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Ponce-Lopez T. Peripheral Inflammation and Insulin Resistance: Their Impact on Blood-Brain Barrier Integrity and Glia Activation in Alzheimer's Disease. Int J Mol Sci 2025; 26:4209. [PMID: 40362446 PMCID: PMC12072112 DOI: 10.3390/ijms26094209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2025] [Revised: 04/22/2025] [Accepted: 04/23/2025] [Indexed: 05/15/2025] Open
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and synaptic dysfunction. The accumulation of amyloid beta (Aβ) plaques and hyperphosphorylated tau protein leads to neuronal dysfunction, neuroinflammation, and glial cell activation. Emerging evidence suggests that peripheral insulin resistance and chronic inflammation, often associated with type 2 diabetes (T2D) and obesity, promote increased proinflammatory cytokines, oxidative stress, and immune cell infiltration. These conditions further damage the blood-brain barrier (BBB) integrity and promote neurotoxicity and chronic glial cell activation. This induces neuroinflammation and impaired neuronal insulin signaling, reducing glucose metabolism and exacerbating Aβ accumulation and tau hyperphosphorylation. Indeed, epidemiological studies have linked T2D and obesity with an increased risk of developing AD, reinforcing the connection between metabolic disorders and neurodegeneration. This review explores the relationships between peripheral insulin resistance, inflammation, and BBB dysfunction, highlighting their role in glial activation and the exacerbation of AD pathology.
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Affiliation(s)
- Teresa Ponce-Lopez
- Centro de Investigación en Ciencias de la Salud (CICSA), Facultad de Ciencias de la Salud, Universidad Anáhuac México Campus Norte, Huixquilucan 52786, Mexico
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Sergi D, Angelini S, Spaggiari R, Castaldo F, Zuliani G, Sanz JM, Passaro A, PANGEA study group. Advanced glycation end-product intake predicts insulin resistance in a sex-dependent fashion. Eur J Nutr 2025; 64:162. [PMID: 40263184 PMCID: PMC12014793 DOI: 10.1007/s00394-025-03672-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Collaborators] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 03/30/2025] [Indexed: 04/24/2025]
Abstract
PURPOSE Dietary advanced glycation end products (AGEs) have been implicated in promoting insulin resistance. However, their impact on insulin resistance in a mixed population made up of males and females remains controversial. The aim of this study was to evaluate whether the relationship between dietary AGEs and insulin resistance may be sex-dependent. METHODS 195 males and 239 females were included in this cross-sectional study. Study participants underwent anthropometric and metabolic assessments. AGE intake was estimated using food frequency questionnaires and databases reporting AGE content in individual food items. The relationship between AGE intake and insulin resistance, estimated using HOMA-IR, was assessed using Pearson correlation test. The predictive power of dietary AGEs towards HOMA-IR was investigated using stepwise linear regression. RESULTS AGE intake correlated positively with HOMA-IR in females (p < 0.01) but not in male study participants (p > 0.05). Moreover, AGE intake was able to increase the predictive power of BMI towards insulin resistance in females but not males. Instead, anthropometric variables were the only discriminants able to predict insulin resistance in males. CONCLUSION Dietary AGEs exert a sex-dependent effect on insulin resistance as their intake is associated with and able to predict HOMA-IR in females but not males. This suggests that females may be more susceptible to the deleterious impact of these glycotoxins on insulin sensitivity. Nevertheless, considering this study not involving a nutritional intervention to directly elucidate whether the effect of AGEs on insulin resistance is sex-dependent, further studies are warranted to confirm the present findings.
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Affiliation(s)
- Domenico Sergi
- Department of Translational Medicine, University of Ferrara, 44121, Ferrara, Italy
| | - Sharon Angelini
- Department of Translational Medicine, University of Ferrara, 44121, Ferrara, Italy
| | - Riccardo Spaggiari
- Department of Translational Medicine, University of Ferrara, 44121, Ferrara, Italy
| | - Fabiola Castaldo
- Department of Translational Medicine, University of Ferrara, 44121, Ferrara, Italy
| | - Giovanni Zuliani
- Department of Translational Medicine, University of Ferrara, 44121, Ferrara, Italy
| | - Juana Maria Sanz
- Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121, Ferrara, Italy.
| | - Angelina Passaro
- Department of Translational Medicine, University of Ferrara, 44121, Ferrara, Italy
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Collaborators
Edoardo Dalla Nora, Gloria Brombo, Eleonora Capati, Cecilia Soavi, Rosella Colonna, Elettra Mantovani, Mario Luca Morieri, Maria Agata Miselli, Alice Omenetto, Sefora Del Mastro, Gabriella Stifani, Daniela Francesconi, Stefano Lazzer, Giovanelli Nicola, Mirco Floreani, Martina Arteni, Alberto Botter, Desy Salvadego, Gianni Biolo, Roberta Situlin, Filippo Giorgio Di Girolamo, Mariella Sturma, Giuseppe Castiglia, Marcello Tence, Greta Del Fabbro, Sara Mazzucco, Paolo De Colle, Boštjan Šimunič, Rado Pišot, Uroš Marušič, Matej Plevnik, Saša Pišot, Dorjana Zerbo, Nina Mohorko, Petra Dolenc, Mojca Gabrijelčič Blenkuš,
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3
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Szablewski L. Associations Between Diabetes Mellitus and Neurodegenerative Diseases. Int J Mol Sci 2025; 26:542. [PMID: 39859258 PMCID: PMC11765393 DOI: 10.3390/ijms26020542] [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: 10/31/2024] [Revised: 01/03/2025] [Accepted: 01/07/2025] [Indexed: 01/27/2025] Open
Abstract
Diabetes mellitus (DM) and neurodegenerative diseases/disturbances are worldwide health problems. The most common chronic conditions diagnosed in persons 60 years and older are type 2 diabetes mellitus (T2DM) and cognitive impairment. It was found that diabetes mellitus is a major risk for cognitive decline, dementia, Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Different mechanisms of associations between these diseases and diabetes mellitus have been suggested. For example, it is postulated that an impaired intracellular insulin signaling pathway, together with hyperglycemia and hyperinsulinemia, may cause pathological changes, such as dysfunction of the mitochondria, oxidative stress inflammatory responses, etc. The association between diabetes mellitus and neurodegenerative diseases, as well as the mechanisms of these associations, needs further investigation. The aim of this review is to describe the associations between diabetes mellitus, especially type 1 (T1DM) and type 2 diabetes mellitus, and selected neurodegenerative diseases, i.e., Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. Suggested mechanisms of these associations are also described.
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Affiliation(s)
- Leszek Szablewski
- Chair and Department of General Biology and Parasitology, Medical University of Warsaw, Chałubińskiego 5, 02-004 Warsaw, Poland
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Li Y, Li H, Chen X, Liang X. Association between various insulin resistance indices and cardiovascular disease in middle-aged and elderly individuals: evidence from two prospectives nationwide cohort surveys. Front Endocrinol (Lausanne) 2024; 15:1483468. [PMID: 39649228 PMCID: PMC11620891 DOI: 10.3389/fendo.2024.1483468] [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: 08/20/2024] [Accepted: 11/04/2024] [Indexed: 12/10/2024] Open
Abstract
Background The estimated glucose disposal rate (eGDR), triglyceride glucose (TyG), triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio, and metabolic score for insulin resistance (METS-IR) are dependent indicators of insulin resistance (IR). We aimed to evaluate the association between these indicators and the current or feature incidence of cardiovascular disease (CVD) in middle-aged and elderly individuals. This study tests the hypothesis that IR indices positively or negatively correlate with CVD, and that the potential predictive performance of the IR indices was not the same. Methods Middle-aged and elderly individuals from the National Health and Nutrition Examination Survey (NHANES) and the China Health and Retirement Longitudinal Study (CHARLS) with complete data on eGDR, TyG, TG/HDL-C, and METS-IR at baseline were obtained. The association between the four indices and CVD was evaluated using multivariate logistic regression analysis. In addition, an adjusted restricted cubic spline (RCS) was applied. Finally, the potential predictive performance of the IR indices was assessed using receiver operating characteristic (ROC) curves. Results We included 7,220 participants (mean age: 61.9 ± 10.7 years; 54.0% male) from the NHANES cohort and 6,426 participants (mean age: 57.9 ± 8.4 years; 45.2% male) from the CHARLS cohort in the study. Multivariate logistic regression analysis indicated that a decreasing eGDR significantly increased the incidence of CVD both presently and in the future. Similarly, a higher TyG level and METS-IR were significantly associated with a higher incidence of CVD at both timeframes. However, the TG/HDL-C ratio was not significantly associated with CVD, heart disease, or stroke. No significant interactions were observed between the continuous or quartile variables of eGDR, TyG, TG/HDL-C, or METS-IR, and the incidence of various endpoints across most subgroups. The ROC curve indicated the superior predictive performance of the IR indices. Furthermore, the eGDR was superior to other IR indices for the prediction of CVD both at present and in the future in middle-aged and elderly individuals. Conclusion As continuous variables, eGDR, TyG, and METS-IR were significantly associated with the incidence of CVD, both currently and in the future, among middle-aged and elderly individuals. Notably, incorporating eGDR, TyG, or METS-IR and the basic model significantly increased the predictive value for CVD. Among these indices, the eGDR index stands out as the most promising parameter for predicting CVD, both at present and in the future.
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Affiliation(s)
- Yan Li
- Department of Clinical Pharmacy, Guangxi Academy of Medical Sciences and the People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China
| | - Huijuan Li
- Phase 1 Clinical Trial Laboratory, Guangxi Academy of Medical Sciences and the People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China
| | - Xiaoyu Chen
- Department of Clinical Pharmacy, Guangxi Academy of Medical Sciences and the People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China
- Phase 1 Clinical Trial Laboratory, Guangxi Academy of Medical Sciences and the People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China
| | - Xueyan Liang
- Phase 1 Clinical Trial Laboratory, Guangxi Academy of Medical Sciences and the People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China
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Erim B, Binici Hİ. Advanced glycation end products: understanding their health risks and effective prevention strategies. NUTRIRE 2024; 49:54. [DOI: 10.1186/s41110-024-00298-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 10/07/2024] [Indexed: 01/03/2025]
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U N, R C T, R KR, Mahalingam G. Glucose transporters and their energy homeostasis function in various organs. VITAMINS AND HORMONES 2024; 128:1-47. [PMID: 40097247 DOI: 10.1016/bs.vh.2024.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2025]
Abstract
Glucose transporters (GLUTs) belong to a membrane-protein family that essentially participates in easing the transportation and absorption of glucose molecules throughout the cellular membranes. From the brain to the eyes, each section delves into the intricate mechanisms of glucose uptake and utilization, shedding light on the unique adaptations and regulatory pathways in different anatomical structures. Beginning with the brain, known for its high energy demands, the chapter explicates the specialized GLUT expression patterns crucial for neuronal function and synaptic transmission. Moving to metabolic powerhouses like the liver, muscles, and adipose tissue, it elucidates the dynamic interplay of GLUT isoforms in energy storage, mobilization, and insulin responsiveness. Furthermore, the chapter navigates through the kidneys, lungs, skin, and reproductive organs, unveiling the diverse roles of GLUTs in renal glucose reabsorption, pulmonary-epithelial transportation, skin barrier associated functions, and gonadal development. It also explores the significance of placental GLUTs in fatal nutrient supply and the implications of cardiac GLUTs in myocardial energy metabolism. Additionally, it examines the intricate regulation of GLUTs at key barriers like the BBB (Blood-Brain Barrier) and placenta, as well as in endocrine glands such as the pancreas, adrenal medulla and thyroid. Moreover, it further elucidates the less-explored territories of GLUT expression in the bones, gastrointestinal tract, and ocular tissues like the retina, unraveling their implications in immune function, bone metabolism, intestinal glucose-sensing, and retinal physiology.
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Affiliation(s)
- Nithya U
- Department of Bio-Medical Sciences, School of Bio, sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Theijeswini R C
- Department of Bio-Medical Sciences, School of Bio, sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Karthick Raja R
- Department of Bio-Medical Sciences, School of Bio, sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Gayathri Mahalingam
- Department of Bio-Medical Sciences, School of Bio, sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India.
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Michalani MLE, Passarelli M, Machado UF. Nuclear Factor-Kappa-B Mediates the Advanced Glycation End Product-Induced Repression of Slc2a4 Gene Expression in 3T3-L1 Adipocytes. Int J Mol Sci 2024; 25:8242. [PMID: 39125811 PMCID: PMC11311564 DOI: 10.3390/ijms25158242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 07/23/2024] [Accepted: 07/24/2024] [Indexed: 08/12/2024] Open
Abstract
Advanced glycated end products (AGEs) are cytotoxic compounds that are mainly increased in diabetes mellitus (DM), kidney failure, inflammation, and in response to the ingestion of AGE-rich diets. AGEs can also impair glycemic homeostasis by decreasing the expression of the Slc2a4 (solute carrier family 2 member 4) gene and its GLUT4 (solute carrier family 2, facilitated glucose transporter member 4) protein in muscle. However, the mechanisms underlying AGE's effect on adipocytes have not been demonstrated yet. This study investigated the effects of AGEs upon Slc2a4/GLUT4 expression in 3T3-L1 adipocytes, as well as the potential role of NFKB (nuclear factor NF-kappa-B) activity in the effects observed. Adipocytes were cultured in the presence of control albumin (CA) or advanced glycated albumin (GA) at concentrations of 0.4, 3.6, and 5.4 mg/mL for 24 h or 72 h. Slc2a4, Rela, and Nfkb1mRNAs were measured by RT-qPCR, GLUT4, IKKA/B, and p50/p65 NFKB subunits using Western blotting, and p50/p65 binding into the Slc2a4 promoter was analyzed by chromatin immunoprecipitation (ChIP) assay. GA at 0.4 mg/mL increased Slc2a4/GLUT4 expression after 24 h and 72 h (from 50% to 100%), but at 5.4 mg/mL, Slc2a4/GLUT4 expression decreased at 72 h (by 50%). Rela and Nfkb1 expression increased after 24 h at all concentrations, but this effect was not observed at 72 h. Furthermore, 5.4 mg/mL of GA increased the p50/p65 nuclear content and binding into Slc2a4 at 72 h. In summary, this study reveals AGE-induced and NFKB-mediated repression of Slc2a4/GLUT4 expression. This can compromise the adipocyte glucose utilization, contributing not only to the worsening of glycemic control in DM subjects but also the impairment of glycemic homeostasis in non-DM subjects under the high intake of AGE-rich foods.
