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Chong ZZ, Souayah N. Neuroinflammation in diabetic peripheral neuropathy and therapeutic implications. Rev Neurosci 2025:revneuro-2025-0031. [PMID: 40228523 DOI: 10.1515/revneuro-2025-0031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Accepted: 03/28/2025] [Indexed: 04/16/2025]
Abstract
Diabetic peripheral neuropathy (DPN) is a serious complication of diabetes mellitus, which is a common cause of disability in individuals with diabetes mellitus. Multiple mechanisms may be involved in the development of DPN. Neuroinflammation is a critical factor contributing to nerve damage during diabetes. Inflammation can induce the development of diabetes mellitus, and long-term hyperglycemia also causes increased oxidative stress and promotes the release of inflammatory cytokines. After reading through the literature, the association of inflammation with the induction of diabetes and DPN was discussed in the review. Inflammation induces nerve damage and nerve conduction impairment. The neuropathic pain in diabetes-induced DPN is also closely associated with the inflammatory response. Given the important roles of inflammation in diabetes-induced DPN, explicit elucidation of neuroinflammation during diabetes mellitus and DPN should hold the potential for developing novel therapeutic strategies for DPN. Experimental studies and limited clinical trials support the value of anti-inflammatory reagents in treating DPN, and the positive outcomes of these investigations warrant further clinical trials.
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Affiliation(s)
- Zhao Zhong Chong
- Department of Neurology, New Jersey Medical School, Rutgers University, 185 S Orange, Newark, NJ 07103, USA
| | - Nizar Souayah
- Department of Neurology, New Jersey Medical School, Rutgers University, 90 Bergen Street DOC 8100, Newark, NJ 07101, USA
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2
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Pilar CM, Florencia AM, Agustina NK, Mariana M, Ornella C, Anna DTL, Adelina B, Verónica BM. Inducing elevated glucose levels in vitro: A model to simulate prediabetes (preDBT) states in primary cultures. Brain Behav Immun 2025; 128:323-335. [PMID: 40239905 DOI: 10.1016/j.bbi.2025.04.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 03/23/2025] [Accepted: 04/12/2025] [Indexed: 04/18/2025] Open
Abstract
There is increasing evidence suggesting a relationship between prediabetes (preDBT, the early stage of Type 2 Diabetes or DBT2) and neurodegenerative disorders (NDDs) such as Alzheimer's disease. The preDBT stage, characterized by impaired fasting glucose (IFG), may represent an early risk factor for cognitive decline and the onset of NDDs. However, the underlying mechanisms connecting preDBT to cognitive impairment and neurodegeneration remain poorly understood. This study aims to explore the effects of IFG on central nervous system (CNS) cells by developing an in vitro model of preDBT using sera from individuals with IFG. Our results demonstrate that exposure of astrocyte-neuron mixed cultures to IFG sera induced hyperglycemia, increased oxidative levels and astrogliosis that would lead to cognitive impairment observed in the analyzed cohort, as evidenced by a battery of cognitive tests. These findings suggest that the early stages of preDBT may trigger changes in CNS cells that correlate with cognitive decline. The study underscores the importance of early diagnosis and intervention in preDBT to prevent progression to DBT2 and associated NDDs.
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Affiliation(s)
- Canal Maria Pilar
- Instituto de Biología Celular y Neurociencia (IBCN), CONICET-UBA, Argentina
| | | | | | - Munner Mariana
- Hospital General de Agudos José María Penna, CABA, Argentina
| | - Caruso Ornella
- Hospital General de Agudos José María Penna, CABA, Argentina
| | | | | | - Baez María Verónica
- Instituto de Biología Celular y Neurociencia (IBCN), CONICET-UBA, Argentina; 1UA de Histología, Embriología, Biología Celular y Genética. Facultad de Medicina, Universidad de Buenos Aires (UBA), Argentina.
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3
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Chong ZZ, Souayah N. Crumbling Pathogenesis and Biomarkers for Diabetic Peripheral Neuropathy. Biomedicines 2025; 13:413. [PMID: 40002826 PMCID: PMC11853266 DOI: 10.3390/biomedicines13020413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Revised: 01/31/2025] [Accepted: 02/06/2025] [Indexed: 02/27/2025] Open
Abstract
Background: Diabetic sensorimotor polyneuropathy (DSP) is a common chronic diabetic complication. Traditionally, DSP was once considered irreversible with a typical loss of axon. However, the superimpose of acquired demyelination on axonal loss in DSP patients has been observed, implying that DSP may be preventable or reversible, particularly within a subgroup of patients exhibiting early-stage acquired demyelination, underscoring the critical importance of identifying early prognostic markers. Methods: We systemically review the literature on the roles of biomarkers in predicting DSP and monitoring the progress. The underlying mechanisms of biomarkers were also discussed. Results: The pathogenesis of DSP is multifaceted, with various pathological mechanisms contributing to its development. Key mechanisms include aberrant glucose metabolism and induction of oxidative stress and inflammation. Several pathological processes, such as disrupted glucose metabolism, nerve damage, impaired microcirculation, genetic variants, and microRNA dysregulation, lead to molecular and protein changes that may be detectable in blood and other biological compartments, thus serving as potential biomarkers for DSP progression. However, the utility of a biomarker depends on its predictive accuracy, practicality, and ease of measurement. Conclusions: Most biomarkers for predicting DSP have demonstrated suboptimal predictive value, and many lack established accuracy in forecasting DSP progression. Consequently, the diagnostic utility of any single biomarker remains limited. A comprehensive combination of biomarkers from various categories may hold incredible promise for accurate detection. As artificial intelligence (AI) techniques, especially machine learning, rapidly advance, these technologies may offer significant potential for developing diagnostic platforms to integrate and interpret complex biomarker data for DSP.
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Affiliation(s)
- Zhao Zhong Chong
- Department of Neurology, New Jersey Medical School, Rutgers University, 185 S. Orange Ave, Newark, NJ 07103, USA
| | - Nizar Souayah
- Department of Neurology, New Jersey Medical School, Rutgers University, 90 Bergen Street DOC 8100, Newark, NJ 07101, USA
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Ang L, Gunaratnam S, Huang Y, Dillon BR, Martin CL, Burant A, Reiss J, Blakely P, Vasbinder A, Zhao L, Mizokami‐Stout K, Tang Y, Feldman EL, Doria A, Spino C, Banerjee M, Hayek SS, Pop‐Busui R. Inflammatory Markers and Measures of Cardiovascular Autonomic Neuropathy in Type 1 Diabetes. J Am Heart Assoc 2025; 14:e036787. [PMID: 39727210 PMCID: PMC12054404 DOI: 10.1161/jaha.124.036787] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 10/28/2024] [Indexed: 12/28/2024]
Abstract
BACKGROUND Cardiovascular autonomic neuropathy (CAN) and inflammation predict more severe outcomes in type 1 diabetes (T1D). However, the link between CAN and inflammation in T1D remains unclear. We examined associations between CAN measures and inflammatory biomarkers in individuals with T1D. METHODS AND RESULTS In a cross-sectional study, we measured cardiovascular autonomic reflex tests and heart rate variability (established CAN measures) and a panel of 39 inflammatory biomarkers, including soluble urokinase plasminogen activator receptor (suPAR), in T1D participants of the TINSAL-T1DN (Targeting Inflammation with Salsalate in Individuals with T1D Neuropathy) trial (n=57, discovery), and the PERL (Preventing Early Renal Loss in Diabetes) trial (n=468, validation). Amongst 39 inflammatory biomarkers measured in TINSAL-T1DN, suPAR levels had the strongest negative correlations with CAN measures: expiration/inspiration (r=-0.48), Valsalva (r=-0.28), 30:15 (r=-0.37), SD of the normal RR interval (r=-0.37), and root mean square of differences of successive RR intervals (r=-0.31) (all P<0.05). Findings were validated in PERL. In unadjusted analyses, median suPAR levels significantly differed between the lowest and highest SD of the normal RR interval tertiles (3.79 versus 3.12 ng/mL, P<0.001) and root mean square of differences of successive RR intervals (3.76 versus 3.17 ng/mL, P<0.001). After adjusting for covariates (age, sex, hemoglobin A1c, and estimated glomerular filtration rate), median suPAR values remained significantly elevated in the lowest tertiles of SD of the normal RR interval (P=0.004) and root mean square of differences of successive RR intervals (P=0.006). CONCLUSIONS Amongst several inflammatory biomarkers, suPAR, an immune-mediated glycoprotein, has a singular association with CAN measures. The potential of targeting suPAR as a disease-modifying approach for CAN in T1D warrants further exploration. REGISTRATION URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02936843, NCT02017171.
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Affiliation(s)
- Lynn Ang
- Department of Internal Medicine, Division of Metabolism, Endocrinology, and DiabetesUniversity of MichiganAnn ArborMIUSA
| | | | - Yiyuan Huang
- Department of BiostatisticsUniversity of MichiganAnn ArborMIUSA
| | | | - Catherine L. Martin
- Department of Internal Medicine, Division of Metabolism, Endocrinology, and DiabetesUniversity of MichiganAnn ArborMIUSA
| | - Aaron Burant
- Department of Internal Medicine, Division of Metabolism, Endocrinology, and DiabetesUniversity of MichiganAnn ArborMIUSA
| | - Jacob Reiss
- Quality DepartmentUniversity of MichiganAnn ArborMIUSA
| | - Pennelope Blakely
- Department of Internal Medicine, Division of CardiologyUniversity of Texas Medical BranchGalvestonTXUSA
| | - Alexi Vasbinder
- Biobehavioral Nursing and Health InformaticsUniversity of Washington School of NursingSeattleWAUSA
| | - Lili Zhao
- Corewell Health William Beaumont University HospitalRoyal OakMIUSA
| | - Kara Mizokami‐Stout
- Department of Internal Medicine, Division of Metabolism, Endocrinology, and DiabetesUniversity of MichiganAnn ArborMIUSA
- Ann Arbor Veteran Affairs HospitalAnn ArborMIUSA
| | - Yaling Tang
- Department of EpidemiologyJoslin Diabetes CenterBostonMAUSA
| | - Eva L. Feldman
- Department of NeurologyUniversity of MichiganAnn ArborMIUSA
| | | | - Cathie Spino
- Department of BiostatisticsUniversity of MichiganAnn ArborMIUSA
| | | | - Salim S. Hayek
- Department of Internal Medicine, Division of CardiologyUniversity of Texas Medical BranchGalvestonTXUSA
- Department of Internal Medicine, Division of CardiologyUniversity of MichiganAnn ArborMIUSA
| | - Rodica Pop‐Busui
- Department of Internal Medicine, Division of Metabolism, Endocrinology, and DiabetesUniversity of MichiganAnn ArborMIUSA
- Department of Internal Medicine, Division of Endocrinology, Diabetes and Clinical NutritionOregon Health and Science UniversityPortlandORUSA
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Li C, Feng Y, Feng L, Li M. Causal relationship between dyslipidemia and diabetic neuropathy: a mendelian randomization study. Metab Brain Dis 2024; 40:78. [PMID: 39729198 DOI: 10.1007/s11011-024-01448-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 10/06/2024] [Indexed: 12/28/2024]
Abstract
Some studies have shown an association between dyslipidemia and diabetic neuropathy (DN), but the genetic association has not been clarified. Therefore, the present study aimed to investigate the genetic causal association between dyslipidemia and DN through a Mendelian randomization (MR) approach. Genetic causal associations between total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL), and high-density lipoprotein cholesterol (HDL) and DN were investigated by MR to provide a basis for the prevention and treatment of DN. Significant and independent single-nucleotide polymorphisms (SNPs) identified in genome-wide association studies were selected as instrumental variables (IVs) for MR analysis. Inverse variance weighted (IVW), MR‒Egger regression, weighted median (WME), simple mode (SM), and weighted mode (WM) methods were used to analyze causal associations. Heterogeneity and multiplicity tests were also performed and analyzed using the leave-one-out method to assess the stability of the results. Genetically predicted TC and DN (OR = 0.793, 95% CI = 0.655⁓0.961, P = 0.019) and LDL and DN (OR = 0.842, 95% CI = 0.711⁓0.998, P = 0.049) may be causally associated, but no causal associations were found between TG and DN (OR = 0.837, 95% CI = 0.631⁓1.111, P = 0.221) or between HDL and DN (OR = 1.192, 95% CI = 0.940⁓1.510, P = 0.149). TC and LDL may have genetic causal associations with DN, though no genetic causal associations were found for TG or HDL with DN. However, this study may have several limitations, and further clinical studies are needed to expand the sample size for future validation.
