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Ullah R, Rehan I, Khan S. Utilizing machine learning algorithms for precise discrimination of glycosuria in fluorescence spectroscopic data. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2024; 319:124582. [PMID: 38833883 DOI: 10.1016/j.saa.2024.124582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 05/02/2024] [Accepted: 05/30/2024] [Indexed: 06/06/2024]
Abstract
Fluorescence spectroscopy coupled with a random forest machine learning algorithm offers a promising non-invasive approach for diagnosing glycosuria, a condition characterized by excess sugar in the urine of diabetic patients. This study investigated the ability of this method to differentiate between diabetic and healthy control urine samples. Fluorescent spectra were captured from urine samples using a Xenon arc lamp emitting light within the 200 to 950 nm wavelength range, with consistent fluorescence emission observed at 450 nm under an excitation wavelength of 370 nm. Healthy control samples were also analyzed within the same spectral range for comparison. To distinguish spectral differences between healthy and infected samples, the random forest (RF) and K-Nearest Neighbors (KNN) machine learning algorithms have been employed. These algorithms automatically recognize spectral patterns associated with diabetes, enabling the prediction of unknown classifications based on established samples. Principal component analysis (PCA) was utilized for dimensionality reduction before feeding the data to RF and KNN for classification. The model's classification performance was evaluated using 10-fold cross-validation, resulting in the proposed RF-based model achieving accuracy of 96 %, specificity of 100 %, sensitivity of 93 %, and precision of 100 %. These results suggest that the proposed method holds promise for a more convenient and potentially more accurate method for diagnosing glycosuria in diabetic patients.
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Affiliation(s)
- Rahat Ullah
- National Institute of Lasers and Optronics College, Pakistan Institute of Engineering and Applied Sciences, Nilore, Islamabad 45650, Pakistan.
| | - Imran Rehan
- National Institute of Lasers and Optronics College, Pakistan Institute of Engineering and Applied Sciences, Nilore, Islamabad 45650, Pakistan; Department of Physics, Islamia College Peshawar, Khyber Pakhtunkhwa 25120, Pakistan
| | - Saranjam Khan
- Department of Physics, Islamia College Peshawar, Khyber Pakhtunkhwa 25120, Pakistan
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Rehan I, Ullah R, Khan S. Non-invasive Characterization of Glycosuria and Identification of Biomarkers in Diabetic Urine Using Fluorescence Spectroscopy and Machine Learning Algorithm. J Fluoresc 2024; 34:1391-1399. [PMID: 37535232 DOI: 10.1007/s10895-023-03366-1] [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: 06/23/2023] [Accepted: 07/24/2023] [Indexed: 08/04/2023]
Abstract
The current study presents a steadfast, simple, and efficient approach for the non-invasive determination of glycosuria of diabetes mellitus using fluorescence spectroscopy. A Xenon arc lamp emitting light in the range of 200-950 nm was used as an excitation source for recording the fluorescent spectra from the urine samples. A consistent fluorescence emission peak of glucose at 450 nm was found in all samples for an excitation wavelength of 370 nm. For confirmation and comparison, the fluorescence spectra of non-diabetic (healthy controls) were also acquired in the same spectral range. It was found that fluorescence emission intensity at 450 nm increases with increasing glucose concentration in urine. In addition, optimized synchronous fluorescence emission at 357 nm was used for simultaneously determining a potential diabetes biomarker, Tryptophan (Trp) in urine. It was also found that the level of tryptophan decreases with the increase in urinary glucose concentration. The quantitative estimation of urinary glucose can be demonstrated based on the intensity of emission light carried by fluorescence light. Moreover, the dissimilarities were further emphasized using the hierarchical cluster analysis (HCA) algorithm. HCA gives an obvious separation in terms of dendrogram between the two data sets based on characteristic peaks acquired from their fluorescence emission signatures. These results recommend that urinary glucose and tryptophan fluorescence emission can be used as potential biomarkers for the non-invasive analysis of diabetes.