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Affiliation(s)
- Maria Luiza Estimo Michalani
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, SP, Brazil;
| | - Marisa Passarelli
- Laboratório de Lípides (LIM-10) do HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01246-000, SP, Brazil
- Programa de Pós-Graduação em Medicina, Universidade Nove de Julho (UNINOVE), São Paulo 01525-000, SP, Brazil
| | - Ubiratan Fabres Machado
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, SP, Brazil;
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Zhu X, Xu W, Song T, Wang X, Wang Q, Li J, Liu X, Hao B, Chen T, Guo J. Changes in the combination of the triglyceride-glucose index and obesity indicators estimate the risk of cardiovascular disease. Cardiovasc Diabetol 2024; 23:192. [PMID: 38844974 PMCID: PMC11157789 DOI: 10.1186/s12933-024-02281-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 05/18/2024] [Indexed: 06/09/2024] Open
Abstract
BACKGROUND Cardiovascular disease (CVD) is closely associated with the triglyceride glucose (TyG) index and its related indicators, particularly its combination with obesity indices. However, there is limited research on the relationship between changes in TyG-related indices and CVD, as most studies have focused on baseline TyG-related indices. METHODS The data for this prospective cohort study were obtained from the China Health and Retirement Longitudinal Study. The exposures were changes in TyG-related indices and cumulative TyG-related indices from 2012 to 2015. The K-means algorithm was used to classify changes in each TyG-related index into four classes (Class 1 to Class 4). Multivariate logistic regressions were used to evaluate the associations between the changes in TyG-related indices and the incidence of CVD. RESULTS In total, 3243 participants were included in this study, of whom 1761 (54.4%) were female, with a mean age of 57.62 years at baseline. Over a 5-year follow-up, 637 (19.6%) participants developed CVD. Fully adjusted logistic regression analyses revealed significant positive associations between changes in TyG-related indices, cumulative TyG-related indices and the incidence of CVD. Among these changes in TyG-related indices, changes in TyG-waist circumference (WC) showed the strongest association with incident CVD. Compared to the participants in Class 1 of changes in TyG-WC, the odds ratio (OR) for participants in Class 2 was 1.41 (95% confidence interval (CI) 1.08-1.84), the OR for participants in Class 3 was 1.54 (95% CI 1.15-2.07), and the OR for participants in Class 4 was 1.94 (95% CI 1.34-2.80). Moreover, cumulative TyG-WC exhibited the strongest association with incident CVD among cumulative TyG-related indices. Compared to the participants in Quartile 1 of cumulative TyG-WC, the OR for participants in Quartile 2 was 1.33 (95% CI 1.00-1.76), the OR for participants in Quartile 3 was 1.46 (95% CI 1.09-1.96), and the OR for participants in Quartile 4 was 1.79 (95% CI 1.30-2.47). CONCLUSIONS Changes in TyG-related indices are independently associated with the risk of CVD. Changes in TyG-WC are expected to become more effective indicators for identifying individuals at a heightened risk of CVD.
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Affiliation(s)
- Xiaoqing Zhu
- Senior Department of Cardiology, The Sixth Medical Center of PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Weihao Xu
- Department of Cardiology, Guangdong Provincial Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
- Department of Geriatrics, Guangdong Provincial Geriatrics Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
- Haikou Cadre's Sanitarium of Hainan Military Region, Haikou, China
| | - Tingting Song
- Senior Department of Cardiology, The Sixth Medical Center of PLA General Hospital, Beijing, China
| | - Xinyan Wang
- Senior Department of Cardiology, The Sixth Medical Center of PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Qingsong Wang
- Senior Department of Cardiology, The Sixth Medical Center of PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Jun Li
- Senior Department of Cardiology, The Sixth Medical Center of PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Xixi Liu
- Senior Department of Cardiology, The Sixth Medical Center of PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Benchuan Hao
- Department of Cardiology, The Second Medical Center, Chinese PLA General Hospital, Beijing, China.
| | - Tao Chen
- Senior Department of Cardiology, The Sixth Medical Center of PLA General Hospital, Beijing, China.
| | - Jun Guo
- Senior Department of Cardiology, The Sixth Medical Center of PLA General Hospital, Beijing, China
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9
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Zhao H, Iyama R, Kurogi E, Hayashi T, Egawa T. Direct and acute effects of advanced glycation end products on proteostasis in isolated mouse skeletal muscle. Physiol Rep 2024; 12:e16121. [PMID: 38898369 PMCID: PMC11186708 DOI: 10.14814/phy2.16121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 06/12/2024] [Accepted: 06/12/2024] [Indexed: 06/21/2024] Open
Abstract
Advanced glycation end products (AGEs) have been implicated in several skeletal muscle dysfunctions. However, whether the adverse effects of AGEs on skeletal muscle are because of their direct action on the skeletal muscle tissue is unclear. Therefore, this study aimed to investigate the direct and acute effects of AGEs on skeletal muscle using an isolated mouse skeletal muscle to eliminate several confounders derived from other organs. The results showed that the incubation of isolated mouse skeletal muscle with AGEs (1 mg/mL) for 2-6 h suppressed protein synthesis and the mechanistic target of rapamycin signaling pathway. Furthermore, AGEs showed potential inhibitory effects on protein degradation pathways, including autophagy and the ubiquitin-proteasome system. Additionally, AGEs stimulated endoplasmic reticulum (ER) stress by modulating the activating transcription factor 6, PKR-like ER kinase, C/EBP homologous protein, and altered inflammatory cytokine expression. AGEs also stimulated receptor for AGEs (RAGE)-associated signaling molecules, including mitogen-activated protein kinases. These findings suggest that AGEs have direct and acute effect on skeletal muscle and disturb proteostasis by modulating intracellular pathways such as RAGE signaling, protein synthesis, proteolysis, ER stress, and inflammatory cytokines.
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Affiliation(s)
- Haiyu Zhao
- Laboratory of Sports and Exercise Medicine, Graduate School of Human and Environmental StudiesKyoto UniversityKyotoJapan
- Laboratory of Molecular Exercise Adaptation Sciences, Graduate School of Human and Environmental StudiesKyoto UniversityKyotoJapan
| | - Ryota Iyama
- Laboratory of Sports and Exercise Medicine, Graduate School of Human and Environmental StudiesKyoto UniversityKyotoJapan
- Laboratory of Molecular Exercise Adaptation Sciences, Graduate School of Human and Environmental StudiesKyoto UniversityKyotoJapan
| | - Eriko Kurogi
- Laboratory of Sports and Exercise Medicine, Graduate School of Human and Environmental StudiesKyoto UniversityKyotoJapan
| | - Tatsuya Hayashi
- Laboratory of Sports and Exercise Medicine, Graduate School of Human and Environmental StudiesKyoto UniversityKyotoJapan
| | - Tatsuro Egawa
- Laboratory of Molecular Exercise Adaptation Sciences, Graduate School of Human and Environmental StudiesKyoto UniversityKyotoJapan
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10
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Khalid M, Adem A. The dynamic roles of advanced glycation end products. VITAMINS AND HORMONES 2024; 125:1-29. [PMID: 38997161 DOI: 10.1016/bs.vh.2024.02.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/14/2024]
Abstract
Advanced glycation end products (AGEs) are a heterogeneous group of potentially harmful molecules that can form as a result of a non-enzymatic reaction between reducing sugars and proteins, lipids, or nucleic acids. The total body pool of AGEs reflects endogenously produced AGEs as well as exogeneous AGEs that come from sources such as diet and the environment. Engagement of AGEs with their cellular receptor, the receptor for advanced glycation end products (RAGE), which is expressed on the surface of various cell types, converts a brief pulse of cellular activation to sustained cellular dysfunction and tissue destruction. The AGEs/RAGE interaction triggers a cascade of intracellular signaling pathways such as mitogen-activated protein kinase/extracellular signal-regulated kinase, phosphoinositide 3-kinases, transforming growth factor beta, c-Jun N-terminal kinases (JNK), and nuclear factor kappa B, which leads to the production of pro-inflammatory cytokines, chemokines, adhesion molecules, and oxidative stress. All these events contribute to the progression of several chronic diseases. This chapter will provide a comprehensive understanding of the dynamic roles of AGEs in health and disease which is crucial to develop interventions that prevent and mitigate the deleterious effects of AGEs accumulation.
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Affiliation(s)
- Mariyam Khalid
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, Khalifa University, Abu Dhabi, United Arab Emirates
| | - Abdu Adem
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, Khalifa University, Abu Dhabi, United Arab Emirates.
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Delligatti CE, Kirk JA. Glycation in the cardiomyocyte. VITAMINS AND HORMONES 2024; 125:47-88. [PMID: 38997172 PMCID: PMC11578284 DOI: 10.1016/bs.vh.2024.04.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 07/14/2024]
Abstract
Glycation is a protein post-translational modification that can occur on lysine and arginine residues as a result of a non-enzymatic process known as the Maillard reaction. This modification is irreversible, so the only way it can be removed is by protein degradation and replacement. Small reactive carbonyl species, glyoxal and methylglyoxal, are the primary glycating agents and are elevated in several conditions associated with an increased risk of cardiovascular disease, including diabetes, rheumatoid arthritis, smoking, and aging. Thus, how protein glycation impacts the cardiomyocyte is of particular interest, to both understand how these conditions increase the risk of cardiovascular disease and how glycation might be targeted therapeutically. Glycation can affect the cardiomyocyte through extracellular mechanisms, including RAGE-based signaling, glycation of the extracellular matrix that modifies the mechanical environment, and signaling from the vasculature. Intracellular glycation of the cardiomyocyte can impact calcium handling, protein quality control and cell death pathways, as well as the cytoskeleton, resulting in a blunted contractility. While reducing protein glycation and its impact on the heart has been an active area of drug development, multiple clinical trials have had mixed results and these compounds have not been translated to the clinic-highlighting the challenges of modulating myocyte glycation. Here we will review protein glycation and its effects on the cardiomyocyte, therapeutic attempts to reverse these, and offer insight as to the future of glycation studies and patient treatment.
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Affiliation(s)
- Christine E Delligatti
- Department of Cell and Molecular Physiology, Loyola University Chicago Stritch School of Medicine, Maywood, IL, United States
| | - Jonathan A Kirk
- Department of Cell and Molecular Physiology, Loyola University Chicago Stritch School of Medicine, Maywood, IL, United States.
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Eiras S. Nε-carboxymethyl-lysine and inflammatory cytokines, markers and mediators of coronary artery disease progression in diabetes. World J Diabetes 2024; 15:575-578. [PMID: 38680703 PMCID: PMC11045414 DOI: 10.4239/wjd.v15.i4.575] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 01/08/2024] [Accepted: 03/01/2024] [Indexed: 04/11/2024] Open
Abstract
This editorial refers to the article "Comparative analysis of Nε-carboxymethyl-lysine and inflammatory markers in diabetic and non-diabetic coronary artery disease patients", published in the recent issue of the World Journal of Diabetes 2023 is based on glucose metabolism, advanced glycation end products (AGEs), inflammation and adiposity on diabetes and coronary artery disease (CAD). This study has included CAD patients who were stratified according to glycosylated hemoglobin higher than 6.5 and sex-matched. A higher prevalence of hypertension, dyslipidemia, and non-vegetarian diet were found in the diabetic group. These risk factors might influence body weight and adiposity and explain the increment of the left atrium. Although this data was not supported by the study. The diet can also explain the non-enzymatic reactions on lipids, proteins, or nucleic acids and consequently an increment of AGEs. These molecules can emit fluorescence. However, one of the non-fluorescent and most abundant AGEs is Nε-carboxymethyl-lysine (CML). Its association with coronary artery stenosis and severity in the diabetic group might suggest its role as a player in CAD progression. Thus, CML, after binding with its receptor (RAGE), can induce calcification cascade through reactive oxygen species and mitogen-activated protein kinase. Moreover, this interaction AGE-RAGE can cause activation of the transcription nuclear factor-kb and induce inflammatory cytokines. It might explain the relationship between CML and pro-inflammatory cytokines in diabetic and CAD patients. Although this is a population from one center, the determination of CML and inflammatory cytokines might improve the diagnosis of severe and progressive CAD. Future and comparative studies among glycosylated hemoglobin, CML, and other AGE levels according to diagnosis and prognosis value might modify the clinical practice. Although these molecules are irreversible, they can act through a specific receptor inducing a signal transduction that might be modu-lated by inhibitors, antibodies, or siRNA. Further mechanistic studies might improve the development of future preventive therapies for diabetic patients.