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Affiliation(s)
- Cong Li
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Yu Feng
- Affiliated Hospital of the Changchun University of Chinese Medicine, Changchun, China
| | - Lina Feng
- Department of Neurology, the Second Affiliated Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, 271000, China.
- Department of Neurology, Third Affiliated Clinical Hospital of the Changchun University of Chinese Medicine, Changchun, 130022, China.
| | - Mingquan Li
- Department of Neurology, Third Affiliated Clinical Hospital of the Changchun University of Chinese Medicine, Changchun, 130022, China.
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Panou T, Gouveri E, Papazoglou D, Papanas N. The role of novel inflammation-associated biomarkers in diabetic peripheral neuropathy. Metabol Open 2024; 24:100328. [PMID: 39559514 PMCID: PMC11570971 DOI: 10.1016/j.metop.2024.100328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 10/31/2024] [Accepted: 10/31/2024] [Indexed: 11/20/2024] Open
Abstract
Diabetic neuropathy is one of the commonest complications of diabetes mellitus. Its most frequent form is diabetic peripheral neuropathy (DPN). Currently, there is no established and widely used biomarker for diagnosis and clinical staging of DPN. There is accumulating evidence that low-grade systemic inflammation is a key element in its pathogenesis. In this context, several clinical studies have so far identified potential biomarkers of DPN. These studies have enrolled both subjects with type 1 diabetes mellitus (T1DM) and subjects with type 2 diabetes mellitus (T2DM), including children with T1DM and elderly T2DM subjects. They have also evaluated participants with prediabetes. Potential biomarkers include a wide spectrum of cytokines, chemokines and immune receptors, notably interleukins (IL), mostly IL-1, IL-6 or IL-10, as well as mediators of the tumour necrosis factor-α (TNF-α) related pathway. Cell-ratios, such as neurtrophil-to-lymphocyte ratio (NLR), have yielded promising results as well. Other works have focused on adipokines and identified several signalling molecules (adiponectin, neuregulin 4, isthmin-1 and omentin) as promising biomarkers of DPN. Finally, epigenetic biomarkers have been investigated. Further experience is being gathered with the use of biomarkers in specific age groups and in the discrimination between painless and painful DPN. Prospective studies appear promising in monitoring of DPN progression, but experience is rather limited. Finally, certain cut-off values have been proposed for DPN screening, but these need confirmation. Future large-scale studies are now required to validate biomarkers and to investigate their potential clinical utility.
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Affiliation(s)
- Theodoros Panou
- Diabetes Centre, Second Department of Internal Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Evanthia Gouveri
- Diabetes Centre, Second Department of Internal Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Dimitrios Papazoglou
- Diabetes Centre, Second Department of Internal Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Nikolaos Papanas
- Diabetes Centre, Second Department of Internal Medicine, Democritus University of Thrace, Alexandroupolis, Greece
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7
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Zhang X, Zhong G, Jiang C, Ha X, Yang Q, Wu H. Exploring the potential anti-diabetic peripheral neuropathy mechanisms of Huangqi Guizhi Wuwu Decoction by network pharmacology and molecular docking. Metab Brain Dis 2024; 40:20. [PMID: 39565454 DOI: 10.1007/s11011-024-01474-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 09/02/2024] [Indexed: 11/21/2024]
Abstract
Diabetic peripheral neuropathy (DPN) is the most prevalent microvascular complication of diabetes and Huangqi Guizhi Wuwu Decoction (HGWD) is frequently employed in classical Chinese medicine for treating DPN. This study aims to investigate the potential therapeutic targets and mechanisms of HGWD for treating DPN using network pharmacology and molecular docking methodologies. The intersection targets of DPN and HGWD were retrieved from the databases, with the resulting intersection targets being imported into the STRING database to construct the protein-protein interaction (PPI) network. Cytoscape 3.9.1 was used to screen the core targets and plot the herb-active ingredient-target (H-A-T) network. To identify the pivotal signaling pathways, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on intersection targets. Molecular docking was subsequently conducted with AutoDock Vina to validate the binding energy between the core active ingredients and the core targets. 91 potential targets of HGWD were identified for the treatment of DPN. Topological analysis revealed core targets, including AKT1, TNF, PPARG, NFKB1, TP53, STAT3, PTGS2, HIF1A, ESR1, and GSK3B, alongside core active ingredients such as protoporphyrin, jaranol, kaempferol, quercetin, and isorhamnetin. GO and KEGG analyses indicated that PI3K/AKT, HIF-1, and AGE/RAGE signaling pathways could be crucial in treating DPN using HGWD. Furthermore, molecular docking results demonstrated robust binding activities between the active ingredients in HGWD and the identified core targets. The above results indicated that HGWD may exerting an anti-DPN effect by modulating the PI3K/AKT, HIF-1, and AGE/RAGE signaling pathways.
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Affiliation(s)
- Xueying Zhang
- The Eighth Clinical Medical College, Guangzhou University of Chinese Medicine, Foshan, China
| | - Guangcheng Zhong
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chen Jiang
- The Eighth Clinical Medical College, Guangzhou University of Chinese Medicine, Foshan, China
| | - Xiaojun Ha
- The Eighth Clinical Medical College, Guangzhou University of Chinese Medicine, Foshan, China
| | - Qingjiang Yang
- The Eighth Clinical Medical College, Guangzhou University of Chinese Medicine, Foshan, China
| | - Haike Wu
- Department of Neurology, Foshan Hospital of Traditional Chinese Medicine, Foshan, China.
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Akácsos-Szász OZ, Pál S, Nyulas KI, Szilveszter M, Simon-Szabó Z, Dénes L, Májai E, Huțanu A, Stoian A, Tilinca MC, Nemes-Nagy E. The Predictive Role of Inflammatory Biomarkers and Their Correlation with the Biochemical Profile in Patients with Vasculopathy Undergoing Surgery. Int J Mol Sci 2024; 25:11989. [PMID: 39596058 PMCID: PMC11593650 DOI: 10.3390/ijms252211989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 11/03/2024] [Accepted: 11/06/2024] [Indexed: 11/28/2024] Open
Abstract
Inflammation is involved in the pathomechanism of vascular diseases. Pro-inflammatory cytokines are important in perioperative monitoring. The aim of the study was the perioperative assessment of biochemical tests and inflammatory markers in patients with vasculopathy, focusing on the identification of subjects prone to complications. The study was performed between 2020 and 2023 at the Clinical County Hospital in Târgu Mureș on enrolled diabetic and non-diabetic patients with vasculopathy and lower limb surgery (amputation or necrectomy). Pre- and postoperative inflammatory markers, biochemical, and hematological tests (n = 62) were performed. Positive correlation was found between preoperative C-reactive protein (CRP) and interleukin-6 (IL-6) levels, and between preoperative triglyceridemia and glycemia/cholesterolemia. Positive correlation was present between pre- and postoperative values of IL-6, tumor necrosis factor-alfa (TNF-α), CRP, and fibrinogen. Preoperative TNF-α values positively correlated with malondialdehyde (MDA) levels, postoperative TNF-α values with transaminase enzymes. Diabetic patients presented higher IL-6 results compared to non-diabetic subjects. We can conclude that dynamic assessment of inflammatory markers is appropriate for monitoring perioperative course. Half of the subjects presented moderately increased preoperative IL-6 levels, and one quarter had critically high values, which might predict prolonged hospitalization. The assessment of oxidative stress, inflammatory markers and biochemical parameters enables the identification of patients prone to complications, so they can benefit from more complex management.
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Affiliation(s)
- Orsolya-Zsuzsa Akácsos-Szász
- Doctoral School, Faculty of Medicine, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureş, 540139 Targu Mures, Romania
| | - Sándor Pál
- Department of Laboratory Medicine, Department of Transfusion Medicine, Medical School, University of Pécs, 7622 Pécs, Hungary
| | - Kinga-Ilona Nyulas
- Doctoral School, Faculty of Medicine, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureş, 540139 Targu Mures, Romania
| | - Mónika Szilveszter
- Clinic of Plastic Surgery, Mureș County Emergency Hospital, 540136 Targu Mures, Romania
| | - Zsuzsánna Simon-Szabó
- Department of Pathophysiology, Faculty of Medicine, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureş, 540139 Targu Mures, Romania;
| | - Lóránd Dénes
- Department of Anatomy, Embryology, Faculty of Medicine, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureş, 540139 Targu Mures, Romania;
| | - Erzsébet Májai
- Department of Toxicology and Biopharmacy, Faculty of Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureş, 540139 Targu Mures, Romania
| | - Adina Huțanu
- Center for Advanced Medical and Pharmaceutical Research, Department of Laboratory Medicine, Faculty of Medicine, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureş, 540139 Targu Mures, Romania
| | - Adina Stoian
- Department of Pathophysiology, Faculty of Medicine, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureş, 540139 Targu Mures, Romania;
| | - Mariana Cornelia Tilinca
- Department of Internal Medicine I, Faculty of Medicine in English, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureş, 540139 Targu Mures, Romania
| | - Enikő Nemes-Nagy
- Department of Chemistry and Medical Biochemistry, Faculty of Medicine in English, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureş, 540139 Targu Mures, Romania;
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Ma J, Chen Y, Si Y, Qian J, Wang C, Jin J, He Q. The multifaceted nature of diabetic erectile dysfunction: uncovering the intricate mechanisms and treatment strategies. Front Endocrinol (Lausanne) 2024; 15:1460033. [PMID: 39583965 PMCID: PMC11581859 DOI: 10.3389/fendo.2024.1460033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 10/07/2024] [Indexed: 11/26/2024] Open
Abstract
Background One of the most common complications of diabetes mellitus is diabetic erectile dysfunction (DMED), a condition that has grown more common in recent years and has a significant impact on patients' daily lives. The complicated pathophysiological changes of DMED, involving vascular, neurological, muscular, and endocrine variables, have not been well addressed by any one treatment technique, and no widely approved treatment strategy has been developed. Aim The objective of this study was to thoroughly examine the complex nature of the pathogenic mechanism of DMED and discover new therapeutic approaches that could improve DMED symptoms. Methods Studies and review articles from the past 10 years were considered. Results The pathogenesis of DMED encompasses vascular dysfunction, endothelial cell damage, cavernous smooth muscle defects, neurological dysfunction, endocrine/metabolic factors, leukomalacia fibrosis, and psychosocial factors, elucidating complex interplay among the mechanisms underlying DMED. It underscores the need of integrating traditional herbal medicine, energy-based medicine treatments, and advanced techniques like stem cell and gene therapy to enhance therapeutic outcomes. Furthermore, it expresses optimism on the therapeutic potential of new nanobiomaterials in DMED. Conclusion Through integrating a complete description of DMED etiology and current therapy methods, this work offers a helpful resource for researchers, doctors, and patients dealing with this difficult condition.