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Affiliation(s)
- Imran Rehan
- National Institute of Lasers and Optronics College, Pakistan Institute of Engineering and Applied Sciences, Islamabad, 45650, Pakistan
- Department of Physics, Islamia College Peshawar, Peshawar, Khyber Pakhtunkhwa, 25120, Pakistan
| | - Rahat Ullah
- National Institute of Lasers and Optronics College, Pakistan Institute of Engineering and Applied Sciences, Islamabad, 45650, Pakistan.
| | - Saranjam Khan
- Department of Physics, Islamia College Peshawar, Peshawar, Khyber Pakhtunkhwa, 25120, Pakistan
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3
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Bansal S, Burman A, Tripathi AK. Advanced glycation end products: Key mediator and therapeutic target of cardiovascular complications in diabetes. World J Diabetes 2023; 14:1146-1162. [PMID: 37664478 PMCID: PMC10473940 DOI: 10.4239/wjd.v14.i8.1146] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 03/21/2023] [Accepted: 05/22/2023] [Indexed: 08/11/2023] Open
Abstract
The incidence of type 2 diabetes mellitus is growing in epidemic proportions and has become one of the most critical public health concerns. Cardiovascular complications associated with diabetes are the leading cause of morbidity and mortality. The cardiovascular diseases that accompany diabetes include angina, myocardial infarction, stroke, peripheral artery disease, and congestive heart failure. Among the various risk factors generated secondary to hyperglycemic situations, advanced glycation end products (AGEs) are one of the important targets for future diagnosis and prevention of diabetes. In the last decade, AGEs have drawn a lot of attention due to their involvement in diabetic patho-physiology. AGEs can be derived exogenously and endogenously through various pathways. These are a non-homogeneous, chemically diverse group of compounds formed non-enzymatically by condensation between carbonyl groups of reducing sugars and free amino groups of protein, lipids, and nucleic acid. AGEs mediate their pathological effects at the cellular and extracellular levels by multiple pathways. At the cellular level, they activate signaling cascades via the receptor for AGEs and initiate a complex series of intracellular signaling resulting in reactive oxygen species generation, inflammation, cellular proliferation, and fibrosis that may possibly exacerbate the damaging effects on cardiac functions in diabetics. AGEs also cause covalent modifications and cross-linking of serum and extracellular matrix proteins; altering their structure, stability, and functions. Early diagnosis of diabetes may prevent its progression to complications and decrease its associated comorbidities. In the present review, we recapitulate the role of AGEs as a crucial mediator of hyperglycemia-mediated detrimental effects in diabetes-associated complications. Furthermore, this review presents an overview of future perspectives for new therapeutic interventions to ameliorate cardiovascular complications in diabetes.
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Affiliation(s)
- Savita Bansal
- Department of Biochemistry, Institute of Home Sciences, University of Delhi, New Delhi 110016, India
| | - Archana Burman
- Department of Biochemistry, Institute of Home Economics, University of Delhi, New Delhi 110016, India
| | - Asok Kumar Tripathi
- Department of Biochemistry, University College of Medical Sciences, University of Delhi, New Delhi 110095, India
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Du T, Brandl B, Hauner H, Skurk T. Skin Autofluorescence Mirrors Surrogate Parameters of Vascular Aging: An Enable Study. Nutrients 2023; 15:nu15071597. [PMID: 37049440 PMCID: PMC10096848 DOI: 10.3390/nu15071597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 03/10/2023] [Accepted: 03/23/2023] [Indexed: 03/28/2023] Open
Abstract
Advanced glycation end-products (AGEs) are implicated in vascular aging due to their pro-inflammatory properties. Skin autofluorescence (SAF) is a measure to estimate their deposition. It is an easily quantifiable marker that has been shown to correlate with cardiovascular risk and parameters of metabolic diseases. Herein, we compared skin autofluorescence with other techniques indicating increased cardiovascular diseases, namely, pulse wave velocity (PWVao) and intima–media thickness (IMT). We also studied the impacts of other parameters in deeply phenotyped cohorts of young, middle-aged, and older individuals. SAF, aortic PWVao, and IMT proved to be significantly correlated with each other and with age. However, based on a moderator analysis, we could not show that these associations were affected by age. Some specific parameters such as creatinine and CRP were found to be significantly associated with skin AGE values after adjusting for confounding variables. In conclusion, SAF is a simple screening tool for vascular health with comparable power to more elaborated technical tests.
