal NAD signaling has been implicated in axonal degeneration in diabetic peripheral neuropathy (DPN). We hypothesized that supplementing NAD precursors could...
Abnormal NAD signaling has been implicated in axonal degeneration in diabetic peripheral neuropathy (DPN). We hypothesized that supplementing NAD precursors could alleviate DPN symptoms through increasing the NAD levels and activating the sirtuin-1 (SIRT1) protein. To test this, we exposed cultured Dorsal Root Ganglion neurons (DRGs) to Nicotinamide Riboside (NR) or Nicotinamide Mononucleotide (NMN), which increased the levels of NAD, the SIRT1 protein, and the deacetylation activity that is associated with increased neurite growth. A SIRT1 inhibitor blocked the neurite growth induced via NR or NMN. We then induced neuropathy in C57BL6 mice with streptozotocin (STZ) or a high fat diet (HFD) and administered NR or NMN for two months. Both the STZ and HFD mice developed neuropathy, which was reversed through the NR or NMN administration: sensory function improved, nerve conduction velocities normalized, and intraepidermal nerve fibers were restored. The NAD levels and SIRT1 activity were reduced in the DRGs from diabetic mice but were preserved with the NR or NMN treatment. We also tested the effect of NR or NMN administration in mice that overexpress the SIRT1 protein in neurons (nSIRT1 OE) and found no additional benefit from the addition of the drug. These findings suggest that supplementing with NAD+ precursors or activating SIRT1 may be a promising treatment for DPN.
Topics: Animals; Mice; Diabetic Neuropathies; NAD; Diabetes Mellitus, Experimental; Sirtuin 1; Mice, Inbred C57BL; Nucleotides; Streptozocin
PubMed: 38256175
DOI: 10.3390/ijms25021102 -
Cells Oct 2023Diabetic peripheral neuropathy (DPN) is the prevalent type of peripheral neuropathy; it primarily impacts extremity nerves. Its multifaceted nature makes the molecular...
Diabetic peripheral neuropathy (DPN) is the prevalent type of peripheral neuropathy; it primarily impacts extremity nerves. Its multifaceted nature makes the molecular mechanisms of diabetic neuropathy intricate and incompletely elucidated. Several types of post-translational modifications (PTMs) have been implicated in the development and progression of DPN, including phosphorylation, glycation, acetylation and SUMOylation. SUMOylation involves the covalent attachment of small ubiquitin-like modifier (SUMO) proteins to target proteins, and it plays a role in various cellular processes, including protein localization, stability, and function. While the specific relationship between high blood glucose and SUMOylation is not extensively studied, recent evidence implies its involvement in the development of DPN in type 1 diabetes. In this study, we investigated the impact of SUMOylation on the onset and progression of DPN in a type 2 diabetes model using genetically modified mutant mice lacking SUMOylation, specifically in peripheral sensory neurons (SNS-Ubc9). Behavioural measurement for evoked pain, morphological analyses of nerve fibre loss in the epidermis, measurement of reactive oxygen species (ROS) levels, and antioxidant molecules were analysed over several months in SUMOylation-deficient and control mice. Our longitudinal analysis at 30 weeks post-high-fat diet revealed that SNS-Ubc9 mice exhibited earlier and more pronounced thermal and mechanical sensation loss and accelerated intraepidermal nerve fibre loss compared to control mice. Mechanistically, these changes are associated with increased levels of ROS both in sensory neuronal soma and in peripheral axonal nerve endings in SNS-Ubc9 mice. In addition, we observed compromised detoxifying potential, impaired respiratory chain complexes, and reduced levels of protective lipids in sensory neurons upon deletion of SUMOylation in diabetic mice. Importantly, we also identified mitochondrial malate dehydrogenase (MDH2) as a SUMOylation target, the activity of which is negatively regulated by SUMOylation. Our results indicate that SUMOylation is an essential neuroprotective mechanism in sensory neurons in type 2 diabetes, the deletion of which causes oxidative stress and an impaired respiratory chain, resulting in energy depletion and subsequent damage to sensory neurons.
Topics: Mice; Animals; Reactive Oxygen Species; Diabetic Neuropathies; Diabetes Mellitus, Experimental; Sumoylation; Diabetes Mellitus, Type 2; Sensory Receptor Cells
PubMed: 37947589
DOI: 10.3390/cells12212511 -
GeroScience Feb 2024Cellular senescence, a cell fate defined by irreversible cell cycle arrest, has been observed to contribute to chronic age-related conditions including non-healing...