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Affiliation(s)
- Sonia Eiras
- Translational Cardiology, Health Research Institute, University Hospital of Santiago de Compostela, Santiago de Compostela 15706, Spain
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Olson LC, Nguyen T, Sabalewski EL, Puetzer JL, Schwartz Z, McClure MJ. S100b treatment overcomes RAGE signaling deficits in myoblasts on advanced glycation end-product cross-linked collagen and promotes myogenic differentiation. Am J Physiol Cell Physiol 2024; 326:C1080-C1093. [PMID: 38314727 DOI: 10.1152/ajpcell.00502.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 01/30/2024] [Accepted: 01/30/2024] [Indexed: 02/07/2024]
Abstract
Advanced glycation end-products (AGEs) stochastically accrue in skeletal muscle and on collagen over an individual's lifespan, stiffening the muscle and modifying the stem cell (MuSC) microenvironment while promoting proinflammatory, antiregenerative signaling via the receptor for advanced glycation end-products (RAGEs). In the present study, a novel in vitro model was developed of this phenomenon by cross linking a 3-D collagen scaffold with AGEs and investigating how myoblasts responded to such an environment. Briefly, collagen scaffolds were incubated with d-ribose (0, 25, 40, 100, or 250 mM) for 5 days at 37°C. C2C12 immortalized mouse myoblasts were grown on the scaffolds for 6 days in growth conditions for proliferation, and 12 days for differentiation and fusion. Human primary myoblasts were also used to confirm the C2C12 data. AGEs aberrantly extended the DNA production stage of C2C12s (but not in human primary myoblasts) which is known to delay differentiation in myogenesis, and this effect was prevented by RAGE inhibition. Furthermore, the differentiation and fusion of myoblasts were disrupted by AGEs, which were associated with reductions in integrins and suppression of RAGE. The addition of S100b (RAGE agonist) recovered the differentiation and fusion of myoblasts, and the addition of RAGE inhibitors (FPS-ZM1 and Azeliragon) inhibited the differentiation and fusion of myoblasts. Our results provide novel insights into the role of the AGE-RAGE axis in skeletal muscle aging, and future work is warranted on the potential application of S100b as a proregenerative factor in aged skeletal muscle.NEW & NOTEWORTHY Collagen cross-linked by advanced glycation end-products (AGEs) induced myoblast proliferation but prevented differentiation, myotube formation, and RAGE upregulation. RAGE inhibition occluded AGE-induced myoblast proliferation, while the delivery of S100b, a RAGE ligand, recovered fusion deficits.
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Affiliation(s)
- Lucas C Olson
- Department of Biomedical Engineering, College of Engineering, Virginia Commonwealth University, Richmond, Virginia, United States
- Department of Gerontology, College of Health Professionals, Virginia Commonwealth University, Richmond, Virginia, United States
| | - Tri Nguyen
- Department of Biomedical Engineering, College of Engineering, Virginia Commonwealth University, Richmond, Virginia, United States
| | - Eleanor L Sabalewski
- Department of Biomedical Engineering, College of Engineering, Virginia Commonwealth University, Richmond, Virginia, United States
| | - Jennifer L Puetzer
- Department of Biomedical Engineering, College of Engineering, Virginia Commonwealth University, Richmond, Virginia, United States
- Department of Orthopaedic Surgery, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, United States
| | - Zvi Schwartz
- Department of Biomedical Engineering, College of Engineering, Virginia Commonwealth University, Richmond, Virginia, United States
- Department of Periodontics, School of Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
| | - Michael J McClure
- Department of Biomedical Engineering, College of Engineering, Virginia Commonwealth University, Richmond, Virginia, United States
- Department of Orthopaedic Surgery, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, United States
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Sharma C, Hamza A, Boyle E, Donu D, Cen Y. Post-Translational Modifications and Diabetes. Biomolecules 2024; 14:310. [PMID: 38540730 PMCID: PMC10968569 DOI: 10.3390/biom14030310] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 03/01/2024] [Accepted: 03/04/2024] [Indexed: 09/22/2024] Open
Abstract
Diabetes and its associated complications have increasingly become major challenges for global healthcare. The current therapeutic strategies involve insulin replacement therapy for type 1 diabetes (T1D) and small-molecule drugs for type 2 diabetes (T2D). Despite these advances, the complex nature of diabetes necessitates innovative clinical interventions for effective treatment and complication prevention. Accumulative evidence suggests that protein post-translational modifications (PTMs), including glycosylation, phosphorylation, acetylation, and SUMOylation, play important roles in diabetes and its pathological consequences. Therefore, the investigation of these PTMs not only sheds important light on the mechanistic regulation of diabetes but also opens new avenues for targeted therapies. Here, we offer a comprehensive overview of the role of several PTMs in diabetes, focusing on the most recent advances in understanding their functions and regulatory mechanisms. Additionally, we summarize the pharmacological interventions targeting PTMs that have advanced into clinical trials for the treatment of diabetes. Current challenges and future perspectives are also provided.
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Affiliation(s)
- Chiranjeev Sharma
- Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23219, USA; (C.S.); (A.H.); (E.B.); (D.D.)
| | - Abu Hamza
- Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23219, USA; (C.S.); (A.H.); (E.B.); (D.D.)
| | - Emily Boyle
- Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23219, USA; (C.S.); (A.H.); (E.B.); (D.D.)
| | - Dickson Donu
- Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23219, USA; (C.S.); (A.H.); (E.B.); (D.D.)
| | - Yana Cen
- Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23219, USA; (C.S.); (A.H.); (E.B.); (D.D.)
- Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA 23219, USA
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Assis SISD, Amendola LS, Okamoto MM, Ferreira GDS, Iborra RT, Santos DR, Santana MDFM, Santana KG, Correa-Giannella ML, Barbeiro DF, Soriano FG, Machado UF, Passarelli M. The Prolonged Activation of the p65 Subunit of the NF-Kappa-B Nuclear Factor Sustains the Persistent Effect of Advanced Glycation End Products on Inflammatory Sensitization in Macrophages. Int J Mol Sci 2024; 25:2713. [PMID: 38473959 DOI: 10.3390/ijms25052713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 02/20/2024] [Accepted: 02/23/2024] [Indexed: 03/14/2024] Open
Abstract
Advanced glycation end products (AGEs) prime macrophages for lipopolysaccharide (LPS)-induced inflammation. We investigated the persistence of cellular AGE-sensitization to LPS, considering the nuclear content of p50 and p65 nuclear factor kappa B (NFKB) subunits and the expression of inflammatory genes. Macrophages treated with control (C) or AGE-albumin were rested for varying intervals in medium alone before being incubated with LPS. Comparisons were made using one-way ANOVA or Student t-test (n = 6). AGE-albumin primed macrophages for increased responsiveness to LPS, resulting in elevated levels of TNF, IL-6, and IL-1beta (1.5%, 9.4%, and 5.6%, respectively), compared to C-albumin. TNF, IL-6, and IL-1 beta secretion persisted for up to 24 h even after the removal of AGE-albumin (area under the curve greater by 1.6, 16, and 5.2 times, respectively). The expressions of Il6 and RelA were higher 8 h after albumin removal, and Il6 and Abca1 were higher 24 h after albumin removal. The nuclear content of p50 remained similar, but p65 showed a sustained increase (2.9 times) for up to 24 h in AGE-albumin-treated cells. The prolonged activation of the p65 subunit of NFKB contributes to the persistent effect of AGEs on macrophage inflammatory priming, which could be targeted for therapies to prevent complications based on the AGE-RAGE-NFKB axis.
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Affiliation(s)
- Sayonara Ivana Santos de Assis
- Laboratório de Lípides (LIM 10), Hospital das Clínicas (HCFMUSP) da Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-000, Brazil
| | - Leonardo Szalo Amendola
- Laboratório de Lípides (LIM 10), Hospital das Clínicas (HCFMUSP) da Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-000, Brazil
| | - Maristela Mitiko Okamoto
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil
| | - Guilherme da Silva Ferreira
- Laboratório de Lípides (LIM 10), Hospital das Clínicas (HCFMUSP) da Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-000, Brazil
| | - Rodrigo Tallada Iborra
- Ciências Biológicas e da Saúde, Campos Mooca, Universidade São Judas Tadeu, São Paulo 03408-050, Brazil
| | - Danielle Ribeiro Santos
- Laboratório de Lípides (LIM 10), Hospital das Clínicas (HCFMUSP) da Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-000, Brazil
| | - Monique de Fátima Mello Santana
- Laboratório de Lípides (LIM 10), Hospital das Clínicas (HCFMUSP) da Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-000, Brazil
| | - Kelly Gomes Santana
- Laboratório de Lípides (LIM 10), Hospital das Clínicas (HCFMUSP) da Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-000, Brazil
| | - Maria Lucia Correa-Giannella
- Laboratório de Carboidratos e Radioimunoensaio (LIM 18), Hospital das Clínicas (HCFMUSP) da Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-000, Brazil
| | - Denise Frediani Barbeiro
- Laboratório de Emergências Clínicas (LIM 51), Hospital das Clínicas (HCFMUSP) da Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-000, Brazil
| | - Francisco Garcia Soriano
- Laboratório de Emergências Clínicas (LIM 51), Hospital das Clínicas (HCFMUSP) da Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-000, Brazil
| | - Ubiratan Fabres Machado
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil
| | - Marisa Passarelli
- Laboratório de Lípides (LIM 10), Hospital das Clínicas (HCFMUSP) da Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-000, Brazil
- Programa de Pós-Graduação em Medicina, Universidade Nove de Julho, São Paulo 01525-000, Brazil
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Tuell D, Ford G, Los E, Stone W. The Role of Glutathione and Its Precursors in Type 2 Diabetes. Antioxidants (Basel) 2024; 13:184. [PMID: 38397782 PMCID: PMC10885928 DOI: 10.3390/antiox13020184] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 01/24/2024] [Accepted: 01/31/2024] [Indexed: 02/25/2024] Open
Abstract
Type 2 diabetes (T2D) is a major worldwide health crisis affecting about 6.2% of the world's population. Alarmingly, about one in five children in the USA have prediabetes. Glutathione (GSH) and its precursors play a promising role in the prevention and management of type T2D. Oxidative stress (OxS) is a probable factor in both T2D initiation and progression. GSH is the major cytosolic water-soluble chemical antioxidant and emerging evidence supports its role in improving T2D outcomes. Dietary supplementation with N-acetyl-cysteine (NAC) and/or glycine (GLY), which are GSH precursors, has also been studied for possible beneficial effects on T2D. This review will focus on the underlying pathophysiological and molecular mechanisms linking GSH and its precursors with T2D and OxS. In addition to their traditional antioxidant roles, the in vivo effects of GSH/NAC/GLY supplements will be evaluated for their potential abilities to modulate the complex pro-oxidant pathophysiological factors (e.g., hyperglycemia) driving T2D progression. Positive feedback loops that amplify OxS over long time intervals are likely to result in irreversible T2D micro- and macro-vascular damage. Most clinical studies with GSH/NAC/GLY have focused on adults or the elderly. Future research with pediatric populations should be a high priority since early intervention is critical.
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Kietsiriroje N, Scott GE, Ajjan RA, Brôz J, Schroeder V, Campbell MD. Plasma levels of mannan-binding lectin-associated serine proteases are increased in type 1 diabetes patients with insulin resistance. Clin Exp Immunol 2024; 215:58-64. [PMID: 37832142 PMCID: PMC10776244 DOI: 10.1093/cei/uxad113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 07/07/2023] [Accepted: 10/12/2023] [Indexed: 10/15/2023] Open
Abstract
Activation of the lectin pathway of the complement system, as demonstrated by elevated levels of mannan-binding lectin proteins (MBL), contributes to vascular pathology in type 1 diabetes (T1D). Vascular complications are greatest in T1D individuals with concomitant insulin resistance (IR), however, whether IR amplifies activiation of the lectin pathway in T1D is unknown. We pooled pretreatment data from two RCTs and performed a cross-sectional analysis on 46 T1D individuals. We employed estimated glucose disposal rate (eGDR), a validated IR surrogate with cut-points of: <5.1, 5.1-8.7, and > 8.7 mg/kg/min to determine IR status, with lower eGDR values conferring higher degrees of IR. Plasma levels of MBL-associated proteases (MASP-1, MASP-2, and MASP-3) and their regulatory protein MAp44 were compared among eGDR classifications. In a subset of 14 individuals, we assessed change in MASPs and MAp44 following improvement in IR. We found that MASP-1, MASP-2, MASP-3, and MAp44 levels increased in a stepwise fashion across eGDR thresholds with elevated MASPs and MAp44 levels conferring greater degrees of IR. In a subset of 14 patients, improvement in IR was associated with significant reductions in MASPs, but not MAp44, levels. In conclusion, IR in T1D amplifies levels of MASP-1/2/3 and their regulator MAp44, and improvement of IR normalizes MASP-1/2/3 levels. Given that elevated levels of these proteins contribute to vascular pathology, amplification of the lectin pathway of the complement system may offer mechanistic insight into the relationship between IR and vascular complications in T1D.
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Affiliation(s)
- Noppadol Kietsiriroje
- Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK
- Endocrinology and Metabolism Unit, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
| | - Georgia E Scott
- School of Nursing and Health Sciences, University of Sunderland, Sunderland, UK
| | - Ramzi A Ajjan
- Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK
| | - Jan Brôz
- Department of Internal Medicine, Charles University, Prague, Czech Republic
| | - Verena Schroeder
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Matthew D Campbell
- Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK
- School of Nursing and Health Sciences, University of Sunderland, Sunderland, UK
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Pedreanez A, Robalino J, Tene D, Salazar P. Advanced glycation end products of dietary origin and their association with inflammation in diabetes - A minireview. Endocr Regul 2024; 58:57-67. [PMID: 38563294 DOI: 10.2478/enr-2024-0007] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/04/2024] Open
Abstract
Advanced glycation end products (AGEs) are a diverse group of compounds that are formed as a result of the non-enzymatic reaction between a reducing sugar such as glucose and the free NH2 groups of an amino acid in a protein or other biomolecule. The chemical reaction, by which these products are generated, is known as the Maillard reaction and occurs as a part of the body's normal metabolism. Such a reaction is enhanced during diabetes due to hyperglycemia, but it can also occur during the preparation, processing, and preservation of certain foods. Therefore, AGEs can also be obtained from the diet (d-AGE) and contribute to an increase of the total serum pool of these compounds. They have been implicated in a wide variety of pathological processes, mainly because of their ability to induce inflammatory responses and oxidative stress increase. They are extensively accumulated as a part of the normal aging, especially in tissues rich in long half-life proteins, which can compromise the physiology of these tissues. d-AGEs are abundant in diets rich in processed fats and sugars. This review is addressed to the current knowledge on these products and their impact on the immunomodulation of various mechanisms that may contribute to exacerbation of the diabetes pathophysiology.