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Fernandes ACF, Melo JB, Genova VM, Santana ÁL, Macedo G. Phytochemicals as Potential Inhibitors of Advanced Glycation End Products: Health Aspects and Patent Survey. RECENT ADVANCES IN FOOD, NUTRITION & AGRICULTURE 2022; 13:3-16. [PMID: 34053432 DOI: 10.2174/2212798412666210528130001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 02/17/2021] [Accepted: 03/06/2021] [Indexed: 12/29/2022]
Abstract
BACKGROUND The glycation of proteins and lipids synthesizes the advanced glycation end products (AGEs), i.e., substances that irreversibly damage macromolecules present in tissues and organs, which contribute to the impairment of biological functions. For instance, the accumulation of AGEs induces oxidative stress, the inflammatory responses, and consequently the on set/worsening of diseases, including obesity, asthma, cognitive impairment, and cancer. There is a current demand on natural and low-cost sources of anti-AGE agents. As a result, food phytochemicals presented promising results to inhibit glycation and consequently, the formation of AGEs. OBJECTIVE Here we describe how the AGEs are present in food via Maillard reaction and in organs via natural aging, as well as the effects of AGEs on the worsening of diseases. Also we described the methods used to detect AGEs in samples, and the current findings on the use of phytochemicals (phenolic compounds, phytosterols, carotenoids, terpenes and vitamins) as natural therapeuticals to inhibit health damages via inhibition of AGEs in vitro and in vivo. METHODS This manuscript reviewed publications available in the PubMed and Science Direct databases dated from the last 20 years on the uses of phytochemicals for the inhibition of AGEs. Recent patents on the use of anti-AGEs drugs were reviewed with the use of Google Advanced Patents database. RESULTS AND DISCUSSION There is no consensus about which concentration of AGEs in blood serum should not be hazardous to the health of individuals. Food phytochemicals derived from agroindustry wastes, including peanut skins, and the bagasses derived from citrus and grapes are promising anti-AGEs agents via scavenging of free radicals, metal ions, the suppression of metabolic pathways that induces inflammation, the activation of pathways that promote antioxidant defense, and the blocking of AGE connection with the receptor for advanced glycation endproducts (RAGE). CONCLUSION Phytochemicals derived from agroindustry are promising anti-AGEs, which can be included to replace synthetic drugs to inhibit AGE formation, and consequently to act as therapeutical strategy to prevent and treat diseases caused by AGEs, including diabetes, ovarian cancer, osteoporosis, and Alzheimer's disease.
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Affiliation(s)
- Annayara C F Fernandes
- Bioprocesses Laboratory, Food and Nutrition Department, School of Food Engineering, University of Campinas, UNICAMP, Campinas, SP, Brazil, Cidade Universitária "ZeferinoVaz", Rua Monteiro Lobato, 80, Campinas 13083-862, Brazil
| | - Jeane B Melo
- Bioprocesses Laboratory, Food and Nutrition Department, School of Food Engineering, University of Campinas, UNICAMP, Campinas, SP, Brazil, Cidade Universitária "ZeferinoVaz", Rua Monteiro Lobato, 80, Campinas 13083-862, Brazil
| | - Vanize M Genova
- Bioprocesses Laboratory, Food and Nutrition Department, School of Food Engineering, University of Campinas, UNICAMP, Campinas, SP, Brazil, Cidade Universitária "ZeferinoVaz", Rua Monteiro Lobato, 80, Campinas 13083-862, Brazil
| | - Ádina L Santana
- Bioprocesses Laboratory, Food and Nutrition Department, School of Food Engineering, University of Campinas, UNICAMP, Campinas, SP, Brazil, Cidade Universitária "ZeferinoVaz", Rua Monteiro Lobato, 80, Campinas 13083-862, Brazil.,264 Food Innovation Center, Nebraska Innovation Campus, University of Nebraska-Lincoln, 1901 N 21st street, Lincoln, NE, USA
| | - Gabriela Macedo
- Bioprocesses Laboratory, Food and Nutrition Department, School of Food Engineering, University of Campinas, UNICAMP, Campinas, SP, Brazil, Cidade Universitária "ZeferinoVaz", Rua Monteiro Lobato, 80, Campinas 13083-862, Brazil
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6