Cellular senescence, a cell fate defined by irreversible cell cycle arrest, has been observed to contribute to chronic age-related conditions including non-healing wounds, such as diabetic foot ulcers. However, the role of cellular senescence in the pathogenesis of diabetic foot ulcers remains unclear. To examine the contribution of senescent phenotypes to these chronic wounds, differential gene and network analyses were performed on publicly available bulk RNA sequencing of whole skin biopsies of wound edge diabetic foot ulcers and uninvolved diabetic foot skin. Wald tests with Benjamini-Hochberg correction were used to evaluate differential gene expression. Results showed that cellular senescence markers, CDKN1A, CXCL8, IGFBP2, IL1A, MMP10, SERPINE1, and TGFA, were upregulated, while TP53 was downregulated in diabetic foot ulcers compared to uninvolved diabetic foot skin. NetDecoder was then used to identify and compare context-specific protein-protein interaction networks using known cellular senescence markers as pathway sources. The diabetic foot ulcer protein-protein interaction network demonstrated significant perturbations with decreased inhibitory interactions and increased senescence markers compared to uninvolved diabetic foot skin. Indeed, TP53 (p53) and CDKN1A (p21) appeared to be key regulators in diabetic foot ulcer formation. These findings suggest that cellular senescence is an important mediator of diabetic foot ulcer pathogenesis.
Topics: Humans; Wound Healing; Diabetic Foot; Skin; Cellular Senescence; Diabetes Mellitus
PubMed: 37380899
DOI: 10.1007/s11357-023-00854-x -
Journal of Managed Care & Specialty... Sep 2023Diabetic peripheral neuropathy, a common comorbidity of diabetes, is a neurodegenerative disorder that targets sensory, autonomic, and motor nerves frequently... (Randomized Controlled Trial)
Randomized Controlled Trial
Diabetic peripheral neuropathy, a common comorbidity of diabetes, is a neurodegenerative disorder that targets sensory, autonomic, and motor nerves frequently associated with painful diabetic neuropathy (PDN). PDN carries an economic burden as the result of reduced work and productivity. A recent multicenter randomized controlled trial, SENZA-PDN (NCT03228420), assessed the impact of high-frequency (10 kHz) spinal cord stimulation (SCS) on pain relief. The effects of high-frequency SCS on health care resource utilization and medical costs are not known. To evaluate the effect of high-frequency (10 kHz) SCS on health care resource utilization (HRU) and medical costs in patients with PDN using data from the SENZA-PDN trial. Participants with PDN were randomly assigned 1:1 to receive either 10 kHz SCS plus conventional medical management (CMM) (SCS treatment group) or CMM alone (CMM treatment group). Patient outcomes and HRU up to the 6-month follow-up are reported here. Costs (2020 USD) for each service was estimated based on publicly available Medicare fee schedules, Medicare claims data, and literature. HRU metrics of inpatient and outpatient contacts and costs are reported as means and SDs. Univariate and bivariate analyses were used to compare SCS and CMM treatment groups at 6 months. At 6-month follow up, the SCS arm experienced approximately half the mean rate of hospitalizations per patient compared with the CMM treatment group (0.08 vs 0.15; = 0.066). The CMM treatment group's total health care costs per patient were approximately 51% higher compared with the SCS treatment group (equivalent to mean annual cost per patient of $9,532 vs $6,300). Our analysis of the SENZA-PDN trial indicates that the addition of 10 kHz SCS therapy results in lower rates of hospitalization and consequently lower health care costs among patients with PDN compared with those receiving conventional management alone.
Topics: United States; Humans; Aged; Diabetic Neuropathies; Spinal Cord Stimulation; Medicare; Patient Acceptance of Health Care; Health Care Costs; Diabetes Mellitus
PubMed: 37610114
DOI: 10.18553/jmcp.2023.29.9.1021 -
Frontiers in Endocrinology 2024The mechanism of Nicotinamide Adenine Dinucleotide (NAD+) metabolism-related genes (NMRGs) in diabetic peripheral neuropathy (DPN) is unclear. This study aimed to find...