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Affiliation(s)
- Adriana Pedreanez
- Catedra de Inmunologia, Escuela de Bioanalisis, Facultad de Medicina, Universidad del Zulia, Maracaibo, Venezuela
| | | | - Diego Tene
- Universidad Nacional del Chimborazo, Facultad de Ciencias de la Salud, Riobamba, Ecuador
| | - Patricio Salazar
- Departamento de Nutricion Clinica, Hospital General Santo Domingo, Ecuador
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Krawczyk M, Burzynska-Pedziwiatr I, Wozniak LA, Bukowiecka-Matusiak M. Impact of Polyphenols on Inflammatory and Oxidative Stress Factors in Diabetes Mellitus: Nutritional Antioxidants and Their Application in Improving Antidiabetic Therapy. Biomolecules 2023; 13:1402. [PMID: 37759802 PMCID: PMC10526737 DOI: 10.3390/biom13091402] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 09/10/2023] [Accepted: 09/11/2023] [Indexed: 09/29/2023] Open
Abstract
Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycaemia and oxidative stress. Oxidative stress plays a crucial role in the development and progression of diabetes and its complications. Nutritional antioxidants derived from dietary sources have gained significant attention due to their potential to improve antidiabetic therapy. This review will delve into the world of polyphenols, investigating their origins in plants, metabolism in the human body, and relevance to the antioxidant mechanism in the context of improving antidiabetic therapy by attenuating oxidative stress, improving insulin sensitivity, and preserving β-cell function. The potential mechanisms of, clinical evidence for, and future perspectives on nutritional antioxidants as adjuvant therapy in diabetes management are discussed.
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20
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Lloyd EM, Pinniger GJ, Murphy RM, Grounds MD. Slow or fast: Implications of myofibre type and associated differences for manifestation of neuromuscular disorders. Acta Physiol (Oxf) 2023; 238:e14012. [PMID: 37306196 DOI: 10.1111/apha.14012] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 05/30/2023] [Accepted: 06/06/2023] [Indexed: 06/13/2023]
Abstract
Many neuromuscular disorders can have a differential impact on a specific myofibre type, forming the central premise of this review. The many different skeletal muscles in mammals contain a spectrum of slow- to fast-twitch myofibres with varying levels of protein isoforms that determine their distinctive contractile, metabolic, and other properties. The variations in functional properties across the range of classic 'slow' to 'fast' myofibres are outlined, combined with exemplars of the predominantly slow-twitch soleus and fast-twitch extensor digitorum longus muscles, species comparisons, and techniques used to study these properties. Other intrinsic and extrinsic differences are discussed in the context of slow and fast myofibres. These include inherent susceptibility to damage, myonecrosis, and regeneration, plus extrinsic nerves, extracellular matrix, and vasculature, examined in the context of growth, ageing, metabolic syndrome, and sexual dimorphism. These many differences emphasise the importance of carefully considering the influence of myofibre-type composition on manifestation of various neuromuscular disorders across the lifespan for both sexes. Equally, understanding the different responses of slow and fast myofibres due to intrinsic and extrinsic factors can provide deep insight into the precise molecular mechanisms that initiate and exacerbate various neuromuscular disorders. This focus on the influence of different myofibre types is of fundamental importance to enhance translation for clinical management and therapies for many skeletal muscle disorders.
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Affiliation(s)
- Erin M Lloyd
- Department of Anatomy, Physiology and Human Biology, School of Human Sciences, The University of Western Australia, Perth, Western Australia, Australia
- Curtin Health Innovation Research Institute, Curtin Medical School, Curtin University, Bentley, Western Australia, Australia
| | - Gavin J Pinniger
- Department of Anatomy, Physiology and Human Biology, School of Human Sciences, The University of Western Australia, Perth, Western Australia, Australia
| | - Robyn M Murphy
- Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe University, Melbourne, Victoria, Australia
| | - Miranda D Grounds
- Department of Anatomy, Physiology and Human Biology, School of Human Sciences, The University of Western Australia, Perth, Western Australia, Australia
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Portero-Otin M, de la Maza MP, Uribarri J. Dietary Advanced Glycation End Products: Their Role in the Insulin Resistance of Aging. Cells 2023; 12:1684. [PMID: 37443718 PMCID: PMC10340703 DOI: 10.3390/cells12131684] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 06/15/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
Insulin resistance (IR) is commonly observed during aging and is at the root of many of the chronic nontransmissible diseases experienced as people grow older. Many factors may play a role in causing IR, but diet is undoubtedly an important one. Whether it is total caloric intake or specific components of the diet, the factors responsible remain to be confirmed. Of the many dietary influences that may play a role in aging-related decreased insulin sensitivity, advanced glycation end products (AGEs) appear particularly important. Herein, we have reviewed in detail in vitro, animal, and human evidence linking dietary AGEs contributing to the bodily burden of AGEs with the development of IR. We conclude that numerous small clinical trials assessing the effect of dietary AGE intake in combination with strong evidence in many animal studies strongly suggest that reducing dietary AGE intake is associated with improved IR in a variety of disease conditions. Reducing AGE content of common foods by simple changes in culinary techniques is a feasible, safe, and easily applicable intervention in both health and disease. Large-scale clinical trials are still needed to provide broader evidence for the deleterious role of dietary AGEs in chronic disease.
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Affiliation(s)
- Manuel Portero-Otin
- Departamento de Medicina Experimental, Facultad de Medicina, Universidad de Lleida, 25196 Lleida, Spain;
| | - M. Pia de la Maza
- Centro de Nutricion y Diabetes, Departamento de Medicina, Clinica Alemana, Universidad del Desarrollo, Santiago 7610658, Chile;
| | - Jaime Uribarri
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10021, USA
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Chen Y, Yao L, Zhao S, Xu M, Ren S, Xie L, Liu L, Wang Y. The oxidative aging model integrated various risk factors in type 2 diabetes mellitus at system level. Front Endocrinol (Lausanne) 2023; 14:1196293. [PMID: 37293508 PMCID: PMC10244788 DOI: 10.3389/fendo.2023.1196293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 05/10/2023] [Indexed: 06/10/2023] Open
Abstract
Background Type 2 diabetes mellitus (T2DM) is a chronic endocrine metabolic disease caused by insulin dysregulation. Studies have shown that aging-related oxidative stress (as "oxidative aging") play a critical role in the onset and progression of T2DM, by leading to an energy metabolism imbalance. However, the precise mechanisms through which oxidative aging lead to T2DM are yet to be fully comprehended. Thus, it is urgent to integrate the underlying mechanisms between oxidative aging and T2DM, where meaningful prediction models based on relative profiles are needed. Methods First, machine learning was used to build the aging model and disease model. Next, an integrated oxidative aging model was employed to identify crucial oxidative aging risk factors. Finally, a series of bioinformatic analyses (including network, enrichment, sensitivity, and pan-cancer analyses) were used to explore potential mechanisms underlying oxidative aging and T2DM. Results The study revealed a close relationship between oxidative aging and T2DM. Our results indicate that nutritional metabolism, inflammation response, mitochondrial function, and protein homeostasis are key factors involved in the interplay between oxidative aging and T2DM, even indicating key indices across different cancer types. Therefore, various risk factors in T2DM were integrated, and the theories of oxi-inflamm-aging and cellular senescence were also confirmed. Conclusion In sum, our study successfully integrated the underlying mechanisms linking oxidative aging and T2DM through a series of computational methodologies.
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Affiliation(s)
- Yao Chen
- Department of Biomedical Engineering, School of Intelligent Medicine, China Medical University, Shenyang, Liaoning, China
| | - Lilin Yao
- Department of Biomedical Engineering, School of Intelligent Medicine, China Medical University, Shenyang, Liaoning, China
| | - Shuheng Zhao
- Department of Biomedical Engineering, School of Intelligent Medicine, China Medical University, Shenyang, Liaoning, China
| | - Mengchu Xu
- Department of Biomedical Engineering, School of Intelligent Medicine, China Medical University, Shenyang, Liaoning, China
| | - Siwei Ren
- Department of Biomedical Engineering, School of Intelligent Medicine, China Medical University, Shenyang, Liaoning, China
| | - Lu Xie
- Shanghai-MOST Key Laboratory of Health and Disease Genomics & Institute for Genome and Bioinformatics, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China
| | - Lei Liu
- Intelligent Medicine Institute, Fudan University, Shanghai, China
| | - Yin Wang
- Department of Biomedical Engineering, School of Intelligent Medicine, China Medical University, Shenyang, Liaoning, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
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Tuell DS, Los EA, Ford GA, Stone WL. The Role of Natural Antioxidant Products That Optimize Redox Status in the Prevention and Management of Type 2 Diabetes. Antioxidants (Basel) 2023; 12:1139. [PMID: 37371869 DOI: 10.3390/antiox12061139] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 05/11/2023] [Accepted: 05/17/2023] [Indexed: 06/29/2023] Open
Abstract
The worldwide prevalence of type 2 diabetes (T2D) and prediabetes is rapidly increasing, particularly in children, adolescents, and young adults. Oxidative stress (OxS) has emerged as a likely initiating factor in T2D. Natural antioxidant products may act to slow or prevent T2D by multiple mechanisms, i.e., (1) reducing mitochondrial oxidative stress, (2) preventing the damaging effects of lipid peroxidation, and (3) acting as essential cofactors for antioxidant enzymes. Natural antioxidant products should also be evaluated in the context of the complex physiological processes that modulate T2D-OxS such as glycemic control, postprandial OxS, the polyol pathway, high-calorie, high-fat diets, exercise, and sleep. Minimizing processes that induce chronic damaging OxS and maximizing the intake of natural antioxidant products may provide a means of preventing or slowing T2D progression. This "optimal redox" (OptRedox) approach also provides a framework in which to discuss the potential benefits of natural antioxidant products such as vitamin E, vitamin C, beta-carotene, selenium, and manganese. Although there is a consensus that early effective intervention is critical for preventing or reversing T2D progression, most research has focused on adults. It is critical, therefore, that future research include pediatric populations.
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Affiliation(s)
- Dawn S Tuell
- Department of Pediatrics, Quillen College of Medicine, Johnson City, TN 37614, USA
| | - Evan A Los
- Department of Pediatrics, Quillen College of Medicine, Johnson City, TN 37614, USA
| | - George A Ford
- Department of Pediatrics, Quillen College of Medicine, Johnson City, TN 37614, USA
| | - William L Stone
- Department of Pediatrics, Quillen College of Medicine, Johnson City, TN 37614, USA
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Luo Y, Vivaldi Marrero E, Choudhary V, Bollag WB. Phosphatidylglycerol to Treat Chronic Skin Wounds in Diabetes. Pharmaceutics 2023; 15:1497. [PMID: 37242739 PMCID: PMC10222993 DOI: 10.3390/pharmaceutics15051497] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 05/02/2023] [Accepted: 05/09/2023] [Indexed: 05/28/2023] Open
Abstract
This review proposes the use of dioleoylphosphatidylglycerol (DOPG) to enhance diabetic wound healing. Initially, the characteristics of diabetic wounds are examined, focusing on the epidermis. Hyperglycemia accompanying diabetes results in enhanced inflammation and oxidative stress in part through the generation of advanced glycation end-products (AGEs), in which glucose is conjugated to macromolecules. These AGEs activate inflammatory pathways; oxidative stress results from increased reactive oxygen species generation by mitochondria rendered dysfunctional by hyperglycemia. These factors work together to reduce the ability of keratinocytes to restore epidermal integrity, contributing to chronic diabetic wounds. DOPG has a pro-proliferative action on keratinocytes (through an unclear mechanism) and exerts an anti-inflammatory effect on keratinocytes and the innate immune system by inhibiting the activation of Toll-like receptors. DOPG has also been found to enhance macrophage mitochondrial function. Since these DOPG effects would be expected to counteract the increased oxidative stress (attributable in part to mitochondrial dysfunction), decreased keratinocyte proliferation, and enhanced inflammation that characterize chronic diabetic wounds, DOPG may be useful in stimulating wound healing. To date, efficacious therapies to promote the healing of chronic diabetic wounds are largely lacking; thus, DOPG may be added to the armamentarium of drugs to enhance diabetic wound healing.
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Affiliation(s)
- Yonghong Luo
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA; (Y.L.); (E.V.M.); (V.C.)
| | - Edymarie Vivaldi Marrero
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA; (Y.L.); (E.V.M.); (V.C.)
| | - Vivek Choudhary
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA; (Y.L.); (E.V.M.); (V.C.)
- Charlie Norwood VA Medical Center, One Freedom Way, Augusta, GA 30904, USA
| | - Wendy B. Bollag
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA; (Y.L.); (E.V.M.); (V.C.)