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Januszewski AS, Chen D, Scott RS, O'Connell RL, Aryal NR, Sullivan DR, Watts GF, Taskinen MR, Barter PJ, Best JD, Simes RJ, Keech AC, Jenkins AJ. Relationship of low molecular weight fluorophore levels with clinical factors and fenofibrate effects in adults with type 2 diabetes. Sci Rep 2021; 11:18708. [PMID: 34548531 PMCID: PMC8455555 DOI: 10.1038/s41598-021-98064-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 08/26/2021] [Indexed: 12/02/2022] Open
Abstract
People with diabetes are at risk of chronic complications and novel biomarkers, such as Advanced glycation end-products (AGEs) may help stratify this risk. We assessed whether plasma low-molecular weight AGEs, also known as LMW-fluorophores (LMW-F), are associated with risk factors, predict complications, and are altered by fenofibrate in adults with type 2 diabetes. Plasma LMW-F were quantified at baseline, after six weeks fenofibrate, and one year post-randomisation to fenofibrate or placebo. LMW-F associations with existing and new composite vascular complications were determined, and effects of fenofibrate assessed. LMW-F correlated positively with age, glycated haemoglobin (HbA1c), pulse pressure, kidney dysfunction and inflammation; and negatively with urate, body mass index, oxidative stress and leptin, albeit weakly (r = 0.04–0.16, all p < 0.01). Independent determinants of LMW-F included smoking, diastolic blood pressure, prior cardiovascular disease or microvascular complications, Caucasian ethnicity, kidney function, HbA1c and diabetes duration (all p ≤ 0.01). Baseline LMW-F tertiles correlated with on-trial macrovascular and microvascular complications (trend p < 0.001) on univariate analyses only. Six weeks of fenofibrate increased LMW-F levels by 21% (p < 0.001). In conclusion, LMW-F levels correlate with many risk factors and chronic diabetes complications, and are increased with fenofibrate. LMW-F tertiles predict complications, but not independently of traditional risk factors.
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Affiliation(s)
- Andrzej S Januszewski
- National Health and Medical Research Council Clinical Trials Centre, The University of Sydney, Level 6 Medical Foundation Building, 92-94 Parramatta Rd, Camperdown, Sydney, NSW, 2050, Australia
| | - David Chen
- National Health and Medical Research Council Clinical Trials Centre, The University of Sydney, Level 6 Medical Foundation Building, 92-94 Parramatta Rd, Camperdown, Sydney, NSW, 2050, Australia.,Monash School of Medicine, Monash University, Melbourne, VIC, Australia
| | - Russell S Scott
- Lipid and Diabetes Research Group, Christchurch Hospital, Christchurch, New Zealand
| | - Rachel L O'Connell
- National Health and Medical Research Council Clinical Trials Centre, The University of Sydney, Level 6 Medical Foundation Building, 92-94 Parramatta Rd, Camperdown, Sydney, NSW, 2050, Australia
| | - Nanda R Aryal
- National Health and Medical Research Council Clinical Trials Centre, The University of Sydney, Level 6 Medical Foundation Building, 92-94 Parramatta Rd, Camperdown, Sydney, NSW, 2050, Australia
| | | | - Gerald F Watts
- Faculty of Health and Medical Sciences, School of Medicine, University of Western Australia, Perth, Australia.,Lipid Disorders Clinic, Cardiometabolic Services, Department of Cardiology, Royal Perth Hospital, Perth, Australia
| | - Marja-Riitta Taskinen
- Cardiovascular Research Unit, Helsinki, Heart and Lung Centre, University Central Hospital, Helsinki, Finland.,Diabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland
| | - Philip J Barter
- Centre for Vascular Research, University of New South Wales, Sydney, NSW, Australia.,Faculty of Medicine, The University of Sydney, Sydney, NSW, Australia
| | - James D Best
- Lee Kong Chian School of Medicine, Nanyang Technical University, Singapore, Singapore
| | - R John Simes
- National Health and Medical Research Council Clinical Trials Centre, The University of Sydney, Level 6 Medical Foundation Building, 92-94 Parramatta Rd, Camperdown, Sydney, NSW, 2050, Australia.,Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Anthony C Keech
- National Health and Medical Research Council Clinical Trials Centre, The University of Sydney, Level 6 Medical Foundation Building, 92-94 Parramatta Rd, Camperdown, Sydney, NSW, 2050, Australia.,Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Alicia J Jenkins
- National Health and Medical Research Council Clinical Trials Centre, The University of Sydney, Level 6 Medical Foundation Building, 92-94 Parramatta Rd, Camperdown, Sydney, NSW, 2050, Australia. .,Department of Medicine, St Vincent's Hospital, University of Melbourne, Melbourne, VIC, Australia.