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Affiliation(s)
- Jianxiong Ma
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Yihao Chen
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Yuhe Si
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jiahua Qian
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Chenxi Wang
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Juan Jin
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Qiang He
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
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Costa CMM, Santos DS, Opretzka LCF, de Assis Silva GS, Santos GC, Evangelista AF, Soares MBP, Villarreal CF. Different mechanisms guide the antinociceptive effect of bone marrow-mononuclear cells and bone marrow-mesenchymal stem/stromal cells in trigeminal neuralgia. Life Sci 2024; 354:122944. [PMID: 39111567 DOI: 10.1016/j.lfs.2024.122944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 07/21/2024] [Accepted: 08/04/2024] [Indexed: 08/10/2024]
Abstract
AIMS Trigeminal neuralgia (TN) is a type of chronic orofacial pain evoked by trivial stimuli that manifests as episodes of excruciating and sudden, recurrent paroxysmal pain. Most patients are refractory to pharmacological therapy used for the treatment of TN. Mononuclear cells (MNC) and mesenchymal stem/stromal cells (MSC) have shown therapeutic potential in painful neuropathies, but their mechanism of action is not fully understood. The present work aimed to investigate the antinociceptive effect and mechanism of action of MNC and MSC in experimental TN. MATERIALS AND METHODS Mice submitted to the chronic constriction injury of the infraorbital nerve (CCI-ION) mouse model of TN received a single intravenous injection of saline, MNC, or MSC (1 × 106 cells/mouse). The effect of the treatments on the behavioral signs of painful neuropathy, morphological aspects of the infraorbital nerve, and inflammatory and oxidative stress markers in the infraorbital nerve were assessed. KEY FINDINGS MNC and MSC improved behavioral painful neuropathy, activated key cell signaling antioxidant pathways by increasing Nrf2 expression, and reduced the proinflammatory cytokines IL-1β and TNF-α. However, treatment with MSC, but not MNC, was associated with a sustained increase of IL-10 and with the re-establishment of the morphometric pattern of the infraorbital nerve, indicating a difference in the mechanism of action between MNC and MSC. In line with this result, in IL-10 knockout mice, MSC transplantation did not induce an antinociceptive effect. SIGNIFICANCE Importantly, these data suggest an IL-10-induced disease-modifying profile related to MSC treatment and reinforce cell therapy's potential in treating trigeminal neuralgia.
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Affiliation(s)
| | | | | | | | - Girlaine Café Santos
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador 40296-710, BA, Brazil.
| | | | - Milena Botelho Pereira Soares
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador 40296-710, BA, Brazil; Institute of Advanced Systems in Health, SENAI CIMATEC, Salvador 41650-010, BA, Brazil.
| | - Cristiane Flora Villarreal
- Faculty of Pharmacy, Federal University of Bahia, Salvador 40170-115, BA, Brazil; Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador 40296-710, BA, Brazil.
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Wu L, Wang XJ, Luo X, Zhang J, Zhao X, Chen Q. Diabetic peripheral neuropathy based on Schwann cell injury: mechanisms of cell death regulation and therapeutic perspectives. Front Endocrinol (Lausanne) 2024; 15:1427679. [PMID: 39193373 PMCID: PMC11348392 DOI: 10.3389/fendo.2024.1427679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Accepted: 07/24/2024] [Indexed: 08/29/2024] Open
Abstract
Diabetic peripheral neuropathy (DPN) is a complication of diabetes mellitus that lacks specific treatment, its high prevalence and disabling neuropathic pain greatly affects patients' physical and mental health. Schwann cells (SCs) are the major glial cells of the peripheral nervous system, which play an important role in various inflammatory and metabolic neuropathies by providing nutritional support, wrapping axons and promoting repair and regeneration. Increasingly, high glucose (HG) has been found to promote the progression of DPN pathogenesis by targeting SCs death regulation, thus revealing the specific molecular process of programmed cell death (PCD) in which SCs are disrupted is an important link to gain insight into the pathogenesis of DPN. This paper is the first to review the recent progress of HG studies on apoptosis, autophagy, pyroptosis, ferroptosis and necroptosis pathways in SCs, and points out the crosstalk between various PCDs and the related therapeutic perspectives, with the aim of providing new perspectives for a deeper understanding of the mechanisms of DPN and the exploration of effective therapeutic targets.
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Affiliation(s)
- Lijiao Wu
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiang Jin Wang
- School of Sports Medicine and Health, Chengdu Sports University, Chengdu, China
| | - Xi Luo
- Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jingqi Zhang
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xinyi Zhao
- College of lntegrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Hunan, China
| | - Qiu Chen
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
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12
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Costa YM, Herculiani CCF, Soares FFC, Azevedo MDCS, Conti PCR, Dionísio TJ, Oliveira GDM, Faria FACD, Santos CF, Garlet GP, Bonjardim LR. Impact of streptozotocin-induced diabetes on experimental masseter pain in rats. Braz Oral Res 2024; 38:e073. [PMID: 39109769 PMCID: PMC11376623 DOI: 10.1590/1807-3107bor-2024.vol38.0073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Accepted: 04/02/2024] [Indexed: 09/20/2024] Open
Abstract
This study aimed to assess the influence of streptozotocin (STZ)-induced diabetes on the nociceptive behavior evoked by the injection of hypertonic saline (HS) into the masseter muscle of rats. Forty male rats were equally divided into four groups: a) isotonic saline control, which received 0.9% isotonic saline (IS), (Ctrl-IS); b) hypertonic saline control, which received 5% HS (Ctrl-HS); c) STZ-induced diabetic, which received IS, (STZ-IS); d) STZ-induced diabetic, which received HS (STZ-HS). Experimental diabetes was induced by a single intraperitoneal injection of STZ at dose of 60 mg/kg dissolved in 0.1 M citrate buffer, and 100 μL of HS or IS were injected into the left masseter to measure the nociceptive behavior. Later on, muscle RNA was extracted to measure the relative expression of the following cytokines: cyclooxygenase-2 (COX-2), tumor necrosis factor (TNF-α), and interleukins (IL)-1β, -2, -6, and -10. One-way analysis of variance (ANOVA) was applied to the data (p < 0.050). We observed a main effect of group on the nociceptive response (ANOVA: F = 11.60, p < 0.001), where the Ctrl-HS group presented the highest response (p < 0.001). However, nociceptive response was similar among the Ctrl-IS, STZ-IS, and STZ-HS group (p > 0.050). In addition, the highest relative gene expression of TNF-α and IL-6 was found in the masseter of control rats following experimental muscle pain (p < 0.050). In conclusion, the loss of somatosensory function can be observed in deep orofacial tissues of STZ-induced diabetic rats.
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Affiliation(s)
- Yuri Martins Costa
- Universidade Estadual de Campinas - Unicamp, Piracicaba Dental School, Department of Biosciences, Piracicaba, SP, Brazil
| | | | - Flávia Fonseca Carvalho Soares
- Universidade de São Paulo - USP, Bauru School of Dentistry, Department of Biological Sciences, Bauru, São Paulo, SP, Brazil
| | | | | | - Thiago José Dionísio
- Universidade de São Paulo - USP, Bauru School of Dentistry, Department of Biological Sciences, Bauru, São Paulo, SP, Brazil
| | | | | | - Carlos Ferreira Santos
- Universidade de São Paulo - USP, Bauru School of Dentistry, Department of Biological Sciences, Bauru, São Paulo, SP, Brazil
| | - Gustavo Pompermaier Garlet
- Universidade de São Paulo - USP, Bauru School of Dentistry, Department of Biological Sciences, Bauru, São Paulo, SP, Brazil
| | - Leonardo Rigoldi Bonjardim
- Universidade de São Paulo - USP, Bauru School of Dentistry, Department of Biological Sciences, Bauru, São Paulo, SP, Brazil
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13
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Chong ZZ, Menkes DL, Souayah N. Targeting neuroinflammation in distal symmetrical polyneuropathy in diabetes. Drug Discov Today 2024; 29:104087. [PMID: 38969091 DOI: 10.1016/j.drudis.2024.104087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 06/24/2024] [Accepted: 07/01/2024] [Indexed: 07/07/2024]
Abstract
Diabetic distal symmetric polyneuropathy is the most common type of peripheral neuropathy complication of diabetes mellitus. Neuroinflammation is emerging as an important contributor to diabetes-induced neuropathy. Long-term hyperglycemia results in increased production of advanced glycation end products (AGEs). AGEs interact with their receptors to activate intracellular signaling, leading to the release of various inflammatory cytokines. Increased release of inflammatory cytokines is associated with diabetes, diabetic neuropathy, and neuropathic pain. Thus, anti-inflammatory intervention is a potential therapy for diabetic distal symmetric polyneuropathy. Further characterization of inflammatory mechanisms might identify novel therapeutic targets to mitigate diabetic neuropathy.
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Affiliation(s)
- Zhao Zhong Chong
- Department of Neurology, Rutgers University, New Jersey Medical School, Newark, NJ 07103, USA.
| | - Daniel L Menkes
- Department of Neurology, Oakland University William Beaumont School of Medicine, Rochester, MI 48309, USA
| | - Nizar Souayah
- Department of Neurology, Rutgers University, New Jersey Medical School, Newark, NJ 07103, USA.
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14
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Pușcașu C, Negreș S, Zbârcea CE, Ungurianu A, Ștefănescu E, Blebea NM, Chiriță C. Evaluating the Antihyperalgesic Potential of Sildenafil-Metformin Combination and Its Impact on Biochemical Markers in Alloxan-Induced Diabetic Neuropathy in Rats. Pharmaceuticals (Basel) 2024; 17:783. [PMID: 38931450 PMCID: PMC11206800 DOI: 10.3390/ph17060783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 06/03/2024] [Accepted: 06/06/2024] [Indexed: 06/28/2024] Open
Abstract
(1) Background: Globally, about 600 million people are afflicted with diabetes, and one of its most prevalent complications is neuropathy, a debilitating condition. At the present time, the exploration of novel therapies for alleviating diabetic-neuropathy-associated pain is genuinely captivating, considering that current therapeutic options are characterized by poor efficacy and significant risk of side effects. In the current research, we evaluated the antihyperalgesic effect the sildenafil (phosphodiesterase-5 inhibitor)-metformin (antihyperglycemic agent) combination and its impact on biochemical markers in alloxan-induced diabetic neuropathy in rats. (2) Methods: This study involved a cohort of 70 diabetic rats and 10 non-diabetic rats. Diabetic neuropathy was induced by a single dose of 130 mg/kg alloxan. The rats were submitted to thermal stimulus test using a hot-cold plate and to tactile stimulus test using von Frey filaments. Moreover, at the end of the experiment, the animals were sacrificed and their brains and livers were collected to investigate the impact of this combination on TNF-α, IL-6, nitrites and thiols levels. (3) Results: The results demonstrated that all sildenafil-metformin combinations decreased the pain sensitivity in the von Frey test, hot plate test and cold plate test. Furthermore, alterations in nitrites and thiols concentrations and pro-inflammatory cytokines (specifically TNF-α and IL-6) were noted following a 15-day regimen of various sildenafil-metformin combinations. (4) Conclusions: The combination of sildenafil and metformin has a synergistic effect on alleviating pain in alloxan-induced diabetic neuropathy rats. Additionally, the combination effectively decreased inflammation, inhibited the rise in NOS activity, and provided protection against glutathione depletion.