- Charlie Norwood VA Medical Center, One Freedom Way, Augusta, GA 30904, USA
- Department of Dermatology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
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25
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Yonamine CY, Passarelli M, Suemoto CK, Pasqualucci CA, Jacob-Filho W, Alves VAF, Marie SKN, Correa-Giannella ML, Britto LR, Machado UF. Postmortem Brains from Subjects with Diabetes Mellitus Display Reduced GLUT4 Expression and Soma Area in Hippocampal Neurons: Potential Involvement of Inflammation. Cells 2023; 12:cells12091250. [PMID: 37174649 PMCID: PMC10177173 DOI: 10.3390/cells12091250] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Revised: 04/13/2023] [Accepted: 04/23/2023] [Indexed: 05/15/2023] Open
Abstract
Diabetes mellitus (DM) is an important risk factor for dementia, which is a common neurodegenerative disorder. DM is known to activate inflammation, oxidative stress, and advanced glycation end products (AGEs) generation, all capable of inducing neuronal dysfunctions, thus participating in the neurodegeneration progress. In that process, disturbed neuronal glucose supply plays a key role, which in hippocampal neurons is controlled by the insulin-sensitive glucose transporter type 4 (GLUT4). We investigated the expression of GLUT4, nuclear factor NF-kappa B subunit p65 [NFKB (p65)], carboxymethyllysine and synapsin1 (immunohistochemistry), and soma area in human postmortem hippocampal samples from control, obese, and obese+DM subjects (41 subjects). Moreover, in human SH-SY5Y neurons, tumor necrosis factor (TNF) and glycated albumin (GA) effects were investigated in GLUT4, synapsin-1 (SYN1), tyrosine hydroxylase (TH), synaptophysin (SYP) proteins, and respective genes; NFKB binding activity in the SLC2A4 promoter; effects of increased histone acetylation grade by histone deacetylase 3 (HDAC3) inhibition. Hippocampal neurons (CA4 area) of obese+DM subjects displayed reduced GLUT4 expression and neuronal soma area, associated with increased expression of NFKB (p65). Challenges with TNF and GA decreased the SLC2A4/GLUT4 expression in SH-SY5Y neurons. TNF decreased SYN1, TH, and SYP mRNAs and respective proteins, and increased NFKB binding activity in the SLC2A4 promoter. Inhibition of HDAC3 increased the SLC2A4 expression and the total neuronal content of CRE-binding proteins (CREB/ICER), and also counterbalanced the repressor effect of TNF upon these parameters. This study revealed reduced postmortem human hippocampal GLUT4 content and neuronal soma area accompanied by increased proinflammatory activity in the brains of DM subjects. In isolated human neurons, inflammatory activation by TNF reduced not only the SLC2A4/GLUT4 expression but also the expression of some genes related to neuronal function (SYN1, TH, SYP). These effects may be related to epigenetic regulations (H3Kac and H4Kac status) since they can be counterbalanced by inhibiting HDAC3. These results uncover the improvement in GLUT4 expression and/or the inhibition of HDAC3 as promising therapeutic targets to fight DM-related neurodegeneration.
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Affiliation(s)
- Caio Yogi Yonamine
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Marisa Passarelli
- Laboratório de Lipides (LIM-10) do HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01246-000, Brazil
- Programa de Pos-Graduação em Medicina, Universidade Nove de Julho (UNINOVE), São Paulo 01525-000, Brazil
| | - Claudia Kimie Suemoto
- Divisao de Geriatria, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo 01246-000, Brazil
| | | | - Wilson Jacob-Filho
- Divisao de Geriatria, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo 01246-000, Brazil
| | - Venâncio Avancini Ferreira Alves
- Laboratório de Investigação Médica em Patologia Hepática, (LIM14) do Hospital das Clínicas (HCFMUSP), Faculdade de Medicina, Universidade de São Paulo, São Paulo 01246-000, Brazil
| | | | - Maria Lucia Correa-Giannella
- Laboratorio de Carboidratos e Radioimunoensaio (LIM-18) do Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo 01246-000, Brazil
| | - Luiz Roberto Britto
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil
| | - Ubiratan Fabres Machado
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil
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26
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Chang YC, Chan MH, Yang YF, Li CH, Hsiao M. Glucose transporter 4: Insulin response mastermind, glycolysis catalyst and treatment direction for cancer progression. Cancer Lett 2023; 563:216179. [PMID: 37061122 DOI: 10.1016/j.canlet.2023.216179] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 03/27/2023] [Accepted: 04/07/2023] [Indexed: 04/17/2023]
Abstract
The glucose transporter family (GLUT) consists of fourteen members. It is responsible for glucose homeostasis and glucose transport from the extracellular space to the cell cytoplasm to further cascade catalysis. GLUT proteins are encoded by the solute carrier family 2 (SLC2) genes and are members of the major facilitator superfamily of membrane transporters. Moreover, different GLUTs also have their transporter kinetics and distribution, so each GLUT member has its uniqueness and importance to play essential roles in human physiology. Evidence from many studies in the field of diabetes showed that GLUT4 travels between the plasma membrane and intracellular vesicles (GLUT4-storage vesicles, GSVs) and that the PI3K/Akt pathway regulates this activity in an insulin-dependent manner or by the AMPK pathway in response to muscle contraction. Moreover, some published results also pointed out that GLUT4 mediates insulin-dependent glucose uptake. Thus, dysfunction of GLUT4 can induce insulin resistance, metabolic reprogramming in diverse chronic diseases, inflammation, and cancer. In addition to the relationship between GLUT4 and insulin response, recent studies also referred to the potential upstream transcription factors that can bind to the promoter region of GLUT4 to regulating downstream signals. Combined all of the evidence, we conclude that GLUT4 has shown valuable unknown functions and is of clinical significance in cancers, which deserves our in-depth discussion and design compounds by structure basis to achieve therapeutic effects. Thus, we intend to write up a most updated review manuscript to include the most recent and critical research findings elucidating how and why GLUT4 plays an essential role in carcinogenesis, which may have broad interests and impacts on this field.
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Affiliation(s)
- Yu-Chan Chang
- Department of Biomedical Imaging and Radiological Science, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Ming-Hsien Chan
- Department of Biomedical Imaging and Radiological Science, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yi-Fang Yang
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Chien-Hsiu Li
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Michael Hsiao
- Genomics Research Center, Academia Sinica, Taipei, Taiwan; Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
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27
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Du H, Ma Y, Wang X, Zhang Y, Zhu L, Shi S, Pan S, Liu Z. Advanced glycation end products induce skeletal muscle atrophy and insulin resistance via activating ROS-mediated ER stress PERK/FOXO1 signaling. Am J Physiol Endocrinol Metab 2023; 324:E279-E287. [PMID: 36724125 DOI: 10.1152/ajpendo.00218.2022] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Skeletal muscle atrophy is often found in patients with type 2 diabetes mellitus (T2DM), which is characterized by insulin resistance. As the largest tissue in the body, skeletal muscle plays important roles in insulin resistance. Advanced glycation end products (AGEs) are a type of toxic metabolite that are representative of multiple pathophysiological changes associated with T2DM. Mice were exposed to AGEs. Forkhead box O1 (FOXO1) was silenced by using a constructed viral vector carrying siRNA. Skeletal muscle atrophy was evaluated by using hematoxylin-eosin (H&E), oil red O, myosin skeletal heavy chain (MHC), and laminin immunofluorescent stains. Reactive oxygen species (ROS) generation was assessed by using the dihydroethidium (DHE) stain. Western blotting was used to evaluate protein expression and phosphorylation. Insulin resistance was monitored via the insulin tolerance test and the glucose infusion rate (GIR). Mice exposed to AGEs showed insulin resistance, which was evidenced by reduced insulin tolerance and GIR. H&E and MHC immunofluorescent stains suggested reduced cross-sectional muscle fiber area. Laminin immunofluorescent and oil red O stains indicated increased intramuscular fibrosis and lipid deposits, respectively. Exposure to AGEs induced ROS generation, increased phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and FOXO1, facilitated FOXO1 nuclear translocation, and elevated expression of muscle atrophy F-box (MAFbx) in gastrocnemius muscle. foxo1 silencing significantly suppressed skeletal muscle atrophy and insulin resistance without affecting ROS production. AGEs exacerbated skeletal muscle atrophy and insulin resistance by activating the PERK/FOXO1 signaling pathway in skeletal muscle.NEW & NOTEWORTHY In this study, we proposed a molecular mechanism underlying the skeletal muscle atrophy-associated insulin resistance in type 2 diabetes mellitus (T2DM). Our investigation suggests that exposure to AGEs, which are characteristic metabolites of T2DM pathology, induces the activation of reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress, leading to the upregulation of the protein kinase RNA-like ER kinase (PERK)/forkhead box O1 (FOXO1)/muscle atrophy F-box pathway and subsequent skeletal muscle atrophy, ultimately resulting in insulin resistance.
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Affiliation(s)
- Haixia Du
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China
- Metabolic and Cardiovascular Diseases Laboratories, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China
- Department 403, PLA Rocket Force University of Engineering, Xi'an, People's Republic of China
| | - Yanpeng Ma
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China
- Metabolic and Cardiovascular Diseases Laboratories, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China
- Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, People's Republic of China
| | - Xiqiang Wang
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China
- Metabolic and Cardiovascular Diseases Laboratories, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China
- Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, People's Republic of China
| | - Yong Zhang
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China
- Metabolic and Cardiovascular Diseases Laboratories, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China
- Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, People's Republic of China
| | - Ling Zhu
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China
- Metabolic and Cardiovascular Diseases Laboratories, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China
- Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, People's Republic of China
| | - Shuang Shi
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China
- Metabolic and Cardiovascular Diseases Laboratories, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China
- Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, People's Republic of China
| | - Shuo Pan
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China
- Metabolic and Cardiovascular Diseases Laboratories, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China
- Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, People's Republic of China
| | - Zhongwei Liu
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China
- Metabolic and Cardiovascular Diseases Laboratories, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China
- Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, People's Republic of China
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28
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Hadzi-Petrushev N, Angelovski M, Mladenov M. Advanced Glycation End Products and Diabetes. CONTEMPORARY ENDOCRINOLOGY 2023:99-127. [DOI: 10.1007/978-3-031-39721-9_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Aerobic Exercise Training Reduces Atherogenesis Induced by Low-Sodium Diet in LDL Receptor Knockout Mice. Antioxidants (Basel) 2022; 11:antiox11102023. [PMID: 36290746 PMCID: PMC9598599 DOI: 10.3390/antiox11102023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 10/03/2022] [Accepted: 10/07/2022] [Indexed: 11/24/2022] Open
Abstract
This study investigated the efficacy of aerobic exercise training (AET) in the prevention of dyslipidemia, insulin resistance (IR), and atherogenesis induced by severe low-sodium (LS) diet. LDL receptor knockout (LDLR KO) mice were fed a low-sodium (LS) (0.15% NaCl) or normal-sodium (NS; 1.27% NaCl) diet, submitted to AET in a treadmill, 5 times/week, 60 min/day, 15 m/min, for 90 days, or kept sedentary. Blood pressure (BP), plasma total cholesterol (TC) and triglyceride (TG) concentrations, lipoprotein profile, and insulin sensitivity were evaluated at the end of the AET protocol. Lipid infiltration, angiotensin II type 1 receptor (AT1), receptor for advanced glycation end products (RAGE), carboxymethyllysine (CML), and 4-hydroxynonenal (4-HNE) contents as well as gene expression were determined in the brachiocephalic trunk. BP and TC and gene expression were similar among groups. Compared to the NS diet, the LS diet increased vascular lipid infiltration, CML, RAGE, 4-HNE, plasma TG, LDL-cholesterol, and VLDL-TG. Conversely, the LS diet reduced vascular AT1 receptor, insulin sensitivity, HDL-cholesterol, and HDL-TG. AET prevented arterial lipid infiltration; increases in CML, RAGE, and 4-HNE contents; and reduced AT1 levels and improved LS-induced peripheral IR. The current study showed that AET counteracted the deleterious effects of chronic LS diet in an atherogenesis-prone model by ameliorating peripheral IR, lipid infiltration, CML, RAGE, 4-HNE, and AT1 receptor in the intima-media of the brachiocephalic trunk. These events occurred independently of the amelioration of plasma-lipid profile, which was negatively affected by the severe dietary-sodium restriction.
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30
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Aftermath of AGE-RAGE Cascade in the pathophysiology of cardiovascular ailments. Life Sci 2022; 307:120860. [PMID: 35940220 DOI: 10.1016/j.lfs.2022.120860] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 07/20/2022] [Accepted: 08/01/2022] [Indexed: 11/21/2022]
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Oxidative Stress in Type 2 Diabetes: The Case for Future Pediatric Redoxomics Studies. Antioxidants (Basel) 2022; 11:antiox11071336. [PMID: 35883827 PMCID: PMC9312244 DOI: 10.3390/antiox11071336] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 06/28/2022] [Accepted: 06/30/2022] [Indexed: 01/27/2023] Open
Abstract
Considerable evidence supports the role of oxidative stress in adult type 2 diabetes (T2D). Due to increasing rates of pediatric obesity, lack of physical activity, and consumption of excess food calories, it is projected that the number of children living with insulin resistance, prediabetes, and T2D will markedly increase with enormous worldwide economic costs. Understanding the factors contributing to oxidative stress and T2D risk may help develop optimal early intervention strategies. Evidence suggests that oxidative stress, triggered by excess dietary fat consumption, causes excess mitochondrial hydrogen peroxide emission in skeletal muscle, alters redox status, and promotes insulin resistance leading to T2D. The pathophysiological events arising from excess calorie-induced mitochondrial reactive oxygen species production are complex and not yet investigated in children. Systems medicine is an integrative approach leveraging conventional medical information and environmental factors with data obtained from “omics” technologies such as genomics, proteomics, and metabolomics. In adults with T2D, systems medicine shows promise in risk assessment and predicting drug response. Redoxomics is a branch of systems medicine focusing on “omics” data related to redox status. Systems medicine with a complementary emphasis on redoxomics can potentially optimize future healthcare strategies for adults and children with T2D.
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32
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Xing J, Chen C. Hyperinsulinemia: beneficial or harmful or both on glucose homeostasis. Am J Physiol Endocrinol Metab 2022; 323:E2-E7. [PMID: 35635329 DOI: 10.1152/ajpendo.00441.2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Insulin, a principal anabolic hormone produced by pancreatic β-cells, has a primary function of storage of nutrients following excessive energy intake. Pre- or early type 2 diabetes stages present hyperinsulinemia (β-cell dysfunction) and insulin resistance. Initiation of hyperinsulinemia is triggered by a loss of first-phase glucose-stimulated insulin secretion with altered membrane ion channel distribution. More factors, including insulin resistance and excessive proliferation of β-cells, deteriorate the hyperinsulinemia, whereas the hyperinsulinemia contributes to further development of insulin resistance and type 2 diabetes; to develop eventually late-stage diabetes with absolute insulin deficiency. In this mini-review, the major focus was put on the causes and pathophysiology of hyperinsulinemia, and the metabolic consequences and current treatment of hyperinsulinemia were discussed. The data used in this narrative review were collected mainly from relevant discoveries in the past 3 years.