BACKGROUND
The mechanism of Nicotinamide Adenine Dinucleotide (NAD+) metabolism-related genes (NMRGs) in diabetic peripheral neuropathy (DPN) is unclear. This study aimed to find new NMRGs biomarkers in DPN.
METHODS
DPN related datasets GSE95849 and GSE185011 were acquired from the Gene Expression Omnibus (GEO) database. 51 NMRGs were collected from a previous article. To explore NMRGs expression in DPN and control samples, differential expression analysis was completed in GSE95849 to obtain differentially expressed genes (DEGs), and the intersection of DEGs and NMRGs was regarded as DE-NMRGs. Next, a protein-protein interaction (PPI) network based on DE-NMRGs was constructed and biomarkers were screened by eight algorithms. Additionally, Gene Set Enrichment Analysis (GSEA) enrichment analysis was completed, biomarker-based column line graphs were constructed, lncRNA-miRNA-mRNA and competing endogenouse (ce) RNA networks were constructed, and drug prediction was completed. Finally, biomarkers expression validation was completed in GSE95849 and GSE185011.
RESULTS
5217 DEGs were obtained from GSE95849 and 21 overlapping genes of DEGs and NMRGs were DE-NMRGs. Functional enrichment analysis revealed that DE-NMRGs were associated with glycosyl compound metabolic process. The PPI network contained 93 protein-interaction pairs and 21 nodes, with strong interactions between NMNAT1 and NAMPT, NADK and NMNAT3, ENPP3 and NUDT12 as biomarkers based on 8 algorithms. Expression validation suggested that ENPP3 and NUDT12 were upregulated in DPN samples (P < 0.05). Moreover, an alignment diagram with good diagnostic efficacy based on ENPP3 and NUDT12 were identified was constructed. GSEA suggested that ENPP3 was enriched in Toll like receptor (TLR) pathway, NUDT12 was enriched in maturity onset diabetes of the young and insulin pathway. Furthermore, 18 potential miRNAs and 36 Transcription factors (TFs) were predicted and the miRNA-mRNA-TF networks were constructed, suggesting that ENPP3 might regulate hsa-miR-34a-5p by affecting MYNN. The ceRNA network suggested that XLOC_013024 might regulate hsa-let-7b-5p by affecting NUDT12. 15 drugs were predicted, with 8 drugs affecting NUDT12 such as resveratrol, and 13 drugs affecting ENPP3 such as troglitazone.
CONCLUSION
ENPP3 and NUDT12 might play key roles in DPN, which provides reference for further research on DPN.
Topics: Humans; NAD; Diabetic Neuropathies; MicroRNAs; Biomarkers; RNA, Messenger; Diabetes Mellitus; Nicotinamide-Nucleotide Adenylyltransferase
PubMed: 38464965
DOI: 10.3389/fendo.2024.1309917 -
BMC Genomics Jan 2024Diabetic foot ulcer (DFU) is one of the most common and severe complications of diabetes, with vascular changes, neuropathy, and infections being the primary...
BACKGROUND
Diabetic foot ulcer (DFU) is one of the most common and severe complications of diabetes, with vascular changes, neuropathy, and infections being the primary pathological mechanisms. Glutamine (Gln) metabolism has been found to play a crucial role in diabetes complications. This study aims to identify and validate potential Gln metabolism biomarkers associated with DFU through bioinformatics and machine learning analysis.
METHODS
We downloaded two microarray datasets related to DFU patients from the Gene Expression Omnibus (GEO) database, namely GSE134431, GSE68183, and GSE80178. From the GSE134431 dataset, we obtained differentially expressed Gln-metabolism related genes (deGlnMRGs) between DFU and normal controls. We analyzed the correlation between deGlnMRGs and immune cell infiltration status. We also explored the relationship between GlnMRGs molecular clusters and immune cell infiltration status. Notably, WGCNA to identify differentially expressed genes (DEGs) within specific clusters. Additionally, we conducted GSVA to annotate enriched genes. Subsequently, we constructed and screened the best machine learning model. Finally, we validated the predictions' accuracy using a nomogram, calibration curves, decision curve analysis (DCA), and the GSE134431, GSE68183, and GSE80178 dataset.