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Affiliation(s)
- Ciprian Pușcașu
- Faculty of Pharmacy, “Carol Davila” University of Medicine and Pharmacy, Traian Vuia 6, 020956 Bucharest, Romania; (C.P.); (S.N.); (A.U.); (E.Ș.); (C.C.)
| | - Simona Negreș
- Faculty of Pharmacy, “Carol Davila” University of Medicine and Pharmacy, Traian Vuia 6, 020956 Bucharest, Romania; (C.P.); (S.N.); (A.U.); (E.Ș.); (C.C.)
| | - Cristina Elena Zbârcea
- Faculty of Pharmacy, “Carol Davila” University of Medicine and Pharmacy, Traian Vuia 6, 020956 Bucharest, Romania; (C.P.); (S.N.); (A.U.); (E.Ș.); (C.C.)
| | - Anca Ungurianu
- Faculty of Pharmacy, “Carol Davila” University of Medicine and Pharmacy, Traian Vuia 6, 020956 Bucharest, Romania; (C.P.); (S.N.); (A.U.); (E.Ș.); (C.C.)
| | - Emil Ștefănescu
- Faculty of Pharmacy, “Carol Davila” University of Medicine and Pharmacy, Traian Vuia 6, 020956 Bucharest, Romania; (C.P.); (S.N.); (A.U.); (E.Ș.); (C.C.)
| | - Nicoleta Mirela Blebea
- Faculty of Pharmacy, “Ovidius” University of Constanța, Căpitan Aviator Al. Şerbănescu 6, 900470 Constanța, Romania;
| | - Cornel Chiriță
- Faculty of Pharmacy, “Carol Davila” University of Medicine and Pharmacy, Traian Vuia 6, 020956 Bucharest, Romania; (C.P.); (S.N.); (A.U.); (E.Ș.); (C.C.)
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15
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Zhang Y, Sun W, Zhang Q, Bai Y, Ji L, Zheng H, Zhu X, Liu X, Zhang S, Xiong Q, Li Y, Chen L, Lu B. Estimated glucose disposal rate predicts the risk of diabetic peripheral neuropathy in type 2 diabetes: A 5-year follow-up study. J Diabetes 2024; 16:e13482. [PMID: 38225901 PMCID: PMC11045912 DOI: 10.1111/1753-0407.13482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 07/01/2023] [Accepted: 09/16/2023] [Indexed: 01/17/2024] Open
Abstract
BACKGROUND Insulin resistance is associated with chronic complications of diabetes, including diabetic peripheral neuropathy (DPN). Estimated glucose disposal rate (eGDR), calculated by the common available clinical factors, was proved to be an excellent tool to measure insulin resistance in large patient population. Few studies have explored the association between eGDR and DPN longitudinally. Therefore, we performed the current study to analyze whether eGDR could predict the risk of DPN. METHODS In this prospective study, 366 type 2 diabetes (T2DM) subjects without DPN were enrolled from six communities in Shanghai in 2011-2014 and followed up until 2019-2020. Neuropathy was assessed by Michigan Neuropathy Screening Instrument (MSNI) at baseline and at the end of follow-up. FINDINGS After 5.91 years, 198 of 366 participants progressed to DPN according to MNSI examination scores. The incidence of DPN in the low baseline eGDR (eGDR < 9.15) group was significantly higher than in the high baseline eGDR (eGDR ≥ 9.15) group (62.37% vs. 45.56%, p = .0013). The incidence of DPN was significantly higher in patients with sustained lower eGDR level (63.69%) compared with those with sustained higher eGDR level (35.80%). Subjects with low baseline eGDR (eGDR < 9.15) had significantly higher risk of DPN at the end of follow-up (odds ratio = 1.75), even after adjusting for other known DPN risk factors. CONCLUSIONS The 5-year follow-up study highlights the importance of insulin resistance represented by eGDR in the development of DPN in T2DM. Diabetic patients with low eGDR are more prone to DPN and, therefore, require more intensive screening and more attention.
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Affiliation(s)
- Yuanpin Zhang
- Department of Endocrinology and MetabolismHuashan Hospital Fudan UniversityShanghaiChina
| | - Wanwan Sun
- Department of Endocrinology and MetabolismHuashan Hospital Fudan UniversityShanghaiChina
| | - Qi Zhang
- Department of Endocrinology and MetabolismHuashan Hospital Fudan UniversityShanghaiChina
| | - Yuetian Bai
- Department of Endocrinology and MetabolismHuashan Hospital Fudan UniversityShanghaiChina
| | - Lijin Ji
- Department of Endocrinology and MetabolismHuashan Hospital Fudan UniversityShanghaiChina
| | - Hangping Zheng
- Department of Endocrinology and MetabolismHuashan Hospital Fudan UniversityShanghaiChina
| | - Xiaoming Zhu
- Department of Endocrinology and MetabolismHuashan Hospital Fudan UniversityShanghaiChina
| | - Xiaoxia Liu
- Department of Endocrinology and MetabolismHuashan Hospital Fudan UniversityShanghaiChina
| | - Shuo Zhang
- Department of Endocrinology and MetabolismHuashan Hospital Fudan UniversityShanghaiChina
| | - Qian Xiong
- Department of EndocrinologyShanghai Gonghui HospitalShanghaiChina
| | - Yiming Li
- Department of Endocrinology and MetabolismHuashan Hospital Fudan UniversityShanghaiChina
| | - Lili Chen
- Department of Endocrinology and MetabolismHuashan Hospital Fudan UniversityShanghaiChina
| | - Bin Lu
- Department of Endocrinology and MetabolismHuashan Hospital Fudan UniversityShanghaiChina
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16
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Roohi TF, Mehdi S, Aarfi S, Krishna KL, Pathak S, Suhail SM, Faizan S. Biomarkers and signaling pathways of diabetic nephropathy and peripheral neuropathy: possible therapeutic intervention of rutin and quercetin. Diabetol Int 2024; 15:145-169. [PMID: 38524936 PMCID: PMC10959902 DOI: 10.1007/s13340-023-00680-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 11/30/2023] [Indexed: 03/26/2024]
Abstract
Diabetic nephropathy and peripheral neuropathy are the two main complications of chronic diabetes that contribute to high morbidity and mortality. These conditions are characterized by the dysregulation of multiple molecular signaling pathways and the presence of specific biomarkers such as inflammatory cytokines, indicators of oxidative stress, and components of the renin-angiotensin system. In this review, we systematically collected and collated the relevant information from MEDLINE, EMBASE, ELSEVIER, PUBMED, GOOGLE, WEB OF SCIENCE, and SCOPUS databases. This review was conceived with primary objective of revealing the functions of these biomarkers and signaling pathways in the initiation and progression of diabetic nephropathy and peripheral neuropathy. We also highlighted the potential therapeutic effectiveness of rutin and quercetin, two plant-derived flavonoids known for their antioxidant and anti-inflammatory properties. The findings of our study demonstrated that both flavonoids can regulate important disease-promoting systems, such as inflammation, oxidative stress, and dysregulation of the renin-angiotensin system. Importantly, rutin and quercetin have shown protective benefits against nephropathy and neuropathy in diabetic animal models, suggesting them as potential therapeutic agents. These findings provide a solid foundation for further comprehensive investigations and clinical trials to evaluate the potential of rutin and quercetin in the management of diabetic nephropathy and peripheral neuropathy. This may contribute to the development of more efficient and comprehensive treatment approaches for diabetes-associated complications.
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Affiliation(s)
- Tamsheel Fatima Roohi
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysore, Karnataka 570015 India
| | - Seema Mehdi
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysore, Karnataka 570015 India
| | - Sadaf Aarfi
- Department of Pharmaceutics, Amity University, Lucknow, Uttar Pradesh India
| | - K. L. Krishna
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysore, Karnataka 570015 India
| | - Suman Pathak
- Department of Dravyaguna, Govt. Ayurvedic Medical College, Shimoga, Karnataka 577 201 India
| | - Seikh Mohammad Suhail
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysore, Karnataka 570015 India
| | - Syed Faizan
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysore, Karnataka 570015 India
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17
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Cheng Y, Chen Y, Li K, Liu S, Pang C, Gao L, Xie J, Wenjing LV, Yu H, Deng B. How inflammation dictates diabetic peripheral neuropathy: An enlightening review. CNS Neurosci Ther 2024; 30:e14477. [PMID: 37795833 PMCID: PMC11017439 DOI: 10.1111/cns.14477] [Citation(s) in RCA: 27] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 08/28/2023] [Accepted: 09/08/2023] [Indexed: 10/06/2023] Open
Abstract
BACKGROUND Diabetic peripheral neuropathy (DPN) constitutes a debilitating complication associated with diabetes. Although, the past decade has seen rapid developments in understanding the complex etiology of DPN, there are no approved therapies that can halt the development of DPN, or target the damaged nerve. Therefore, clarifying the pathogenesis of DPN and finding effective treatment are the crucial issues for the clinical management of DPN. AIMS This review is aiming to summary the current knowledge on the pathogenesis of DPN, especially the mechanism and application of inflammatory response. METHODS We systematically summarized the latest studies on the pathogenesis and therapeutic strategies of diabetic neuropathy in PubMed. RESULTS In this seminal review, the underappreciated role of immune activation in the progression of DPN is scrutinized. Novel insights into the inflammatory regulatory mechanisms of DPN have been unearthed, illuminating potential therapeutic strategies of notable clinical significance. Additionally, a nuanced examination of DPN's complex etiology, including aberrations in glycemic control and insulin signaling pathways, is presented. Crucially, an emphasis has been placed on translating these novel understandings into tangible clinical interventions to ameliorate patient outcomes. CONCLUSIONS This review is distinguished by synthesizing cutting-edge mechanisms linking inflammation to DPN and identifying innovative, inflammation-targeted therapeutic approaches.
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Affiliation(s)
- Yifan Cheng
- Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial People's HospitalAffiliated People's Hospital, Hangzhou Medical CollegeHangzhouChina
| | - Yinuo Chen
- Department of NeurologyFirst Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang ProvinceChina
- First School of Clinical MedicineWenzhou Medical UniversityWenzhouZhejiang ProvinceChina
| | - Kezheng Li
- Department of NeurologyFirst Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang ProvinceChina
- First School of Clinical MedicineWenzhou Medical UniversityWenzhouZhejiang ProvinceChina
| | - Shuwei Liu
- First School of Clinical MedicineWenzhou Medical UniversityWenzhouZhejiang ProvinceChina
| | - Chunyang Pang
- Department of NeurologyFirst Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang ProvinceChina
| | - Lingfei Gao
- Department of NeurologyFirst Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang ProvinceChina
| | - Jiali Xie
- Department of Neurology, Shanghai East HospitalTongji UniversityShanghaiP.R. China
| | - L. V. Wenjing
- Department of GeriatricsThe Affiliated Hospital of Qingdao UniversityQingdaoShandong ProvinceChina
| | - Huan Yu
- Department of PediatricsSecond Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Binbin Deng
- Department of NeurologyFirst Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang ProvinceChina
- First School of Clinical MedicineWenzhou Medical UniversityWenzhouZhejiang ProvinceChina
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18
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Sen A, Mohanraj PS, Ranjan A, Rajendran V, ArulVijayaVani S, Balan Y, Bansal A. Unraveling the Role of Tumor Necrosis Factor-Alpha in Diabetic Peripheral Neuropathy: A Systematic Review and Meta-Analysis. Cureus 2023; 15:e49926. [PMID: 38179375 PMCID: PMC10764202 DOI: 10.7759/cureus.49926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/04/2023] [Indexed: 01/06/2024] Open
Abstract
Diabetic peripheral neuropathy (DPN) is a prevalent and debilitating complication of diabetes mellitus, leading to sensory abnormalities, decreased balance, and increased risk of foot problems. Although tumor necrosis factor-alpha (TNF-α) has emerged as a potential factor in the pathogenesis of DPN, its role remains contested. This study intends to thoroughly analyze the association between TNF-α and DPN by combining data from various global studies. This systematic review and meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and included 23 articles investigating TNF-α levels in DPN patients for systematic review and 11 articles for meta-analysis. Data were extracted, and heterogeneity was examined. A random-effect model was chosen due to high heterogeneity. The major outcome measure across studies was serum TNF-α levels. The meta-analysis found a significant mean difference of 15.2464 (95% confidence interval = 4.4963; 25.9965) under the random-effect model due to the substantial heterogeneity (I2 = 98.1%) among included studies. The meta-analysis indicates a consistent elevation in TNF-α levels in individuals with DPN compared to those without neuropathy. This underlines the potential of TNF-α as a biomarker and contributor to diabetic neuropathy. Despite heterogeneity, the study's extensive scope and systematic approach enhance the trustworthiness and generalizability of the findings.