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Affiliation(s)
- JingJing Xing
- School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia
| | - Chen Chen
- School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia
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33
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Munguía L, Ortiz M, González C, Portilla A, Meaney E, Villarreal F, Nájera N, Ceballos G. Beneficial Effects of Flavonoids on Skeletal Muscle Health: A Systematic Review and Meta-Analysis. J Med Food 2022; 25:465-486. [PMID: 35394826 DOI: 10.1089/jmf.2021.0054] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Skeletal muscle (SkM) is a highly dynamic tissue that responds to physiological adaptations or pathological conditions, and SkM mitochondria play a major role in bioenergetics, regulation of intracellular calcium homeostasis, pro-oxidant/antioxidant balance, and apoptosis. Flavonoids are polyphenolic compounds with the ability to modulate molecular pathways implicated in the development of mitochondrial myopathy. Therefore, it is pertinent to explore its potential application in conditions such as aging, disuse, denervation, diabetes, obesity, and cancer. To evaluate preclinical and clinical effects of flavonoids on SkM structure and function. We performed a systematic review of published studies, with no date restrictions applied, using PubMed and Scopus. The following search terms were used: "flavonoids" OR "flavanols" OR "flavones" OR "anthocyanidins" OR "flavanones" OR "flavan-3-ols" OR "catechins" OR "epicatechin" OR "(-)-epicatechin" AND "skeletal muscle." The studies included in this review were preclinical studies, clinical trials, controlled clinical trials, and randomized-controlled trials that investigated the influence of flavonoids on SkM health. Three authors, independently, assessed trials for the review. Any disagreement was resolved by consensus. The use of flavonoids could be a potential tool for the prevention of muscle loss. Their effects on metabolism and on mitochondria function suggest their use as muscle regulators.
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Affiliation(s)
- Levy Munguía
- Higher School of Medicine, Instituto Politécnico Nacional, Mexico City, México
| | - Miguel Ortiz
- Higher School of Medicine, Instituto Politécnico Nacional, Mexico City, México
| | - Cristian González
- Higher School of Medicine, Instituto Politécnico Nacional, Mexico City, México
| | - Andrés Portilla
- Higher School of Medicine, Instituto Politécnico Nacional, Mexico City, México
| | - Eduardo Meaney
- Higher School of Medicine, Instituto Politécnico Nacional, Mexico City, México
| | - Francisco Villarreal
- Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California, USA
| | - Nayelli Nájera
- Higher School of Medicine, Instituto Politécnico Nacional, Mexico City, México
| | - Guillermo Ceballos
- Higher School of Medicine, Instituto Politécnico Nacional, Mexico City, México
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Advanced Glycation End Products and Diabetes Mellitus: Mechanisms and Perspectives. Biomolecules 2022; 12:biom12040542. [PMID: 35454131 PMCID: PMC9030615 DOI: 10.3390/biom12040542] [Citation(s) in RCA: 352] [Impact Index Per Article: 117.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/28/2022] [Accepted: 03/31/2022] [Indexed: 02/06/2023] Open
Abstract
Persistent hyperglycemic state in type 2 diabetes mellitus leads to the initiation and progression of non-enzymatic glycation reaction with proteins and lipids and nucleic acids. Glycation reaction leads to the generation of a heterogeneous group of chemical moieties known as advanced glycated end products (AGEs), which play a central role in the pathophysiology of diabetic complications. The engagement of AGEs with its chief cellular receptor, RAGE, activates a myriad of signaling pathways such as MAPK/ERK, TGF-β, JNK, and NF-κB, leading to enhanced oxidative stress and inflammation. The downstream consequences of the AGEs/RAGE axis involve compromised insulin signaling, perturbation of metabolic homeostasis, RAGE-induced pancreatic beta cell toxicity, and epigenetic modifications. The AGEs/RAGE signaling instigated modulation of gene transcription is profoundly associated with the progression of type 2 diabetes mellitus and pathogenesis of diabetic complications. In this review, we will summarize the exogenous and endogenous sources of AGEs, their role in metabolic dysfunction, and current understandings of AGEs/RAGE signaling cascade. The focus of this review is to recapitulate the role of the AGEs/RAGE axis in the pathogenesis of type 2 diabetes mellitus and its associated complications. Furthermore, we present an overview of future perspectives to offer new therapeutic interventions to intervene with the AGEs/RAGE signaling pathway and to slow down the progression of diabetes-related complications.
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35
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Haghparast Azad M, Niktab I, Dastjerdi S, Abedpoor N, Rahimi G, Safaeinejad Z, Peymani M, Forootan FS, Asadi-Shekaari M, Nasr Esfahani MH, Ghaedi K. The combination of endurance exercise and SGTC (Salvia-Ginseng-Trigonella-Cinnamon) ameliorate mitochondrial markers' overexpression with sufficient ATP production in the skeletal muscle of mice fed AGEs-rich high-fat diet. Nutr Metab (Lond) 2022; 19:17. [PMID: 35248109 PMCID: PMC8897771 DOI: 10.1186/s12986-022-00652-w] [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: 08/02/2021] [Accepted: 02/17/2022] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Skeletal muscle mitochondria is one of the most important affected sites of T2DM and its molecular mechanism is yet to be elucidated. Some recent theories believed that mitochondrial markers are upregulated in response to high fat induced T2DM; however, the reasons and the affected factors are still uncertain. In this regard, we aimed to investigate the effect of high fat induced T2DM on mitochondrial markers of skeletal muscle, and an herbal component along with endurance exercise, as probable treatments, in AGE-rich high-fat diet (AGEs-HFD) induced T2DM mice. METHODS T2DM was induced by 16 weeks of AGEs-HFD consumption in male C57BL/6 mice, followed by 8 weeks of drugs ingestion and endurance exercise treatments (n = 6 in each group and total number of 42 mice). The herbal component was an aquatic extract of Salvia officinalis, Trigonella foenum-graecum, Panax ginseng, and Cinnamomum zeylanicum, termed "SGTC". We then examined the relative expression of several mitochondrial markers, including Ppargc1α, Tfam, and electron transport chain genes and ATP levels, in skeletal muscle samples. RESULTS T2DM was successfully induced according to morphological, biochemical, and molecular observations. All mitochondrial markers, including Ppargc1a, Tfam, Cpt2, and electron transport chain genes, were upregulated in T2DM group compared to controls with no significant changes in the ATP levels. Most mitochondrial markers were downregulated by drug treatment compared to T2DM, but the ATP level was not significantly altered. All mitochondrial markers were upregulated in exercised group compared to T2DM with mild increase in the ATP level. The Ex + SGTC group had moderate level of mitochondrial markers compared to T2DM, but the highest ATP production. CONCLUSION The highly significant overexpression of mitochondrial markers may be in response to free fatty acid overload. However, the lack of significant change in the ATP level may be a result of ROS generation due to electron leakage in the AGEsRAGE axis and electron transport chain. Almost all treatments ameliorate mitochondrial markers' overexpression. The SGTC appears to regulate this with its antioxidant properties. Instead, exercise upregulated mitochondrial markers efficiently; however, the most efficient results, i.e. the most ATP production among the treatments, were observed in the Ex + SGTC group.
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Affiliation(s)
- Maryam Haghparast Azad
- ACECR Institute of Higher Education, Isfahan, Iran.,Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Iman Niktab
- ACECR Institute of Higher Education, Isfahan, Iran.,Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Shaghayegh Dastjerdi
- ACECR Institute of Higher Education, Isfahan, Iran.,Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Navid Abedpoor
- Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Golbarg Rahimi
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Hezar Jerib Ave., Azadi Sq., P.O. Code 81746-73441, Isfahan, Iran
| | - Zahra Safaeinejad
- Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Maryam Peymani
- Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran.
| | - Farzad Seyed Forootan
- Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran. .,Legal Medicine Research Center, Legal Medicine Organization, Tehran, Iran.
| | - Majid Asadi-Shekaari
- Neuroscience Research Center, Neuropharmacology Institute, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Hossein Nasr Esfahani
- Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Kamran Ghaedi
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Hezar Jerib Ave., Azadi Sq., P.O. Code 81746-73441, Isfahan, Iran.
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Advanced Glycation End Products: A Sweet Flavor That Embitters Cardiovascular Disease. Int J Mol Sci 2022; 23:ijms23052404. [PMID: 35269546 PMCID: PMC8910157 DOI: 10.3390/ijms23052404] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 02/16/2022] [Accepted: 02/17/2022] [Indexed: 12/24/2022] Open
Abstract
Epidemiological studies demonstrate the role of early and intensive glycemic control in the prevention of micro and macrovascular disease in both type 1 and type 2 diabetes mellitus (DM). Hyperglycemia elicits several pathways related to the etiopathogenesis of cardiovascular disease (CVD), including the generation of advanced glycation end products (AGEs). In this review, we revisit the role played by AGEs in CVD based in clinical trials and experimental evidence. Mechanistic aspects concerning the recognition of AGEs by the advanced glycosylation end product-specific receptor (AGER) and its counterpart, the dolichyl-diphosphooligosaccharide-protein glycosyltransferase (DDOST) and soluble AGER are discussed. A special focus is offered to the AGE-elicited pathways that promote cholesterol accumulation in the arterial wall by enhanced oxidative stress, inflammation, endoplasmic reticulum stress and impairment in the reverse cholesterol transport (RCT).
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Wu Y, Dong L, Song Y, Wu Y, Zhang Y, Wang S. Preventive effects of polysaccharides from Physalis alkekengi L. on dietary advanced glycation end product-induced insulin resistance in mice associated with the modulation of gut microbiota. Int J Biol Macromol 2022; 204:204-214. [PMID: 35108598 DOI: 10.1016/j.ijbiomac.2022.01.152] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 12/28/2021] [Accepted: 01/24/2022] [Indexed: 12/21/2022]
Abstract
Advanced glycation end products (AGEs) are commonly found in thermally processed foods, and long-term high AGE feeding has been reported to have negative effects on body health. In the current study, the effect of Physalis alkekengi L. fruit polysaccharide (PFP) on preventing dietary AGE-induced insulin resistance (IR) in mice was investigated. The results showed that PFP administration can significantly ameliorate hyperglycemia, dyslipidemia, and insulin resistance induced by dietary AGEs in mice. Compared to AGE-treated mice, the homeostasis model assessment for insulin resistance (HOMA-IR) index and insulin sensitivity (HOMA-IS) index of PFP-treated mice were improved significantly (p < 0.05). The levels of endotoxin and inflammatory cytokines in the liver decreased, while the levels of insulin receptor substrate-1 and insulin receptor substrate-2 in the liver increased (p < 0.05). The 16S rRNA analysis showed that PFP administration reversed the Bacteroidetes/Firmicutes ratio and reduced lipopolysaccharide generation and inflammation-related bacteria, including Desulfovibrio and Acetatifactor. In addition, PFP administration also increased short-chain fatty acid levels in feces compared to dietary AGE-treated mice. Spearman's correlation analysis showed that certain specific genera, including Alistipes and Caproiciproducens, are closely related to IR-related parameters. These findings suggest that PFP can prevent dietary AGE-induced IR by modulating the gut microbiota and increasing microbial metabolites.
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Affiliation(s)
- Yuekun Wu
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China
| | - Lu Dong
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China
| | - Yujie Song
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China
| | - Yajing Wu
- State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science and Technology, Tianjin 300457, China
| | - Yan Zhang
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China.
| | - Shuo Wang
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China.
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Passarelli M, Machado UF. AGEs-Induced and Endoplasmic Reticulum Stress/Inflammation-Mediated Regulation of GLUT4 Expression and Atherogenesis in Diabetes Mellitus. Cells 2021; 11:104. [PMID: 35011666 PMCID: PMC8750246 DOI: 10.3390/cells11010104] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 12/23/2021] [Accepted: 12/27/2021] [Indexed: 02/08/2023] Open
Abstract
In recent decades, complex and exquisite pathways involved in the endoplasmic reticulum (ER) and inflammatory stress responses have been demonstrated to participate in the development and progression of numerous diseases, among them diabetes mellitus (DM). In those pathways, several players participate in both, reflecting a complicated interplay between ER and inflammatory stress. In DM, ER and inflammatory stress are involved in both the pathogenesis of the loss of glycemic control and the development of degenerative complications. Furthermore, hyperglycemia increases the generation of advanced glycation end products (AGEs), which in turn refeed ER and inflammatory stress, contributing to worsening glycemic homeostasis and to accelerating the development of DM complications. In this review, we present the current knowledge regarding AGEs-induced and ER/inflammation-mediated regulation of the expression of GLUT4 (solute carrier family 2, facilitated glucose transporter member 4), as a marker of glycemic homeostasis and of cardiovascular disease (CVD) development/progression, as a leading cause of morbidity and mortality in DM.
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Affiliation(s)
- Marisa Passarelli
- Laboratório de Lípides (LIM-10), Hospital das Clínicas (HCFMUSP) da Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-000, Brazil;
- Programa de Pos-Graduação em Medicina, Universidade Nove de Julho, São Paulo 01525-000, Brazil
| | - Ubiratan Fabres Machado
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil
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Insulin Signal Transduction Perturbations in Insulin Resistance. Int J Mol Sci 2021; 22:ijms22168590. [PMID: 34445300 PMCID: PMC8395322 DOI: 10.3390/ijms22168590] [Citation(s) in RCA: 95] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/23/2021] [Accepted: 07/28/2021] [Indexed: 12/11/2022] Open
Abstract
Type 2 diabetes mellitus is a widespread medical condition, characterized by high blood glucose and inadequate insulin action, which leads to insulin resistance. Insulin resistance in insulin-responsive tissues precedes the onset of pancreatic β-cell dysfunction. Multiple molecular and pathophysiological mechanisms are involved in insulin resistance. Insulin resistance is a consequence of a complex combination of metabolic disorders, lipotoxicity, glucotoxicity, and inflammation. There is ample evidence linking different mechanistic approaches as the cause of insulin resistance, but no central mechanism is yet described as an underlying reason behind this condition. This review combines and interlinks the defects in the insulin signal transduction pathway of the insulin resistance state with special emphasis on the AGE-RAGE-NF-κB axis. Here, we describe important factors that play a crucial role in the pathogenesis of insulin resistance to provide directionality for the events. The interplay of inflammation and oxidative stress that leads to β-cell decline through the IAPP-RAGE induced β-cell toxicity is also addressed. Overall, by generating a comprehensive overview of the plethora of mechanisms involved in insulin resistance, we focus on the establishment of unifying mechanisms to provide new insights for the future interventions of type 2 diabetes mellitus.