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7
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Sarron E, Pérot M, Barbezier N, Delayre-Orthez C, Gay-Quéheillard J, Anton PM. Early exposure to food contaminants reshapes maturation of the human brain-gut-microbiota axis. World J Gastroenterol 2020; 26:3145-3169. [PMID: 32684732 PMCID: PMC7336325 DOI: 10.3748/wjg.v26.i23.3145] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 05/12/2020] [Accepted: 05/30/2020] [Indexed: 02/06/2023] Open
Abstract
Early childhood growth and development is conditioned by the consecutive events belonging to perinatal programming. This critical window of life will be very sensitive to any event altering programming of the main body functions. Programming of gut function, which is starting right after conception, relates to a very well-established series of cellular and molecular events associating all types of cells present in this organ, including neurons, endocrine and immune cells. At birth, this machinery continues to settle with the establishment of extra connection between enteric and other systemic systems and is partially under the control of gut microbiota activity, itself being under the densification and the diversification of microorganisms' population. As thus, any environmental factor interfering on this pre-established program may have a strong incidence on body functions. For all these reasons, pregnant women, fetuses and infants will be particularly susceptible to environmental factors and especially food contaminants. In this review, we will summarize the actual understanding of the consequences of repeated low-level exposure to major food contaminants on gut homeostasis settlement and on brain/gut axis communication considering the pivotal role played by the gut microbiota during the fetal and postnatal stages and the presumed consequences of these food toxicants on the individuals especially in relation with the risks of developing later in life non-communicable chronic diseases.
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Affiliation(s)
- Elodie Sarron
- Transformations and Agroressources (EA 7519), Institut Polytechnique UniLaSalle, Université d'Artois, Beauvais 60026, France
| | - Maxime Pérot
- Transformations and Agroressources (EA 7519), Institut Polytechnique UniLaSalle, Université d'Artois, Beauvais 60026, France
| | - Nicolas Barbezier
- Transformations and Agroressources (EA 7519), Institut Polytechnique UniLaSalle, Université d'Artois, Beauvais 60026, France
| | - Carine Delayre-Orthez
- Transformations and Agroressources (EA 7519), Institut Polytechnique UniLaSalle, Université d'Artois, Beauvais 60026, France
| | - Jérôme Gay-Quéheillard
- Périnatalité et risques Toxiques, UMR-I-01, Université de Picardie Jules Verne, Amiens 80000, France
| | - Pauline M Anton
- Transformations and Agroressources (EA 7519), Institut Polytechnique UniLaSalle, Université d'Artois, Beauvais 60026, France
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Bansal S, Kare PK, Tripathi AK, Madhu SV. Advanced Glycation End Products: A Potential Contributor of Oxidative Stress for Cardio-Vascular Problems in Diabetes. OXIDATIVE STRESS IN HEART DISEASES 2019:437-459. [DOI: 10.1007/978-981-13-8273-4_20] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Szkudlarek A, Pożycka J, Maciążek-Jurczyk M. Influence of Piracetam on Gliclazide-Glycated Human Serum Albumin Interaction. A Spectrofluorometric Study. Molecules 2018; 24:molecules24010111. [PMID: 30597970 PMCID: PMC6337564 DOI: 10.3390/molecules24010111] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Revised: 12/18/2018] [Accepted: 12/25/2018] [Indexed: 12/24/2022] Open
Abstract
Advanced Glycation End-Products (AGEs) are created in the last step of protein glycation and can be a factor in aging and in the development or worsening of many degenerative diseases (diabetes, chronic kidney disease, atherosclerosis, Alzheimer’s disease, etc.). Albumin is the most susceptible to glycation plasma protein. Modified albumin by AGEs may be more resistant to enzymatic degradation, which further increases the local accumulation of AGEs in tissues. The aim of the present study was to analyze in vitro glycation of serum albumin in the presence of piracetam (PIR) and the gliclazide (GLZ)-glycated albumin interaction. The analysis of PIR as an inhibitor and GLZ interaction with nonglycated human albumin (HSA) and glycated by fructose human albumin (gHSAFRC), in the absence and presence of piracetam (gHSAFRC-PIR), was performed by fluorescence quenching of macromolecules. On the basis of obtained data we concluded that under the influence of glycation, association constant (Ka) of gliclazide to human serum albumin decreases and GLZ binds to HSA with less strength than under physiological conditions. PIR strongly inhibited the formation of AGEs in the system where the efficiency of HSA glycation was the largest. The analysis of piracetam influence on the GLZ-glycated albumin interaction has shown that piracetam increases the binding strength of GLZ to glycated albumin and weakens its therapeutic effect. Based on the obtained data we concluded that monitoring therapy and precautions are required in the treatment when the combinations of gliclazide and piracetam are used at the same time.