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Affiliation(s)
- Aniruddha Sen
- Biochemistry, All India Institute of Medical Sciences, Gorakhpur, Gorakhpur, IND
| | | | - Amit Ranjan
- Physical Medicine and Rehabilitation, All India Institute of Medical Sciences, Gorakhpur, Gorakhpur, IND
| | - Vinoth Rajendran
- Community Medicine & Family Medicine, All India Institute of Medical Sciences, Gorakhpur, Gorakhpur, IND
| | - Subramaniam ArulVijayaVani
- Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research Karaikal, Karaikal, IND
| | - Yuvaraj Balan
- Biochemistry, All India Institute of Medical Sciences, Madurai, Madurai, IND
| | - Akash Bansal
- Biochemistry, All India Institute of Medical Sciences, Gorakhpur, Gorakhpur, IND
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19
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Cheng MK, Guo YY, Kang XN, Zhang L, Wang D, Ren HH, Yuan G. Advances in cardiovascular-related biomarkers to predict diabetic peripheral neuropathy. World J Diabetes 2023; 14:1226-1233. [PMID: 37664477 PMCID: PMC10473952 DOI: 10.4239/wjd.v14.i8.1226] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 06/24/2023] [Accepted: 07/07/2023] [Indexed: 08/11/2023] Open
Abstract
Diabetic peripheral neuropathy (DPN) is a common chronic complication of diabetes mellitus. One of the most common types is distal symmetric poly-neuropathy, which begins as bilateral symmetry pain and hyperesthesia and gradually progresses into hypoesthesia with nerve fibre disorder and is frequently accompanied by depression and anxiety. Notably, more than half of patients with DPN can be asymptomatic, which tends to delay early detection. Furthermore, the study of adverse outcomes showed that DPN is a prominent risk factor for foot ulceration, gangrene and nontraumatic amputation, which decreases quality of life. Thus, it is essential to develop convenient diagnostic biomarkers with high sensitivity for screening and early intervention. It has been reported that there may be common pathways for microvascular and macrovascular complications of diabetes. The pathogenesis of both disorders involves vascular endothelial dys-function. Emerging evidence indicates that traditional and novel cardiovascular-related biomarkers have the potential to characterize patients by subclinical disease status and improve risk prediction. Additionally, beyond traditional cardiovascular-related biomarkers, novel cardiovascular-related biomarkers have been linked to diabetes and its complications. In this review, we evaluate the association between major traditional and nontraditional car-diovascular-related biomarkers of DPN, such as cardiac troponin T, B-type natriuretic peptide, C-reactive protein, myeloperoxidase, and homocysteine, and assess the evidence for early risk factor-based management strategies to reduce the incidence and slow the progression of DPN.
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Affiliation(s)
- Meng-Ke Cheng
- Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, Hubei Province, China
| | - Yao-Yao Guo
- Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, Hubei Province, China
| | - Xiao-Nan Kang
- Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, Hubei Province, China
| | - Lu Zhang
- Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, Hubei Province, China
| | - Dan Wang
- Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, Hubei Province, China
| | - Hui-Hui Ren
- Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, Hubei Province, China
| | - Gang Yuan
- Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, Hubei Province, China
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20
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Pușcașu C, Ungurianu A, Șeremet OC, Andrei C, Mihai DP, Negreș S. The Influence of Sildenafil-Metformin Combination on Hyperalgesia and Biochemical Markers in Diabetic Neuropathy in Mice. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1375. [PMID: 37629665 PMCID: PMC10456948 DOI: 10.3390/medicina59081375] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/19/2023] [Accepted: 07/24/2023] [Indexed: 08/27/2023]
Abstract
Background and objectives: Worldwide, approximately 500 million people suffer from diabetes and at least 50% of these people develop neuropathy. Currently, therapeutic strategies for reducing diabetic neuropathy (DN)-associated pain are limited and have several side effects. The purpose of the study was to evaluate the antihyperalgesic action of different sildenafil (phosphodiesterase-5 inhibitor) and metformin (antihyperglycemic agent) combinations in alloxan-induced DN. Methods: The study included 100 diabetic mice and 20 non-diabetic mice that were subjected to hot and cold stimulus tests. Furthermore, we determined the influence of this combination on TNF-α, IL-6 and nitrites levels in brain and liver tissues. Results: In both the hot-plate and tail withdrawal test, all sildenafil-metformin combinations administered in our study showed a significant increase in pain reaction latencies when compared to the diabetic control group. Furthermore, all combinations decreased blood glucose levels due to the hypoglycemic effect of metformin. Additionally, changes in nitrite levels and pro-inflammatory cytokines (TNF-α and IL-6) were observed after 14 days of treatment with different sildenafil-metformin combinations. Conclusions: The combination of these two substances increased the pain reaction latency of diabetic animals in a dose-dependent manner. Moreover, all sildenafil-metformin combinations significantly reduced the concentration of nitrites in the brain and liver, which are final products formed under the action of iNOS.
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Affiliation(s)
| | | | - Oana Cristina Șeremet
- Faculty of Pharmacy, “Carol Davila” University of Medicine and Pharmacy, Traian Vuia 6, 020956 Bucharest, Romania; (C.P.); (S.N.)
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Ding R, Zhu S, Zhao X, Yue R. Vascular endothelial growth factor levels in diabetic peripheral neuropathy: a systematic review and meta-analysis. Front Endocrinol (Lausanne) 2023; 14:1169405. [PMID: 37251664 PMCID: PMC10213658 DOI: 10.3389/fendo.2023.1169405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 04/28/2023] [Indexed: 05/31/2023] Open
Abstract
Objective Vascular endothelial growth factors (VEGFs, including VEGF-A, VEGF-B, VEGF-C, VEGF-D and PLGF) have important roles in the development and function of the peripheral nervous system. Studies have confirmed that VEGFs, especially VEGF-A (so called VEGF) may be associated with the diabetic peripheral neuropathy (DPN) process. However, different studies have shown inconsistent levels of VEGFs in DPN patients. Therefore, we conducted this meta-analysis to evaluate the relationship between cycling levels of VEGFs and DPN. Methods This study searched 7 databases, including PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), VIP Database, WanFang Database, and Chinese Biomedical Literature (CBM), to find the target researches. The random effects model was used to calculate the overall effect. Results 14 studies with 1983 participants were included, among which 13 studies were about VEGF and 1 was VEGF-B, so only the effects of VEGF were pooled. The result showed that there were obviously increased VEGF levels in DPN patients compared with diabetic patients without DPN (SMD:2.12[1.34, 2.90], p<0.00001) and healthy people (SMD:3.50[2.24, 4.75], p<0.00001). In addition, increased circulating VEGF levels were not associated with an increased risk of DPN (OR:1.02[0.99, 1.05], p<0.00001). Conclusion Compared with healthy people and diabetic patients without DPN, VEGF content in the peripheral blood of DPN patients is increased, but current evidence does not support the correlation between VEGF levels and the risk of DPN. This suggests that VEGF may play a role in the pathogenesis and repairment of DPN.
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Affiliation(s)
- Rui Ding
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shicong Zhu
- Department of Respiratory, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaoyan Zhao
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Rensong Yue
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
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22
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Li Y, Li Y, Deng N, Shi H, Caika S, Sen G. Training and External Validation of a Predict Nomogram for Type 2 Diabetic Peripheral Neuropathy. Diagnostics (Basel) 2023; 13:diagnostics13071265. [PMID: 37046484 PMCID: PMC10093299 DOI: 10.3390/diagnostics13071265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/19/2023] [Accepted: 03/21/2023] [Indexed: 03/30/2023] Open
Abstract
Background: Diabetic peripheral neuropathy (DPN) is a critical clinical disease with high disability and mortality rates. Early identification and treatment of DPN is critical. Our aim was to train and externally validate a prediction nomogram for early prediction of DPN. Methods: 3012 patients with T2DM were retrospectively studied. These patients were hospitalized between 1 January 2017 and 31 December 2020 in the First Affiliated Hospital of Xinjiang Medical University in Xinjiang, China. A total of 901 patients with T2DM from the Suzhou BenQ Hospital in Jiangsu, China who were hospitalized between 1 January 2019 and 31 December 2020 were considered for external validation. The least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression were performed to identify independent predictors and establish a nomogram to predict the occurrence of DPN. The performance of the nomogram was evaluated using a receiver operating characteristic curve (ROC), a calibration curve, and a decision curve analysis (DCA). Findings: Age, 25-hydroxyvitamin D3 [25(OH)D3], Duration of T2DM, high-density lipoprotein (HDL), hemoglobin A1c (HbA1c), and fasting blood glucose (FBG) were used to establish a nomogram model for predicting the risk of DPN. In the training and validation cohorts, the areas under the curve of the nomogram constructed from the above six factors were 0.8256 (95% CI: 0.8104–0.8408) and 0.8608 (95% CI: 0.8376–0.8840), respectively. The nomogram demonstrated excellent performance in the calibration curve and DCA. Interpretation: This study has developed and externally validated a nomogram model which exhibits good predictive ability in assessing DPN risk among the type 2 diabetes population. It provided clinicians with an accurate and effective tool for the early prediction and timely management of DPN.
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Affiliation(s)
- Yongsheng Li
- Department of Preventive Medicine, Medical College, Tarim University, Alar 843300, China
| | - Yongnan Li
- Nursing Department, Suzhou BenQ Hospital, Suzhou 215163, China
| | - Ning Deng
- College of Biomedical Engineering and Instrument Science, Ministry of Education Key Laboratory of Biomedical Engineering, Zhejiang University, Hangzhou 310027, China
| | - Haonan Shi
- College of Public Health, Xinjiang Medical University, Urumqi 830011, China
| | - Siqingaowa Caika
- The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China
| | - Gan Sen
- Department of Medical Engineering and Technology, Xinjiang Medical University, Urumqi 830011, China
- Correspondence:
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23
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TNF-α levels, hypertension, glycated hemoglobin, and lower limb pain are predictors of diabetic neuropathy. Int J Diabetes Dev Ctries 2023. [DOI: 10.1007/s13410-023-01170-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/19/2023] Open
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Nussrat SW, Ad'hiah AH. Interleukin-39 is a novel cytokine associated with type 2 diabetes mellitus and positively correlated with body mass index. Endocrinol Diabetes Metab 2023; 6:e409. [PMID: 36757903 PMCID: PMC10164431 DOI: 10.1002/edm2.409] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 01/27/2023] [Accepted: 01/29/2023] [Indexed: 02/10/2023] Open
Abstract
INTRODUCTION It is suggested that cytokines play a key role in the pathogenesis of type 2 diabetes mellitus (T2DM). Therefore, this study explored two recently discovered cytokines, interleukin (IL)-37 (anti-inflammatory) and IL-39 (pro-inflammatory), in T2DM due to limited data in this context. METHODS Serum IL-37 and IL-39 levels were determined in 106 T2DM patients and 109 controls using enzyme-linked immunosorbent assay kits. RESULTS Serum levels (median and interquartile range) of IL-37 (79 [47-102] vs. 60 [46-89] ng/L; probability [p] = .04) and IL-39 (66 [59-69] vs. 31 [19-42] ng/L; p < .001) were significantly elevated in T2DM patients compared to controls. As indicated by the area under the curve (AUC), IL-39 (AUC = 0.973; p < .001) was more predictable for T2DM than IL-37 (AUC = 0.582; p = .039). Elevated levels of IL-39 were significantly associated with T2DM (odds ratio = 1.30; p < .001), while IL-37 did not show this association. Classification of IL-37 and IL-39 levels by demographic and clinical characteristics of patients revealed some significant differences including gender (IL-39), body mass index (BMI; IL-37 and IL-39) and diabetic neuropathy (IL-39). BMI was positively correlated with IL-39 (correlation coefficient [rs ] = 0.27; p = .005) and glycosylated haemoglobin (rs = 0.31; p = .001), and negatively correlated with age at onset (rs = -0.24; p = .015). CONCLUSIONS IL-37 and IL-39 levels were elevated in the serum of T2DM patients. Besides, IL-39 is proposed to be a novel cytokine associated with T2DM and positively correlated with BMI.