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40
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Yu W, Fan L, Wang M, Cao B, Hu X. Pterostilbene Improves Insulin Resistance Caused by Advanced Glycation End Products (AGEs) in Hepatocytes and Mice. Mol Nutr Food Res 2021; 65:e2100321. [PMID: 34085383 DOI: 10.1002/mnfr.202100321] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 05/15/2021] [Indexed: 11/07/2022]
Abstract
SCOPE Increased consumption of modern processed foods rich in AGEs is drawing worldwide concerns because they are related with rising diabetes prevalence. This study aimed to investigate if pterostilbene (PTE) regulates glucose metabolism and insulin signaling, as well as its potential mechanism in the context of AGEs exposure. METHODS AND RESULTS In vitro, Lo2 and HepG2 cells are treated with vehicle, AGEs with or without PTE. AGEs exposure directly impair insulin action as evidenced by assays of insulin-stimulated glucose uptake, consumption, and output. However, PTE efficiently rescue the AGE-induced phenotypes in both cell lines, and enhance IRS-1/PI3K/AKT insulin signaling in a dose-dependent manner. In vivo, C57BL6 mice are fed with regular, high AGEs diet and high AGEs plus PTE. PTE administration effectively improves hyperglycemia, glucose tolerance, and impaired hepatic insulin signaling induced by AGEs, consistent with the in vitro experiments. Moreover, PTE reduce AGEs accumulation in liver and serum. RNA-seq data indicate that PTE counteracts several AGEs-induced dysfunctions including diabetes related process, glucose metabolic process, immune response, and so on. CONCLUSION PTE treatment prominently reduced AGEs accumulation and alleviated AGEs-associated diabetes symptoms. PTE could be used as a promising glucose-sensitizing agent for nutritional intervention.
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Affiliation(s)
- Wenzhe Yu
- School of Medicine, Xiamen University, Xiamen, 361102, P. R. China
| | - Lida Fan
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Heath, Xiamen University, Xiamen, 361102, P. R. China
| | - Mingfu Wang
- School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong, 999077, P. R. China
| | - Bin Cao
- School of Medicine, Xiamen University, Xiamen, 361102, P. R. China
| | - Xiaoqian Hu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Heath, Xiamen University, Xiamen, 361102, P. R. China
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41
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Ahmad K, Shaikh S, Lee EJ, Lee YH, Choi I. Consequences of Dicarbonyl Stress on Skeletal Muscle Proteins in Type 2 Diabetes. Curr Protein Pept Sci 2021; 21:878-889. [PMID: 31746292 DOI: 10.2174/1389203720666191119100759] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Revised: 05/27/2019] [Accepted: 10/22/2019] [Indexed: 12/15/2022]
Abstract
Skeletal muscle is the largest organ in the body and constitutes almost 40% of body mass. It is also the primary site of insulin-mediated glucose uptake, and skeletal muscle insulin resistance, that is, diminished response to insulin, is characteristic of Type 2 diabetes (T2DM). One of the foremost reasons posited to explain the etiology of T2DM involves the modification of proteins by dicarbonyl stress due to an unbalanced metabolism and accumulations of dicarbonyl metabolites. The elevated concentration of dicarbonyl metabolites (i.e., glyoxal, methylglyoxal, 3-deoxyglucosone) leads to DNA and protein modifications, causing cell/tissue dysfunctions in several metabolic diseases such as T2DM and other age-associated diseases. In this review, we recapitulated reported effects of dicarbonyl stress on skeletal muscle and associated extracellular proteins with emphasis on the impact of T2DM on skeletal muscle and provided a brief introduction to the prevention/inhibition of dicarbonyl stress.
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Affiliation(s)
- Khurshid Ahmad
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan, 38541, Korea
| | - Sibhghatulla Shaikh
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan, 38541, Korea
| | - Eun Ju Lee
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan, 38541, Korea
| | - Yong-Ho Lee
- Department of Biomedical Sciences, Daegu Catholic University, Gyeongsan, 38430, Korea
| | - Inho Choi
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan, 38541, Korea
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42
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Oliveira JS, de Almeida C, de Souza ÂMN, da Cruz LD, Alfenas RCG. Effect of dietary advanced glycation end-products restriction on type 2 diabetes mellitus control: a systematic review. Nutr Rev 2021; 80:294-305. [PMID: 34010398 DOI: 10.1093/nutrit/nuab020] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
CONTEXT Reducing dietary advanced glycation end-products (AGEs) may favor diabetes control. OBJECTIVE Critically analyze studies about the effect of dietary AGEs restriction on inflammation, oxidative stress, and glycemic control in patients with type 2 diabetes mellitus (DM2). DATA SOURCE This systematic review was conducted according to PRISMA methodology. The PubMed, Web of Science, LILACS, and Cochrane Library databases were searched, using the terms "type 2 diabetes," "advanced glycation end products" and "diet." DATA EXTRACTION Seven original studies were included in this review. The duration of the studies ranged from 1 day to 16 weeks. All extracted data were compiled, compared, and critically analyzed. DATA ANALYSIS Glycemic variables were considered the primary outcomes. The secondary outcomes were glycation, inflammatory, and oxidative stress markers. CONCLUSION Although serum insulin, homeostasis model assessment of insulin resistance, and glycated hemoglobin values were lower after the consumption of AGEs restricted diets in most studies, there was a lack of unanimity regarding dietary AGEs' positive effect on inflammation, oxidative stress, and blood glucose. SYSTEMATIC REVIEW REGISTRATION PROSPERO registration no. CRD42020152640.
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Affiliation(s)
- Julia S Oliveira
- J.S. Oliveira, C. Almeida, A.M.N. Souza, L.D. Cruz, and R.C.G. Alfenas are with Departamento de Nutrição e Saúde, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brazil
| | - Carolina de Almeida
- J.S. Oliveira, C. Almeida, A.M.N. Souza, L.D. Cruz, and R.C.G. Alfenas are with Departamento de Nutrição e Saúde, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brazil
| | - Ângela M N de Souza
- J.S. Oliveira, C. Almeida, A.M.N. Souza, L.D. Cruz, and R.C.G. Alfenas are with Departamento de Nutrição e Saúde, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brazil
| | - Luciana D da Cruz
- J.S. Oliveira, C. Almeida, A.M.N. Souza, L.D. Cruz, and R.C.G. Alfenas are with Departamento de Nutrição e Saúde, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brazil
| | - Rita C G Alfenas
- J.S. Oliveira, C. Almeida, A.M.N. Souza, L.D. Cruz, and R.C.G. Alfenas are with Departamento de Nutrição e Saúde, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brazil
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Dozio E, Vettoretti S, Lungarella G, Messa P, Corsi Romanelli MM. Sarcopenia in Chronic Kidney Disease: Focus on Advanced Glycation End Products as Mediators and Markers of Oxidative Stress. Biomedicines 2021; 9:405. [PMID: 33918767 PMCID: PMC8068965 DOI: 10.3390/biomedicines9040405] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 04/06/2021] [Accepted: 04/08/2021] [Indexed: 02/07/2023] Open
Abstract
Sarcopenia is common in chronic kidney disease (CKD), and it is independently associated with morbidity and mortality. Advanced glycation end products (AGE) are mainly known as aging products. In CKD, AGE accumulate due to increased production and reduced kidney excretion. The imbalance between oxidant/antioxidant capacities in CKD patients is one of the main factors leading to AGE synthesis. AGE can, in turn, promote CKD progression and CKD-related complications by increasing reactive oxygen species generation, inducing inflammation, and promoting fibrosis. All these derangements can further increase AGE and uremic toxin accumulation and promote loss of muscle mass and function. Since the link between AGE and sarcopenia in CKD is far from being fully understood, we revised hereby the data supporting the potential contribution of AGE as mediators of oxidative stress in the pathogenesis of sarcopenia. Understanding how AGE and oxidative stress impact the onset of sarcopenia in CKD may help to identify new potential markers of disease progression and/or therapeutic targets.
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Affiliation(s)
- Elena Dozio
- Department of Biomedical Science for Health, Laboratory of Clinical Pathology, Università degli Studi di Milano, 20133 Milan, Italy;
| | - Simone Vettoretti
- Unit of Nephrology, Dialysis and Kidney Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, 20122 Milan, Italy; (S.V.); (P.M.)
| | - Giuseppe Lungarella
- Department of Molecular and Developmental Medicine, Università di Siena, 53100 Siena, Italy;
| | - Piergiorgio Messa
- Unit of Nephrology, Dialysis and Kidney Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, 20122 Milan, Italy; (S.V.); (P.M.)
- Department of Clinical Science and Community Health, Università degli Studi di Milano, 20133 Milan, Italy
| | - Massimiliano M. Corsi Romanelli
- Department of Biomedical Science for Health, Laboratory of Clinical Pathology, Università degli Studi di Milano, 20133 Milan, Italy;
- Service of Laboratory Medicine1-Clinical Pathology, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy
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Cruz-Pineda WD, Parra-Rojas I, Rodríguez-Ruíz HA, Illades-Aguiar B, Matia-García I, Garibay-Cerdenares OL. The regulatory role of insulin in energy metabolism and leukocyte functions. J Leukoc Biol 2021; 111:197-208. [PMID: 33724523 PMCID: PMC9291603 DOI: 10.1002/jlb.2ru1220-847r] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 02/08/2021] [Accepted: 02/10/2021] [Indexed: 12/15/2022] Open
Abstract
Insulin is the hormone responsible for maintaining glucose homeostasis in the body, in addition to participating in lipid metabolism, protein synthesis, and the inhibition of gluconeogenesis. These functions are well characterized in the classic organ target cells that are responsible for general energy regulation: the liver, skeletal muscle, and adipose tissue. However, these actions are not restricted to these tissues because insulin has been shown to affect most cells in the body. This review describes the role of insulin in leukocyte signaling pathways, metabolism and functions, and how insulin resistance could affect this signaling and deteriorate leukocyte metabolism and function, in addition to showing evidence that suggests leukocytes may substantially contribute to the development of systemic insulin resistance.
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Affiliation(s)
- Walter David Cruz-Pineda
- Laboratorio de Investigación en Obesidad y Diabetes, Facultad de Ciencias Químico-Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, Guerrero, Mexico
| | - Isela Parra-Rojas
- Laboratorio de Investigación en Obesidad y Diabetes, Facultad de Ciencias Químico-Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, Guerrero, Mexico
| | - Hugo Alberto Rodríguez-Ruíz
- Laboratorio de Investigación en Obesidad y Diabetes, Facultad de Ciencias Químico-Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, Guerrero, Mexico.,Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico-Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, Guerrero, Mexico
| | - Berenice Illades-Aguiar
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico-Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, Guerrero, Mexico
| | - Inés Matia-García
- Laboratorio de Investigación en Obesidad y Diabetes, Facultad de Ciencias Químico-Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, Guerrero, Mexico
| | - Olga Lilia Garibay-Cerdenares
- CONACyT-Universidad Autónoma de Guerrero, Chilpancingo, Guerrero, Mexico.,Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico-Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, Guerrero, Mexico
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Pringle NA, van de Venter M, Koekemoer TC. Comprehensive in vitro antidiabetic screening of Aspalathus linearis using a target-directed screening platform and cellomics. Food Funct 2021; 12:1020-1038. [PMID: 33416070 DOI: 10.1039/d0fo02611e] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The antidiabetic potential of Aspalathus linearis has been investigated for over a decade, however, its characterisation remains incomplete with results scattered across numerous journals making the information difficult to compare and integrate. To explore whether any potential antidiabetic mechanisms for A. linearis have been neglected and to compare the suitability of extracts of green and "fermented" A. linearis as potential antidiabetic treatment strategies, this study utilised a comprehensive in vitro antidiabetic target-directed screening platform in combination with high content screening and analysis/cellomics. The antidiabetic screening platform consisted of 20 different screening assays that incorporated 5 well-characterised antidiabetic targets i.e. the intestine, liver, skeletal muscle, adipose tissue/obesity and pancreatic β-cells. Both the green and fermented extracts of A. linearis demonstrated very broad antidiabetic mechanisms as they revealed several promising activities that could be useful in combatting insulin resistance, inflammation, oxidative stress, protein glycation and pancreatic β-cell dysfunction and death - with a strong tendency to attenuate postprandial hyperglycaemia and the subsequent metabolic dysfunction which arises as a result of poor glycaemic control. The green extract was more successful at combatting oxidative stress in INS-1 pancreatic β-cells and enhancing intracellular calcium levels in the absence of glucose. Conversely, the fermented extract demonstrated a greater ability to inhibit α-glucosidase activity as well as palmitic acid-induced free fatty acid accumulation in C3A hepatocytes and differentiated L6 myotubes, however, further studies are required to clarify the potentially toxic and pro-inflammatory nature of the fermented extract.
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Affiliation(s)
- Nadine A Pringle
- Department of Biochemistry and Microbiology, Nelson Mandela University, Port Elizabeth, South Africa.
| | - Maryna van de Venter
- Department of Biochemistry and Microbiology, Nelson Mandela University, Port Elizabeth, South Africa.
| | - Trevor C Koekemoer
- Department of Biochemistry and Microbiology, Nelson Mandela University, Port Elizabeth, South Africa.