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Affiliation(s)
- Agnieszka Szkudlarek
- Department of Physical Pharmacy, Medical University; School of Pharmacy with the Division of Laboratory Medicine, 4, 41-200 Sosnowiec, Poland.
| | - Jadwiga Pożycka
- Department of Physical Pharmacy, Medical University; School of Pharmacy with the Division of Laboratory Medicine, 4, 41-200 Sosnowiec, Poland.
| | - Małgorzata Maciążek-Jurczyk
- Department of Physical Pharmacy, Medical University; School of Pharmacy with the Division of Laboratory Medicine, 4, 41-200 Sosnowiec, Poland.
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10
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Nday CM, Eleftheriadou D, Jackson G. Shared pathological pathways of Alzheimer's disease with specific comorbidities: current perspectives and interventions. J Neurochem 2018; 144:360-389. [PMID: 29164610 DOI: 10.1111/jnc.14256] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 11/10/2017] [Accepted: 11/10/2017] [Indexed: 02/06/2023]
Abstract
Alzheimer's disease (AD) belongs to one of the most multifactorial, complex and heterogeneous morbidity-leading disorders. Despite the extensive research in the field, AD pathogenesis is still at some extend obscure. Mechanisms linking AD with certain comorbidities, namely diabetes mellitus, obesity and dyslipidemia, are increasingly gaining importance, mainly because of their potential role in promoting AD development and exacerbation. Their exact cognitive impairment trajectories, however, remain to be fully elucidated. The current review aims to offer a clear and comprehensive description of the state-of-the-art approaches focused on generating in-depth knowledge regarding the overlapping pathology of AD and its concomitant ailments. Thorough understanding of associated alterations on a number of molecular, metabolic and hormonal pathways, will contribute to the further development of novel and integrated theranostics, as well as targeted interventions that may be beneficial for individuals with age-related cognitive decline.
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Affiliation(s)
- Christiane M Nday
- Department of Chemical Engineering, Laboratory of Inorganic Chemistry, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Despoina Eleftheriadou
- Department of Chemical Engineering, Laboratory of Inorganic Chemistry, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Graham Jackson
- Department of Chemistry, University of Cape Town, Rondebosch, Cape Town, South Africa
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11
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Deluyker D, Evens L, Bito V. Advanced glycation end products (AGEs) and cardiovascular dysfunction: focus on high molecular weight AGEs. Amino Acids 2017; 49:1535-1541. [DOI: 10.1007/s00726-017-2464-8] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 07/07/2017] [Indexed: 12/27/2022]
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12
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Prasad K, Mishra M. Do Advanced Glycation End Products and Its Receptor Play a Role in Pathophysiology of Hypertension? Int J Angiol 2017; 26:1-11. [PMID: 28255209 PMCID: PMC5330762 DOI: 10.1055/s-0037-1598183] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
There is a close relationship between arterial stiffness and blood pressure. The studies suggest that the advanced glycation end products (AGEs) and its cell receptor (RAGE) are involved in the arterial stiffness in two ways: changes in arterial structure and vascular function. Plasma levels of AGEs and expression of RAGE are elevated, while the levels of soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE) are lowered in patients with hypertension (HTN). There is a positive correlation between plasma levels of AGEs and arterial stiffness, and an inverse association between arterial stiffness/HTN, and serum levels of sRAGE and esRAGE. Various measures can reduce the levels of AGEs and expression of RAGE, and elevate sRAGE. Arterial stiffness and blood pressure could be reduced by lowering the serum levels of AGEs, and increasing the levels of sRAGE. Levels of AGEs can be lowered by reducing the consumption of AGE-rich diet, short duration of cooking in moist heat at low temperature, and cessation of cigarette smoking. Drugs such as aminoguanidine, vitamins, angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II receptor blockers, statins, and metformin inhibit AGE formation. Alagebrium, an AGE breakers reduces levels of AGEs. Clinical trials with some drugs tend to reduce stiffness. Systemic administration of sRAGE has beneficial effect in animal studies. In conclusion, AGE-RAGE axis is involved in arterial stiffness and HTN. The studies suggest that inhibition of AGEs formation, reduction of AGE consumption, blockade of AGE-RAGE interaction, suppression of RAGE expression, and exogenous administration of sRAGE may be novel therapeutic strategies for treatment of arterial stiffness and HTN.