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Affiliation(s)
- Shahad W Nussrat
- Department of Biotechnology, College of Science, University of Baghdad, Baghdad, Iraq
| | - Ali H Ad'hiah
- Tropical-Biological Research Unit, College of Science, University of Baghdad, Baghdad, Iraq
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25
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Mehdi S, Mehmood MH, Ahmed MG, Ashfaq UA. Antidiabetic activity of Berberis brandisiana is possibly mediated through modulation of insulin signaling pathway, inflammatory cytokines and adipocytokines in high fat diet and streptozotocin-administered rats. Front Pharmacol 2023; 14:1085013. [PMID: 37089941 PMCID: PMC10117783 DOI: 10.3389/fphar.2023.1085013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 03/22/2023] [Indexed: 04/25/2023] Open
Abstract
Medicinal plants play a key role in protection of chronic non-communicable ailments like diabetes, hypertension and dyslipidemia. Berberis brandisiana Ahrendt (Berberidaceae) is traditionally used to treat diabetes, liver problems, wounds, arthritis, infections, swelling and tumors. It is also known to be enriched with multiple phytoconstituents including berbamine, berberine, quercetin, gallic acid, caffeic acid, vanillic acid, benzoic acid, chlorogenic acid, syringic acid, p-coumaric acid, m-coumaric acid and ferulic acid. The efficacy of B. brandisiana has not been established yet in diabetes. This study has been planned to assess the antidiabetic activity of B. brandisiana in high fat diet and streptozotocin (HFD/STZ)-induced diabetes using animals. Administration of aqueous methanolic extract of B. brandisiana (AMEBB) and berbamine (Berb) for 8 weeks caused a dose dependent marked (p < 0.01) rise in serum insulin and HDL levels with a significant decline (p < 0.01) in glucose, triglycerides, glycosylated hemoglobin (HbA1c), cholesterol, LDL, LFTs and RFTs levels when compared with only HFD/STZ-administered rats. AMEBB and Berb also modulated inflammatory biomarkers (TNF-α, IL-6) and adipocytokines (leptin, adiponectin and chemerin). AMEBB (150 mg/kg and 300 mg/kg) and Berb (80 mg/kg and 160 mg/kg) treated rats showed a marked increase (p < 0.001) in catalase levels (Units/mg) in pancreas (42.4 ± 0.24, 47.4 ± 0.51), (38.2 ± 0.583, 48.6 ± 1.03) and liver (52 ± 1.41, 63.2 ± 0.51), (57.2 ± 0.58, 61.6 ± 1.24) and superoxide dismutase levels (Units/mg) in pancreas (34.8 ± 1.46, 38.2 ± 0.58), (33.2 ± 0.80, 40.4 ± 1.96) and liver (31.8 ± 1.52, 36.8 ± 0.96), (30 ± 0.70, 38.4 ± 0.81),respectively while a significant (p < 0.01) decrease in serum melondialdehyde levels (nmol/g) in pancreas (7.34 ± 0.17, 6.22 ± 0.22), (7.34 ± 0.20, 6.34 ± 0.11) and liver (9.08 ± 0.31,8.18 ± 0.29), (9.34 ± 0.10, 8.86 ± 0.24) compared to the data of only HFD/STZ-fed rats. Histopathological studies of pancreas, liver, kidney, heart and aorta revealed restoration of normal tissue architect in AMEBB and Berb treated rats. When mRNA expressions of candidate genes were assessed, AMEBB and Berb showed upregulation of IRS-1, SIRT1, GLUT-4 and downregulation of ADAM17. These findings suggest that AMEBB and Berb possess antidiabetic activity, possibly due to its effect on oxidative stress, glucose metabolism, inflammatory biomarkers and adipocytokines levels. Further upregulation of IRS-1, SIRT1, GLUT-4 and downregulation of ADAM17, demonstrated its potential impact on glucose homeostasis, insulin resistance and chronic inflammatory markers. Thus, this study provides support to the medicinal use of B. brandisiana and berbamine in diabetes.
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Affiliation(s)
- Shumaila Mehdi
- Department of Pharmacology, Faculty of Pharmaceutical Sciences, Government College University, Faisalabad, Pakistan
| | - Malik Hassan Mehmood
- Department of Pharmacology, Faculty of Pharmaceutical Sciences, Government College University, Faisalabad, Pakistan
- *Correspondence: Malik Hassan Mehmood, ,
| | - Mobeen Ghulam Ahmed
- Department of Pharmacology, Faculty of Pharmaceutical Sciences, Government College University, Faisalabad, Pakistan
| | - Usman Ali Ashfaq
- Department of Biotechnology and Bioinformatics, Faculty of Life Sciences, Government College University, Faisalabad, Pakistan
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26
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Siddiqui K, George TP, Mujammami M, Isnani A, Alfadda AA. The association of cell adhesion molecules and selectins (VCAM-1, ICAM-1, E-selectin, L-selectin, and P-selectin) with microvascular complications in patients with type 2 diabetes: A follow-up study. Front Endocrinol (Lausanne) 2023; 14:1072288. [PMID: 36843591 PMCID: PMC9948618 DOI: 10.3389/fendo.2023.1072288] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 01/09/2023] [Indexed: 02/11/2023] Open
Abstract
OBJECTIVE Chronic hyperglycemia induces pathogenic changes in the vascular endothelium and leads to the development of microvascular complications in patients with type 2 diabetes mellitus. Early identification of markers of diabetes complications may help to minimize the risk of the development and progression of microvascular complications. METHODS This follow-up study was conducted in type 2 diabetic cohort aged between 30-70 years. Out of 160 eligible participants, 70 of them completed follow-up. Levels of cell adhesion molecules and selectins (VCAM-1, ICAM-1, E-selectin, L-selectin and P-selectin) at baseline and follow-up were measured using Randox Evidence biochip analyzer (UK). Development of microvascular complications (diabetic neuropathy, retinopathy and nephropathy) was evaluated. RESULTS During the follow-up (2 years, median), 31 (44.3%) developed diabetic neuropathy, 10 (14.3%) developed diabetic retinopathy and, 27 (38.6%) developed diabetic nephropathy. A significant difference in levels of cell adhesion molecules and selectins were found in type 2 diabetic patients with and without microvascular complications. Multiple logistic regression analysis reveals that baseline level of VCAM-1 is significantly associated with microvascular complications; diabetic neuropathy(p=0.028), retinopathy (p=0.007) and nephropathy(p=<0.001). Additionally, levels of P-selectin (p=0.05) and L-selectin (p=0.008) is associated with diabetic nephropathy while retinopathy associated with L-selectin (p=0.005) only. CONCLUSION Cell adhesion molecules and selectins are indicators of microvascular complication among patients with type 2 diabetes (T2D). Association of these markers with the development of microvascular complications may provide additive information for developing strategies for diabetes management and prediction of microvascular complications.
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Affiliation(s)
- Khalid Siddiqui
- Strategic Center for Diabetes Research, College of Medicine, King Saud University, Riyadh, Saudi Arabia
- *Correspondence: Khalid Siddiqui,
| | - Teena P. George
- Strategic Center for Diabetes Research, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Muhammad Mujammami
- Strategic Center for Diabetes Research, College of Medicine, King Saud University, Riyadh, Saudi Arabia
- University Diabetes Center, King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia
- Department of Medicine, College of Medicine, and King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia
| | - Arthur Isnani
- Obesity Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Assim A. Alfadda
- Strategic Center for Diabetes Research, College of Medicine, King Saud University, Riyadh, Saudi Arabia
- Department of Medicine, College of Medicine, and King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia
- Obesity Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia
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Zhao P, Ding C, Fu X, Zhang Y, Gu J, Hu J, Wang C, Yang M, Sheng Y, Zhang Y, Chen X, Mao P, Liu CF. Ultrasound exploration of muscle characteristic changes and diabetic peripheral neuropathy in diabetic patients. JOURNAL OF CLINICAL ULTRASOUND : JCU 2022; 50:1403-1411. [PMID: 36218110 DOI: 10.1002/jcu.23365] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 09/13/2022] [Accepted: 09/18/2022] [Indexed: 06/16/2023]
Abstract
PURPOSE Using brightness mode ultrasound combined with shear wave elastography, this study aims to detect structural and functional changes of the medial head of gastrocnemius (MG) in type 2 diabetes mellitus (T2DM) patients with or without diabetic peripheral neuropathy (DPN). METHODS 149 T2DM patients (DPN group and non-DPN group) and 60 healthy volunteers (control group) were enrolled. We measured the absolute difference of fascicle length (FL), pennation angle (PA), and shear wave velocity (SWV) of both MG in neutral position and maximal ankle joint's plantar flexion and calculated ΔFL, ΔPA, and ΔSWV. These three parameters, along with muscle thickness (MT), were compared among the three groups. RESULTS In the DPN group, the MG's MT, ΔPA, and ΔSWV were significantly lower than in the non-DPN group (p < 0.01); these parameters achieved the highest scores in the control group (p < 0.01). The area under the receiver operating characteristic curve of the combination of ΔSWV and ΔFL was the largest for predicting inpatients with or without DPN. CONCLUSIONS Decreased muscle mass (MT) and muscle contractibility (ΔFL and ΔSWV) were detected in patients with T2DM, with or without DPN. ΔSWV and ΔFL of the MG showed high-diagnostic accuracy for DPN warning signs.
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Affiliation(s)
- Ping Zhao
- Department of Ultrasound, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Changwei Ding
- Department of Ultrasound, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Xinxu Fu
- Department of Ultrasound, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yingchun Zhang
- Department of Ultrasound, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Jiarui Gu
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Ji Hu
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Caishan Wang
- Department of Ultrasound, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Min Yang
- Department of Ultrasound, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yujing Sheng
- Department of Ultrasound, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Ying Zhang
- Department of Ultrasound, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiaofang Chen
- Department of Ultrasound, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Pan Mao
- Department of Ultrasound, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Chun-Feng Liu
- Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, China
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Abstract
Distal symmetric diabetic peripheral polyneuropathy (DPN) is the most common form of neuropathy in the world, affecting 30 to 50% of diabetic individuals and resulting in significant morbidity and socioeconomic costs. This review summarizes updates in the diagnosis and management of DPN. Recently updated clinical criteria facilitate bedside diagnosis, and a number of new technologies are being explored for diagnostic confirmation in specific settings and for use as surrogate measures in clinical trials. Evolving literature indicates that distinct but overlapping mechanisms underlie neuropathy in type 1 versus type 2 diabetes, and there is a growing focus on the role of metabolic factors in the development and progression of DPN. Exercise-based lifestyle interventions have shown therapeutic promise. A variety of potential disease-modifying and symptomatic therapies are in development. Innovations in clinical trial design include the incorporation of detailed pain phenotyping and biomarkers for central sensitization.