RESULTS
In both the DFU and normal control groups, we confirmed the presence of deGlnMRGs and an activated immune response. From the GSE134431 dataset, we obtained 20 deGlnMRGs, including CTPS1, NAGS, SLC7A11, GGT1, GCLM, RIMKLA, ARG2, ASL, ASNS, ASNSD1, PPAT, GLS2, GLUD1, MECP2, ASS1, PRODH, CTPS2, ALDH5A1, DGLUCY, and SLC25A12. Furthermore, two clusters were identified in DFU. Immune infiltration analysis indicated the presence of immune heterogeneity in these two clusters. Additionally, we established a Support Vector Machine (SVM) model based on 5 genes (R3HCC1, ZNF562, MFN1, DRAM1, and PTGDS), which exhibited excellent performance on the external validation datasetGSE134431, GSE68183, and GSE80178 (AUC = 0.929).
CONCLUSION
This study has identified five Gln metabolism genes associated with DFU, revealing potential novel biomarkers and therapeutic targets for DFU. Additionally, the infiltration of immune-inflammatory cells plays a crucial role in the progression of DFU.
Topics: Humans; Diabetic Foot; Glutamine; Computational Biology; Databases, Factual; Biomarkers; Diabetes Mellitus
PubMed: 38287255
DOI: 10.1186/s12864-024-10038-2 -
BMJ Open Sep 2023Diabetes mellitus has been associated with increased dry eye disease (DED) and exacerbates DED pathology.
BACKGROUND
Diabetes mellitus has been associated with increased dry eye disease (DED) and exacerbates DED pathology.
OBJECTIVE
To investigate the potential relationship between corneal nerve loss and ocular pain among diabetic patients with dry eye (DE).
DESIGN
A cross-sectional study.
SETTING
He Eye Specialist Hospital, Shenyang, China.
PARTICIPANTS
This study recruited 124 eyes of 62 diabetic patients diagnosed with DED between August and October 2022.
MAIN OUTCOME MEASURES
Best-corrected visual acuity, intraocular pressure, non-invasive tear breakup time, tear meniscus height, tear film lipid layer, conjunctival hyperaemia (redness score), conjunctivocorneal epithelial staining (CS score), central corneal sensitivity and vitro confocal corneal microscopy was assessed in all subjects. The Ocular Surface Disease Index Questionnaire assessed DE symptoms and ocular pain.
RESULTS
The study's final analysis included 26 patients (52 eyes) without ocular pain and 36 patients (72 eyes) with ocular pain. The corneal nerve fibre density (CNFD), corneal nerve branch density (CNBD) and corneal nerve fibre length (CNFL) in patients with ocular pain were significantly lower than those without (p<0.001, p=0.004, and p<0.001, respectively). CNFD, CNBD and CNFL negatively correlated with ocular pain (r=-0.385, r=-0.260, r=-0.358, respectively). Moreover, CNFD, CNBD and CNFL have a significant (p<0.05) positive correlation with corneal sensitivity (r=0.523, r=0.330, r=0.421, respectively).
CONCLUSIONS
Corneal nerve loss was associated with ocular pain and decreased corneal sensitivity in diabetic patients with DE. Further studies into the neurological role of ocular surface diseases can elaborate diagnostics, prognosis and treatment of diabetic patients with DE.
TRIAL REGISTRATION NUMBER
ClinicalTrials.gov (NCT05193331).
Topics: Male; Humans; Cross-Sectional Studies; Cornea; Diabetic Neuropathies; Dry Eye Syndromes; Pain; Diabetes Mellitus
PubMed: 37751961
DOI: 10.1136/bmjopen-2023-076932 -
European Review For Medical and... Aug 2023This study aimed to investigate the relationship between serum asprosin level and diabetic peripheral neuropathy (DPN) in community patients with type 2 diabetes...
OBJECTIVE
This study aimed to investigate the relationship between serum asprosin level and diabetic peripheral neuropathy (DPN) in community patients with type 2 diabetes mellitus (T2DM).
PATIENTS AND METHODS
A total of 498 patients with T2DM were recruited from Zhuoma Community Health Service Station and Chengbei West Street Community Health Service Center in Changzhi City of Shanxi Province between November 2019 and July 2021. Their height, weight, and body mass index (BMI), as well as fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c), triglyceride (TG), and serum asprosin levels, were analyzed. Patients were divided into the DPN group (n = 329) and the non-DPN group (n = 169) according to the presence or absence of DPN. The t-test, Mann-Whitney U test, and χ² test were used to compare the indicators between the two groups. Pearson or Spearman correlation analysis was used to evaluate the correlation between serum asprosin and other clinical data. Multivariate logistic regression analysis was used to analyze the influencing factors of DPN.