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García-Gómez E, Bobadilla-Bravo M, Díaz-Díaz E, Vázquez-Martínez ER, Nava-Salazar S, Torres-Ramos Y, García-Romero CS, Camacho-Arroyo I, Cerbón M. High Plasmatic Levels of Advanced Glycation End Products are Associated with Metabolic Alterations and Insulin Resistance in Preeclamptic Women. Curr Mol Med 2021; 20:751-759. [DOI: 10.2174/1566524020666200220141414] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 01/16/2020] [Accepted: 01/27/2020] [Indexed: 11/22/2022]
Abstract
Aims:
The purpose of this study was to investigate the association between
plasmatic levels of advanced end glycation products (AGEs) and the metabolic profile in
subjects diagnosed with preeclampsia, due to the known relation of these molecules with
oxidative stress and inflammation, which in turn are related with PE pathogenesis.
Background:
It has been reported that increased levels of AGEs are observed in patients
with preeclampsia as compared with healthy pregnant subjects, which was mainly
associated with oxidative stress and inflammation. Besides, in women with preeclampsia,
there are metabolic changes such as hyperinsulinemia, glucose intolerance, dyslipidemia,
among others, that are associated with an exacerbated insulin resistance. Additionally,
some parameters indicate the alteration of hepatic function, such as increased levels of liver
enzymes. However, the relationship of levels of AGEs with altered lipidic, hepatic, and
glucose metabolism parameters in preeclampsia has not been evaluated.
Objective:
To investigate the association between plasmatic levels of AGEs and hepatic,
lipid, and metabolic profiles in women diagnosed with preeclampsia.
Methods:
Plasma levels of AGEs were determined by a competitive enzyme-linked
immunosorbent assay (ELISA) in 15 patients diagnosed with preeclampsia and 28
normoevolutive pregnant subjects (control group). Hepatic (serum creatinine, gammaglutamyl
transpeptidase, aspartate transaminase, alanine transaminase, uric acid, and
lactate dehydrogenase), lipid (apolipoprotein A, apolipoprotein B, total cholesterol,
triglycerides, low-density lipoproteins, and high-density lipoproteins), and metabolic
variables (glucose, insulin, and insulin resistance) were assessed.
Results:
Plasmatic levels of AGEs were significantly higher in patients with preeclampsia
as compared with the control. A positive correlation between circulating levels of AGEs and
gamma-glutamyl transpeptidase, uric acid, glucose, insulin, and HOMA-IR levels was found
in patients with preeclampsia. In conclusion, circulating levels of AGEs were higher in
patients with preeclampsia than those observed in healthy pregnant subjects. Besides,
variables of hepatic and metabolic profile, particularly those related to insulin resistance,
were higher in preeclampsia as compared with healthy pregnant subjects. Interestingly,
there is a positive correlation between AGEs levels and insulin resistance.
Conclusions:
Circulating levels of AGEs were higher in patients with preeclampsia than
those observed in healthy pregnant subjects. Besides, hepatic and metabolic profiles,
particularly those related to insulin resistance, were higher in preeclampsia as compared
with healthy pregnant subjects. Interestingly, there is a positive correlation between AGEs
levels and insulin resistance, suggesting that excessive glycation and an impaired
metabolic profile contribute to the physiopathology of preeclampsia.
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Affiliation(s)
- Elizabeth García-Gómez
- Unidad de Investigacion en Reproduccion Humana, Consejo Nacional de Ciencia y Tecnologia (CONACyT)- Instituto Nacional de Perinatologia, Mexico
| | - Mariana Bobadilla-Bravo
- Unidad de Investigacion en Reproduccion Humana, Instituto Nacional de Perinatologia-Facultad de Quimica, Universidad Nacional Autonoma de Mexico, Mexico
| | - Eulises Díaz-Díaz
- Departamento de Biologia de la Reproduccion, Instituto Nacional de Ciencias Medicas y Nutricion “Salvador Zubiran”, Mexico
| | - Edgar Ricardo Vázquez-Martínez
- Unidad de Investigacion en Reproduccion Humana, Instituto Nacional de Perinatologia-Facultad de Quimica, Universidad Nacional Autonoma de Mexico, Mexico
| | - Sonia Nava-Salazar
- Departamento de Inmunobioquimica, Instituto Nacional de Perinatologia "Isidro Espinosa de los Reyes, Mexico
| | - Yessica Torres-Ramos
- Departamento de Inmunobioquimica, Instituto Nacional de Perinatologia "Isidro Espinosa de los Reyes, Mexico
| | - Carmen Selene García-Romero
- Departamento de Infectologia e Inmunologia, Instituto Nacional de Perinatologia "Isidro Espinosa de los Reyes", Ciudad de Mexico, Mexico
| | - Ignacio Camacho-Arroyo
- Unidad de Investigacion en Reproduccion Humana, Instituto Nacional de Perinatologia-Facultad de Quimica, Universidad Nacional Autonoma de Mexico, Mexico
| | - Marco Cerbón
- Unidad de Investigacion en Reproduccion Humana, Instituto Nacional de Perinatologia-Facultad de Quimica, Universidad Nacional Autonoma de Mexico, Mexico
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Estrogen and Glycemic Homeostasis: The Fundamental Role of Nuclear Estrogen Receptors ESR1/ESR2 in Glucose Transporter GLUT4 Regulation. Cells 2021; 10:cells10010099. [PMID: 33430527 PMCID: PMC7827878 DOI: 10.3390/cells10010099] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/03/2021] [Accepted: 01/04/2021] [Indexed: 02/07/2023] Open
Abstract
Impaired circulating estrogen levels have been related to impaired glycemic homeostasis and diabetes mellitus (DM), both in females and males. However, for the last twenty years, the relationship between estrogen, glycemic homeostasis and the mechanisms involved has remained unclear. The characterization of estrogen receptors 1 and 2 (ESR1 and ESR2) and of insulin-sensitive glucose transporter type 4 (GLUT4) finally offered a great opportunity to shed some light on estrogen regulation of glycemic homeostasis. In this manuscript, we review the relationship between estrogen and DM, focusing on glycemic homeostasis, estrogen, ESR1/ESR2 and GLUT4. We review glycemic homeostasis and GLUT4 expression (muscle and adipose tissues) in Esr1−/− and Esr2−/− transgenic mice. We specifically address estradiol-induced and ESR1/ESR2-mediated regulation of the solute carrier family 2 member 4 (Slc2a4) gene, examining ESR1/ESR2-mediated genomic mechanisms that regulate Slc2a4 transcription, especially those occurring in cooperation with other transcription factors. In addition, we address the estradiol-induced translocation of ESR1 and GLUT4 to the plasma membrane. Studies make it clear that ESR1-mediated effects are beneficial, whereas ESR2-mediated effects are detrimental to glycemic homeostasis. Thus, imbalance of the ESR1/ESR2 ratio may have important consequences in metabolism, highlighting that ESR2 hyperactivity assumes a diabetogenic role.
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RNA-sequencing analysis reveals the potential contribution of lncRNAs in palmitic acid-induced insulin resistance of skeletal muscle cells. Biosci Rep 2020; 40:221488. [PMID: 31833538 PMCID: PMC6944669 DOI: 10.1042/bsr20192523] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 11/28/2019] [Accepted: 12/12/2019] [Indexed: 02/06/2023] Open
Abstract
Insulin resistance (IR) has been considered as the common pathological basis and developmental driving force for most metabolic diseases. Long noncoding RNAs (lncRNAs) have emerged as pivotal regulators in modulation of glucose and lipid metabolism. However, the comprehensive profile of lncRNAs in skeletal muscle cells under the insulin resistant status and the possible biological effects of them were not fully studied. In this research, using C2C12 myotubes as cell models in vitro, deep RNA-sequencing was performed to profile lncRNAs and mRNAs between palmitic acid-induced IR C2C12 myotubes and control ones. The results revealed that a total of 144 lncRNAs including 70 up-regulated and 74 down-regulated (|fold change| > 2, q < 0.05) were significantly differentially expressed in palmitic acid-induced insulin resistant cells. In addition, functional annotation analysis based on the Gene Ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) databases revealed that the target genes of the differentially expressed lncRNAs were significantly enriched in fatty acid oxidation, lipid oxidation, PPAR signaling pathway, and insulin signaling pathway. Moreover, Via qPCR, most of selected lncRNAs in myotubes and db/db mice skeletal muscle showed the consistent expression trends with RNA-sequencing. Co-expression analysis also explicated the key lncRNA–mRNA interactions and pointed out a potential regulatory network of candidate lncRNA ENSMUST00000160839. In conclusion, the present study extended the skeletal muscle lncRNA database and provided novel potential regulators for future genetic and molecular studies on insulin resistance, which is helpful for prevention and treatment of the related metabolic diseases.
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Rusbana TB, Agista AZ, Saputra WD, Ohsaki Y, Watanabe K, Ardiansyah A, Budijanto S, Koseki T, Aso H, Komai M, Shirakawa H. Supplementation with Fermented Rice Bran Attenuates Muscle Atrophy in a Diabetic Rat Model. Nutrients 2020; 12:E2409. [PMID: 32806520 PMCID: PMC7469067 DOI: 10.3390/nu12082409] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 08/09/2020] [Accepted: 08/11/2020] [Indexed: 12/25/2022] Open
Abstract
Fermented rice bran (FRB), a prospective supplement, has been proven to ameliorate certain medical conditions. However, its nutraceutical effect on muscle atrophy has never been investigated. The present study aimed to evaluate the effect of FRB on muscle atrophy in a streptozotocin (STZ)-induced diabetic rat model. Three groups of Sprague-Dawley rats, namely the control, STZ, and FRB groups, were treated as follows. The diabetic groups (STZ and FRB) were injected intraperitoneally with STZ (40 mg/kg BW), whereas the control group was injected with the vehicle. The STZ and control groups were fed the AIN93M diet, and the FRB group was fed 10% of FRB based on the AIN93M diet. The diabetic groups had reduced muscle size compared to the control group; however, these changes were alleviated in the FRB group. Moreover, the FRB group had a significantly lower expression of FBXO32/Atrogin-1 and TRIM63/MuRF1 (p < 0.05) due to blocked NF-κB activation. In conclusion, the anti-inflammatory effect of FRB may be beneficial for ameliorating muscle atrophy in diabetic conditions.
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Affiliation(s)
- Tubagus Bahtiar Rusbana
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan; (T.B.R.); (A.Z.A.); (W.D.S.); (Y.O.); (M.K.)
- Department of Food Technology, Faculty of Agriculture, University of Sultan Ageng Tirtayasa, Serang 42110, Indonesia
| | - Afifah Zahra Agista
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan; (T.B.R.); (A.Z.A.); (W.D.S.); (Y.O.); (M.K.)
| | - Wahyu Dwi Saputra
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan; (T.B.R.); (A.Z.A.); (W.D.S.); (Y.O.); (M.K.)
| | - Yusuke Ohsaki
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan; (T.B.R.); (A.Z.A.); (W.D.S.); (Y.O.); (M.K.)
- International Education and Research Center for Food Agricultural Immunology, Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan
| | - Kouichi Watanabe
- Cellular Biology Laboratory, Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan; (K.W.); (H.A.)
- International Education and Research Center for Food Agricultural Immunology, Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan
| | - Ardy Ardiansyah
- Department of Food Technology, Universitas Bakrie, Jakarta 12920, Indonesia;
| | - Slamet Budijanto
- Faculty of Agricultural Engineering and Technology, IPB University, Bogor 16680, Indonesia;
| | - Takuya Koseki
- Faculty of Agriculture, Yamagata University, Tsuruoka 997-8555, Japan;
| | - Hisashi Aso
- Cellular Biology Laboratory, Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan; (K.W.); (H.A.)
- International Education and Research Center for Food Agricultural Immunology, Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan
| | - Michio Komai
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan; (T.B.R.); (A.Z.A.); (W.D.S.); (Y.O.); (M.K.)
| | - Hitoshi Shirakawa
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan; (T.B.R.); (A.Z.A.); (W.D.S.); (Y.O.); (M.K.)
- International Education and Research Center for Food Agricultural Immunology, Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan
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50
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Daryabor G, Atashzar MR, Kabelitz D, Meri S, Kalantar K. The Effects of Type 2 Diabetes Mellitus on Organ Metabolism and the Immune System. Front Immunol 2020; 11:1582. [PMID: 32793223 PMCID: PMC7387426 DOI: 10.3389/fimmu.2020.01582] [Citation(s) in RCA: 285] [Impact Index Per Article: 57.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 06/15/2020] [Indexed: 12/14/2022] Open
Abstract
Metabolic abnormalities such as dyslipidemia, hyperinsulinemia, or insulin resistance and obesity play key roles in the induction and progression of type 2 diabetes mellitus (T2DM). The field of immunometabolism implies a bidirectional link between the immune system and metabolism, in which inflammation plays an essential role in the promotion of metabolic abnormalities (e.g., obesity and T2DM), and metabolic factors, in turn, regulate immune cell functions. Obesity as the main inducer of a systemic low-level inflammation is a main susceptibility factor for T2DM. Obesity-related immune cell infiltration, inflammation, and increased oxidative stress promote metabolic impairments in the insulin-sensitive tissues and finally, insulin resistance, organ failure, and premature aging occur. Hyperglycemia and the subsequent inflammation are the main causes of micro- and macroangiopathies in the circulatory system. They also promote the gut microbiota dysbiosis, increased intestinal permeability, and fatty liver disease. The impaired immune system together with metabolic imbalance also increases the susceptibility of patients to several pathogenic agents such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Thus, the need for a proper immunization protocol among such patients is granted. The focus of the current review is to explore metabolic and immunological abnormalities affecting several organs of T2DM patients and explain the mechanisms, whereby diabetic patients become more susceptible to infectious diseases.
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Affiliation(s)
- Gholamreza Daryabor
- Autoimmune Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohamad Reza Atashzar
- Department of Immunology, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | | | - Seppo Meri
- Department of Bacteriology and Immunology and the Translational Immunology Research Program (TRIMM), The University of Helsinki and HUSLAB, Helsinki University Hospital, Helsinki, Finland
| | - Kurosh Kalantar
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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