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Affiliation(s)
- Qihua Fan
- Department of Neurology, Division of Neuromuscular Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - A Gordon Smith
- Department of Neurology, Division of Neuromuscular Medicine, Virginia Commonwealth University, Richmond, VA, USA
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Saggam A, Kale P, Shengule S, Patil D, Gautam M, Tillu G, Joshi K, Gairola S, Patwardhan B. Ayurveda-based Botanicals as Therapeutic Adjuvants in Paclitaxel-induced Myelosuppression. Front Pharmacol 2022; 13:835616. [PMID: 35273508 PMCID: PMC8902067 DOI: 10.3389/fphar.2022.835616] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 01/19/2022] [Indexed: 12/31/2022] Open
Abstract
Chemotherapy-induced myelosuppression is one of the major challenges in cancer treatment. Ayurveda-based immunomodulatory botanicals Asparagus racemosus Willd (AR/Shatavari) and Withania somnifera (L.). Dunal (WS/Ashwagandha) have potential role to manage myelosuppression. We have developed a method to study the effects of AR and WS as therapeutic adjuvants to counter paclitaxel (PTX)-induced myelosuppression. Sixty female BALB/c mice were divided into six groups—vehicle control (VC), PTX alone, PTX with aqueous and hydroalcoholic extracts of AR (ARA, ARH) and WS (WSA, WSH). The myelosuppression was induced in mice by intraperitoneal administration of PTX at 25 mg/kg dose for three consecutive days. The extracts were orally administered with a dose of 100 mg/kg for 15 days prior to the induction with PTX administration. The mice were observed daily for morbidity parameters and were bled from retro-orbital plexus after 2 days of PTX dosing. The morbidity parameters simulate clinical adverse effects of PTX that include activity (extreme tiredness due to fatigue), behavior (numbness and weakness due to peripheral neuropathy), body posture (pain in muscles and joints), fur aspect and huddling (hair loss). The collected samples were used for blood cell count analysis and cytokine profiling using Bio-Plex assay. The PTX alone group showed a reduction in total leukocyte and neutrophil counts (4,800 ± 606; 893 ± 82) when compared with a VC group (9,183 ± 1,043; 1,612 ± 100) respectively. Pre-administration of ARA, ARH, WSA, and WSH extracts normalized leukocyte counts (10,000 ± 707; 9,166 ± 1,076; 10,333 ± 1,189; 9,066 ± 697) and neutrophil counts (1,482 ± 61; 1,251 ± 71; 1,467 ± 121; 1,219 ± 134) respectively. Additionally, higher morbidity score in PTX group (7.4 ± 0.7) was significantly restricted by ARA (4.8 ± 1.1), ARH (5.1 ± 0.6), WSA (4.5 ± 0.7), and WSH (5 ± 0.8). (Data represented in mean ± SD). The extracts also significantly modulated 20 cytokines to evade PTX-induced leukopenia, neutropenia, and morbidity. The AR and WS extracts significantly prevented PTX-induced myelosuppression (p < 0.0001) and morbidity signs (p < 0.05) by modulating associated cytokines. The results indicate AR and WS as therapeutic adjuvants in cancer management.
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Affiliation(s)
- Akash Saggam
- AYUSH-Center of Excellence, Center for Complementary and Integrative Health, School of Health Sciences, Savitribai Phule Pune University, Pune, India.,Serum Institute of India Pvt. Ltd., Pune, India
| | | | | | - Dada Patil
- Serum Institute of India Pvt. Ltd., Pune, India
| | | | - Girish Tillu
- AYUSH-Center of Excellence, Center for Complementary and Integrative Health, School of Health Sciences, Savitribai Phule Pune University, Pune, India
| | - Kalpana Joshi
- Department of Biotechnology, Sinhgad College of Engineering, Pune, India
| | | | - Bhushan Patwardhan
- AYUSH-Center of Excellence, Center for Complementary and Integrative Health, School of Health Sciences, Savitribai Phule Pune University, Pune, India
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30
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Chanda D, Ray S, Chakraborti D, Sen S, Mitra A. Interleukin-6 Levels in Patients With Diabetic Polyneuropathy. Cureus 2022; 14:e21952. [PMID: 35155045 PMCID: PMC8820488 DOI: 10.7759/cureus.21952] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/06/2022] [Indexed: 11/30/2022] Open
Abstract
Introduction Diabetic polyneuropathy (DPN) is a common chronic complication of type 2 diabetes. The pathogenesis of DPN is still debated, but proinflammatory cytokine mediators like interleukin-6 (IL-6) are possibly involved. We conducted this cross-sectional observational study to assess whether IL-6 levels increase in patients with DPN. Materials and methods This study was conducted at the Institute of Post Graduate Medical Education and Research Hospital in Kolkata, India, from 2016 to 2017. The study included 57 patients aged 30 to 60 years diagnosed with type 2 diabetes with neuropathy on clinical examination and nerve conduction study. Patients with neuropathy due to other causes were excluded. The study participants were assigned into one of four groups. Group 1 (n=15) served as healthy control patients, Group 2 (n=12) contained patients with type 2 diabetes without neuropathy, Group 3 (n=20) contained patients with type 2 diabetes with painful neuropathy, and Group 4 (n=10) contained patients with type 2 diabetes with painless neuropathy. We compared IL-6 levels between each group. Results There was no significant difference in serum IL-6 levels between healthy controls (Group 1) and patients with type 2 diabetes without neuropathy (Group 2). However, we noted a significant increase in serum IL-6 levels among patients with painful DPN (Group 3) compared to control groups. Interestingly, serum IL-6 levels were higher in patients with painful DPN (Group 3) than patients with painless DPN (Group 4). Conclusions IL-6 increases significantly in painful diabetic neuropathy patients compared to patients with diabetes with painless neuropathy and thus may have a role in the pathogenesis of pain in DPN. Serum IL6 level can be a potential noninvasive marker of painful DPN, and it can help distinguish painful DPN from other causes of pain in patients with diabetes.
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Affiliation(s)
- Debarati Chanda
- Physiology, Jagannath Gupta Institute of Medical Science and Hospital, Kolkata, IND
| | - Saswati Ray
- Physiology, Jagannath Gupta Institute of Medical Science and Hospital, Kolkata, IND
| | - Debjani Chakraborti
- Physiology, Jagannath Gupta Institute of Medical Science and Hospital, Kolkata, IND
| | - Sangita Sen
- Physiology, Institute of Post Graduate Medical Education & Research, Kolkata, IND
| | - Asis Mitra
- Internal Medicine, Ruby General Hospital, Kolkata, IND
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Cheng Y, Cao W, Zhang J, Wang J, Liu X, Wu Q, Lin Q. Determinants of Diabetic Peripheral Neuropathy and Their Clinical Significance: A Retrospective Cohort Study. Front Endocrinol (Lausanne) 2022; 13:934020. [PMID: 35957831 PMCID: PMC9360478 DOI: 10.3389/fendo.2022.934020] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 06/22/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND In this study, we investigated the epidemiological characteristics and predictors of diabetic peripheral neuropathy (DPN) in adult patients with type 2 diabetes mellitus (DM). METHODS The study was designed as a retrospective cohort trial at the First Affiliated Hospital of Wenzhou Medical University. From January 2017 to December 2020, a total of 1,262 patients with DM were enrolled to assess the risk factors for DPN. The patients were divided into two groups (DPN group and non-DPN group). The Mann-Whitney U test or t-test, receiver operating characteristic (ROC) analyses, univariate chi-square analyses, and multiple logistic regression analyses were used to analyze the adjusted predictors of DPN. RESULTS The overall prevalence of DPN in DM patients was 72.7% (n = 793/1,091). Multivariate analysis revealed that age > 66 years (odds ratio [OR], 2.647; 95% confidence interval [CI] 1.469-4.770; p = 0.002), history of hypertension (OR, 1.829; 95% CI 1.146-2.920; p = 0.011), neutrophil (NE) levels exceeding 4.0 × 109/L (OR 0.256; 95% CI 0.162-0.405; p = 0.001), lymphocyte (LY) levels over 3.0 × 109/L (OR 7.173; 95% CI 4.258-12.086; p = 0.000), HbA1c > 7.7% (OR 3.151; 95% CI 1.959-5.068; p = 0.000), and FT3 > 4.4 pmol/L (OR 0.417; 95% CI 0.263-0.662; p = 0.000) were six significant predictive factors for the prevalence of DPN. CONCLUSIONS High levels of LY, HbA1c, history of hypertension, and > 66 years of age increase the risk of DPN in adult patients with DM, while high levels of NE and FT3 were protective factors of DPN. Thus, the prediction of DPN can significantly be improved by identifying older patients over the age of 66 and history of hypertension, as well as establishing the biochemical cutoff values of NE, LY, HbA1c, and FT3.
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Affiliation(s)
- Yifan Cheng
- Department of Neurology, Center for Rehabilitation Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, China
| | - Wen Cao
- Department of Neurology, The Third Hospital of Peking University, Beijing, China
| | - Junzhe Zhang
- Department of Orthopaedic Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Jiabin Wang
- Department of Neurology, Hebei Medical University, Shijiazhuang, China
| | - Xiang Liu
- Department of Neurology, Hebei Medical University, Shijiazhuang, China
| | - Qianqian Wu
- Department of Geriatrics, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou, China
| | - Qingxia Lin
- Department of Psychiatry, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- *Correspondence: Qingxia Lin,
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Fan Q, Gordon Smith A. Recent updates in the treatment of diabetic polyneuropathy. Fac Rev 2022. [PMID: 36311537 DOI: 10.1270/r/11-30] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/13/2023] Open
Abstract
Distal symmetric diabetic peripheral polyneuropathy (DPN) is the most common form of neuropathy in the world, affecting 30 to 50% of diabetic individuals and resulting in significant morbidity and socioeconomic costs. This review summarizes updates in the diagnosis and management of DPN. Recently updated clinical criteria facilitate bedside diagnosis, and a number of new technologies are being explored for diagnostic confirmation in specific settings and for use as surrogate measures in clinical trials. Evolving literature indicates that distinct but overlapping mechanisms underlie neuropathy in type 1 versus type 2 diabetes, and there is a growing focus on the role of metabolic factors in the development and progression of DPN. Exercise-based lifestyle interventions have shown therapeutic promise. A variety of potential disease-modifying and symptomatic therapies are in development. Innovations in clinical trial design include the incorporation of detailed pain phenotyping and biomarkers for central sensitization.
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Affiliation(s)
- Qihua Fan
- Department of Neurology, Division of Neuromuscular Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - A Gordon Smith
- Department of Neurology, Division of Neuromuscular Medicine, Virginia Commonwealth University, Richmond, VA, USA
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Bönhof GJ, Herder C, Ziegler D. Diagnostic Tools, Biomarkers, and Treatments in Diabetic polyneuropathy and Cardiovascular Autonomic Neuropathy. Curr Diabetes Rev 2022; 18:e120421192781. [PMID: 33845748 DOI: 10.2174/1573399817666210412123740] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 02/24/2021] [Accepted: 03/02/2021] [Indexed: 11/22/2022]
Abstract
The various manifestations of diabetic neuropathy, including distal symmetric sensorimotor polyneuropathy (DSPN) and cardiovascular autonomic neuropathy (CAN), are among the most prevalent chronic complications of diabetes. Major clinical complications of diabetic neuropathies, such as neuropathic pain, chronic foot ulcers, and orthostatic hypotension, are associated with considerable morbidity, increased mortality, and diminished quality of life. Despite the substantial individual and socioeconomic burden, the strategies to diagnose and treat diabetic neuropathies remain insufficient. This review provides an overview of the current clinical aspects and recent advances in exploring local and systemic biomarkers of both DSPN and CAN assessed in human studies (such as biomarkers of inflammation and oxidative stress) for better understanding of the underlying pathophysiology and for improving early detection. Current therapeutic options for DSPN are (I) causal treatment, including lifestyle modification, optimal glycemic control, and multifactorial risk intervention, (II) pharmacotherapy derived from pathogenetic concepts, and (III) analgesic treatment against neuropathic pain. Recent advances in each category are discussed, including non-pharmacological approaches, such as electrical stimulation. Finally, the current therapeutic options for cardiovascular autonomic complications are provided. These insights should contribute to a broader understanding of the various manifestations of diabetic neuropathies from both the research and clinical perspectives.