RESULTS
Compared with the non-DPN group, the DPN group had higher serum asprosin (p < 0.05). The prevalence of DPN gradually increased according to the tertiles of asprosin (56%, 67%, and 75%; p < 0.05). Multivariate logistic regression analysis showed that after adjustment for covariates, patients with asprosin concentrations between 295.4-367.0 pg/ml and concentrations > 367.0 pg/ml had a higher risk of diabetic neuropathy compared than those with asprosin levels < 295.4 pg/ml (p < 0.05).
CONCLUSIONS
Serum asprosin was found to be positively correlated with DPN, and it resulted as an influencing factor for DPN in patients with T2DM in the community. With the increase of asprosin, the risk of DPN also increased.
Topics: Humans; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Body Mass Index; Fasting; Glycated Hemoglobin
PubMed: 37667933
DOI: 10.26355/eurrev_202308_33408 -
International Journal of Molecular... Mar 2024Non-healing wounds and skin losses constitute significant challenges for modern medicine and pharmacology. Conventional methods of wound treatment are effective in basic... (Review)
Review
Non-healing wounds and skin losses constitute significant challenges for modern medicine and pharmacology. Conventional methods of wound treatment are effective in basic healthcare; however, they are insufficient in managing chronic wound and large skin defects, so novel, alternative methods of therapy are sought. Among the potentially innovative procedures, the use of skin substitutes may be a promising therapeutic method. Skin substitutes are a heterogeneous group of materials that are used to heal and close wounds and temporarily or permanently fulfill the functions of the skin. Classification can be based on the structure or type (biological and synthetic). Simple constructs (class I) have been widely researched over the years, and can be used in burns and ulcers. More complex substitutes (class II and III) are still studied, but these may be utilized in patients with deep skin defects. In addition, 3D bioprinting is a rapidly developing method used to create advanced skin constructs and their appendages. The aforementioned therapies represent an opportunity for treating patients with diabetic foot ulcers or deep skin burns. Despite these significant developments, further clinical trials are needed to allow the use skin substitutes in the personalized treatment of chronic wounds.
Topics: Humans; Skin, Artificial; Bioengineering; Biomedical Engineering; Diabetic Foot; Burns
PubMed: 38612513
DOI: 10.3390/ijms25073702 -
BMC Health Services Research Oct 2023International evidence suggests that an integrated multidisciplinary approach to diabetic foot management is necessary to prevent ulceration and progression to...
BACKGROUND
International evidence suggests that an integrated multidisciplinary approach to diabetic foot management is necessary to prevent ulceration and progression to amputation. Many health systems have introduced policies or models of care supporting the introduction of this evidence into practice, but little is known about the experiences of those involved in implementation. This study addresses this gap by examining the experiences of podiatrists providing integrated diabetic foot care.
METHODS
Between October 2017 and April 2018, an online survey comprising closed and open-ended questions on podiatrists' demographics, clinical activity, links with other services, continuous professional development activities and experiences of implementing the Model of Care was administered to podiatrists (n = 73) working for Ireland's Health Service Executive in the community and hospital setting. Data were analysed using descriptive statistics and qualitative content analysis.
RESULTS
The response rate was 68% (n = 50), with 46% (n = 23), 38% (n = 19) and 16% (n = 8) working across hospital, community and both settings, respectively. Most reported treating high-risk patients (66%), those with active foot disease (61%) and educating people about the risk of diabetes to the lower limb (80%). Reported challenges towards integrated diabetic foot care include a perceived lack of awareness of the role of podiatry amongst other healthcare professionals, poor integration between hospital and community podiatry services, especially where new services had been developed, and insufficient number of podiatrists to meet service demands.
CONCLUSION
Previous evidence has shown that there is often a gap between what is set out by a policy and what it looks like when delivered to service users. Results from the current study support this, highlighting that while most podiatrists work in line with national recommendations, there are specific gaps and challenges that need to be addressed to ensure successful policy implementation.
Topics: Humans; Diabetic Foot; Ireland; Foot Diseases; Podiatry; Surveys and Questionnaires; Diabetes Mellitus
PubMed: 37884981
DOI: 10.1186/s12913-023-10144-z