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Affiliation(s)
- Gidon J Bönhof
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Department of Endocrinology, Medical Faculty and University Hospital, Heinrich Heine University, Düsseldorf, Germany
| | - Christian Herder
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Department of Endocrinology, Medical Faculty and University Hospital, Heinrich Heine University, Düsseldorf, Germany
- German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
| | - Dan Ziegler
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Department of Endocrinology, Medical Faculty and University Hospital, Heinrich Heine University, Düsseldorf, Germany
- German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
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Kim K, Oh TJ, Park YS, Chang W, Cho HC, Lee J, Lee YK, Choi SH, Jang HC. Association Between Fat Mass or Fat Fibrotic Gene Expression and Polyneuropathy in Subjects With Obesity: A Korean Metabolic Bariatric Surgery Cohort. Front Endocrinol (Lausanne) 2022; 13:881093. [PMID: 35651981 PMCID: PMC9149169 DOI: 10.3389/fendo.2022.881093] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 03/28/2022] [Indexed: 11/13/2022] Open
Abstract
AIM We aimed to investigate the association between obesity-related parameters and polyneuropathy (PN) and to evaluate inflammatory and fibrotic gene expression of fat as a potential mediator in subjects scheduled to undergo metabolic bariatric surgery (MBS). METHODS This was a cross-sectional study of MBS cohort. Body composition and visceral fat area (VFA) were quantified by bioimpedance analysis and computed tomography scan. PN was defined by Michigan Neuropathy Screening Instrument-Physical Examination score was > 2. We measured mRNA expression level of FN1, TIMP1, CCL2, and CXCL8 in omental fat tissue. RESULTS Of 189 subjects (mean age, 39.4 years; 69 [36.5%] male; mean body mass index, 38.5 kg/m2), prevalence of PN was 9.1% in subjects without diabetes (n = 110) and 20.3% in those with diabetes (n = 79). Nondiabetic subjects with PN had higher homeostatic model assessment-insulin resistance (6.8 ± 3.5 vs 4.5 ± 2.8, p = 0.041), and increased fat mass (58.5 ± 12.5 kg vs 50.5 ± 10.7 kg, p = 0.034), and VFA (309.4 ± 117.6 cm2vs 243.5 ± 94.2 cm2, p = 0.046) compared to those without PN. These obesity-related parameters were significantly associated with the presence of PN after adjusting for conventional risk factors of PN only in subjects without diabetes. In contrast, a fibrotic gene such as TIMP1 was independently associated with PN (adjusted odds ratio of 1.56; 95% confidence interval 1.06, 2.30) only in subjects with diabetes. CONCLUSION Increased adiposity was independently associated with PN in obese subjects without diabetes. In contrast, this association was not significant after adjusting conventional risk factors of PN in obese subjects with diabetes but increased fibrotic gene expression in fat was associated with PN in this group.
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Affiliation(s)
- Kyuho Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Tae Jung Oh
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
- *Correspondence: Tae Jung Oh,
| | - Young Suk Park
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Won Chang
- Department of Radiology, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Hyen Chung Cho
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Jihye Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Yun Kyung Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Sung Hee Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
| | - Hak Chul Jang
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
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Allam MA, Nassar YA, Shabana HS, Mostafa S, Khalil F, Zidan H, Abo-Ghebsha M, Abdelghaffar A, Essmat A, Elmahdi E. Prevalence and Clinical Significance of Subclinical Hypothyroidism in Diabetic Peripheral Neuropathy. Int J Gen Med 2021; 14:7755-7761. [PMID: 34785933 PMCID: PMC8579825 DOI: 10.2147/ijgm.s337779] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 10/26/2021] [Indexed: 12/14/2022] Open
Abstract
Background and Aim Diabetic peripheral neuropathy (DPN) is one of the most common and disabling complications of DM. Many studies documented the prevalence of clinical and subclinical hypothyroidism (SCH) in diabetic patients but not in the particular group of patients with DPN. The present study aimed to determine the prevalence of SCH in DPN patients and to evaluate its association with severity of DPN. Patients and Methods The present cross-sectional study was conducted on 300 consecutive patients with DPN. The clinical manifestations of DPN were documented according to the validated Arabic version of the Michigan Neuropathy Screening Instrument. Severity of DPN was categorized into mild (6–8 points), moderate (9–11 points) or severe (12+ points) according to the Toronto Clinical Scoring System. All patients were submitted to careful history-taking and full clinical and neurological examination. Patients were diagnosed with SCH if they had TSH level above the upper limit of the normal reference range in association with normal free thyroxine (FT4) level. Results SCH was prevalent in 53 patients (17.7%, 95% CI: 13.5%–22.5%). Patients with SCH had significantly higher frequency of severe DPN (52.8% versus 28.3%, p=0.003). It was also shown that patients with SCH had significantly higher HbA1c (8.4 ± 1.0 versus 7.3 ± 1.2%, p<0.001) and HOMA-IR (3.7 ± 0.8 versus 2.7 ± 0.9, p<0.001) when compared with patients without SCH. Logistic regression analysis identified patients’ age [OR (95% CI): 1.06 (1.03–1.08), p<0.001], HbA1c [OR (95% CI): 2.2 (1.7–2.9), p<0.001] and SCH [OR (95% CI): 7.7 (3.6–15.5), p<0.001] as independent predictors of DPN severity. Conclusion The present study showed that SCH is highly prevalent in DPN patients and is independently related to its severity.
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Affiliation(s)
- Mahmoud A Allam
- Department of Internal Medicine, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Youssef A Nassar
- Department of Internal Medicine, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Hosameldeen S Shabana
- Department of Internal Medicine, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Sadek Mostafa
- Department of Internal Medicine, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Farag Khalil
- Department of Internal Medicine, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Hendawy Zidan
- Department of Internal Medicine, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Mohammed Abo-Ghebsha
- Department of Clinical Pathology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Amir Abdelghaffar
- Department of Neurology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Ahmed Essmat
- Department of Neurology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Essam Elmahdi
- Department of Internal Medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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Baka P, Escolano-Lozano F, Birklein F. Systemic inflammatory biomarkers in painful diabetic neuropathy. J Diabetes Complications 2021; 35:108017. [PMID: 34389235 DOI: 10.1016/j.jdiacomp.2021.108017] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 04/21/2021] [Accepted: 08/03/2021] [Indexed: 12/29/2022]
Abstract
OBJECTIVES We conducted a systematic review of the literature with meta-analysis to determine whether painful diabetic neuropathy is associated with a specific inflammatory profile. METHODS The study is based on the PRISMA statement for systematic reviews. We performed a search of published studies up until January 2021 in MEDLINE and Web of Science based on heading and free text terms. The search strategy included the phrases: diabetic peripheral neuropathy, painful peripheral neuropathy individually and in combination with the terms: inflammation and inflammatory biomarkers. We screened titles and abstracts and performed data extraction. We also manually searched the article titles in the reference lists of key studies and reviews published in the last 20 years. DATA EXTRACTION Data extracted from the studies included study design, inclusion and exclusion criteria, sample type including serum and plasma, source of the sample including patients with peripheral diabetic neuropathy or patients with painful and painless neuropathy of any etiology. Blood concentrations of all measured cytokines were recorded. Whenever possible we calculated the effect size and confidence interval. Non-human studies were excluded from the meta-analysis. RESULTS Thirteen studies were included in this meta-analysis. The study design was cross-sectional, case control or cohort type studies. Specific inflammatory mediators are significantly higher in painful than in painless diabetic neuropathy as well as in painful neuropathies of any etiology. Markers of inflammation are also increased in those patients with diabetes mellitus, who suffer from peripheral neuropathy in comparison to patients with diabetes mellitus but no signs of peripheral neuropathy. A proinflammatory state may be the common denominator of pain and peripheral neuropathy in patients with diabetes mellitus but the inflammatory profiles seem to differ.
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Affiliation(s)
- Panoraia Baka
- University Hospital Mainz, Neurology Department, Mainz, Germany.
| | | | - Frank Birklein
- University Hospital Mainz, Neurology Department, Mainz, Germany
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Chen YM, Zhu Q, Cai J, Zhao ZJ, Yao BB, Zhou LM, Ji LD, Xu J. Upregulation of T Cell Receptor Signaling Pathway Components in Gestational Diabetes Mellitus Patients: Joint Analysis of mRNA and circRNA Expression Profiles. Front Endocrinol (Lausanne) 2021; 12:774608. [PMID: 35046894 PMCID: PMC8763273 DOI: 10.3389/fendo.2021.774608] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Accepted: 12/01/2021] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE Gestational diabetes mellitus (GDM) is one of the most common complications of pregnancy, and its pathogenesis is still unclear. Studies have shown that circular RNAs (circRNAs) can regulate blood glucose levels by targeting mRNAs, but the role of circRNAs in GDM is still unknown. Therefore, a joint microarray analysis of circRNAs and their target mRNAs in GDM patients and healthy pregnant women was carried out. METHODS In this study, microarray analyses of mRNA and circRNA in 6 GDM patients and 6 healthy controls were conducted to identify the differentially expressed mRNA and circRNA in GDM patients, and some of the discovered mRNAs and circRNAs were further validated in additional 56 samples by quantitative realtime PCR (qRT-PCR) and droplet digital PCR (ddPCR). RESULTS Gene ontology and pathway analyses showed that the differentially expressed genes were significantly enriched in T cell immune-related pathways. Cross matching of the differentially expressed mRNAs and circRNAs in the top 10 KEGG pathways identified 4 genes (CBLB, ITPR3, NFKBIA, and ICAM1) and 4 corresponding circRNAs (circ-CBLB, circ-ITPR3, circ-NFKBIA, and circ-ICAM1), and these candidates were subsequently verified in larger samples. These differentially expressed circRNAs and their linear transcript mRNAs were all related to the T cell receptor signaling pathway, and PCR results confirmed the initial microarray results. Moreover, circRNA/miRNA/mRNA interactions and circRNA-binding proteins were predicted, and circ-CBLB, circ-ITPR3, and circ-ICAM1 may serve as GDM-related miRNA sponges and regulate the expression of CBLB, ITPR3, NFKBIA, and ICAM1 in cellular immune pathways. CONCLUSION Upregulation of T cell receptor signaling pathway components may represent the major pathological mechanism underlying GDM, thus providing a potential approach for the prevention and treatment of GDM.
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Affiliation(s)
- Yan-ming Chen
- Department of Science and Education, Affiliated People’s Hospital of Ningbo University, Ningbo, China
- Department of Preventive Medicine, School of Medicine, Ningbo University, Ningbo, China
| | - Qiong Zhu
- Department of Pediatrics, Affiliated People’s Hospital of Ningbo University, Ningbo, China
| | - Jie Cai
- Department of Reproductive Medicine, Ningbo Women and Children’s Hospital, Ningbo, China
| | - Zhi-jia Zhao
- Department of Preventive Medicine, School of Medicine, Ningbo University, Ningbo, China
| | - Bin-bin Yao
- Department of Preventive Medicine, School of Medicine, Ningbo University, Ningbo, China
| | - Li-ming Zhou
- Department of Reproductive Medicine, Ningbo Women and Children’s Hospital, Ningbo, China
| | - Lin-dan Ji
- Department of Science and Education, Affiliated People’s Hospital of Ningbo University, Ningbo, China
- Department of Biochemistry, School of Medicine, Ningbo University, Ningbo, China
- Zhejiang Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, China
- *Correspondence: Lin-dan Ji, ; Jin Xu,
| | - Jin Xu
- Department of Preventive Medicine, School of Medicine, Ningbo University, Ningbo, China
- Zhejiang Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, China
- *Correspondence: Lin-dan Ji, ; Jin Xu,
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