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Affiliation(s)
- Kailash Prasad
- Department of Physiology, College of Medicine, University of Saskatchewan, Saskatchewan, Canada
| | - Manish Mishra
- Department of Physiology, College of Medicine, University of Saskatchewan, Saskatchewan, Canada
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13
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Lobo JP, Brescansin CP, Santos-Weiss ICR, Welter M, Souza EMD, Rego FGDM, Picheth G, Alberton D. Serum Fluorescent Advanced Glycation End (F-AGE) products in gestational diabetes patients. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2017; 61:233-237. [PMID: 28225992 PMCID: PMC10118810 DOI: 10.1590/2359-3997000000238] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 11/11/2016] [Indexed: 11/21/2022]
Abstract
Objectives Advanced glycation end products (AGEs) are involved in the pathogenesis and complications of diabetes mellitus (DM). Gestational DM (GDM) is characterized by increased glycemia and oxidative stress, which are factors associated with high serum AGE concentrations. The aim of this study was to evaluate the utility of a serum fluorescence AGE (F-AGE) method as a screening tool for gestational diabetes. Subjects and methods Serum samples from 225 GDM patients and 217 healthy pregnant women (healthy controls) were diluted 50-fold in phosphate-buffered saline, and the AGEs were estimated by fluorometric analysis (λEx 350 nm/ λEm 440 nm). Results No significant (P > 0.05) differences in AGE concentrations, expressed in Arbitrary Units (UA/mL × 104), were observed in the women with GDM or in the healthy controls. Furthermore, F-AGE concentrations did not change significantly during the pregnancy (12-32 weeks of gestation). Only the GDM group had a positive correlation (r = 0.421; P < 0.001) between F-AGEs and serum creatinine concentrations. Conclusion It was not possible to distinguish women with gestational diabetes from the healthy controls on the basis of serum F-AGE concentrations.
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Affiliation(s)
- João Paulo Lobo
- Pós-Graduação em Ciências Farmacêuticas, Departamento de Análise Clínica, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brasil
| | - Catiane Pompilio Brescansin
- Pós-Graduação em Ciências Farmacêuticas, Departamento de Análise Clínica, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brasil
| | - Izabella C R Santos-Weiss
- Pós-Graduação em Ciências Farmacêuticas, Departamento de Análise Clínica, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brasil
| | - Marciane Welter
- Pós-Graduação em Ciências Farmacêuticas, Departamento de Análise Clínica, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brasil
| | | | - Fabiane Gomes de Moraes Rego
- Pós-Graduação em Ciências Farmacêuticas, Departamento de Análise Clínica, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brasil
| | - Geraldo Picheth
- Pós-Graduação em Ciências Farmacêuticas, Departamento de Análise Clínica, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brasil
| | - Dayane Alberton
- Pós-Graduação em Ciências Farmacêuticas, Departamento de Análise Clínica, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brasil
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Kim YS, Jung DH, Lee IS, Pyun BJ, Kim JS. Osteomeles schwerinae extracts inhibits the binding to receptors of advanced glycation end products and TGF-β1 expression in mesangial cells under diabetic conditions. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2016; 23:388-397. [PMID: 27002409 DOI: 10.1016/j.phymed.2016.02.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Revised: 02/03/2016] [Accepted: 02/06/2016] [Indexed: 06/05/2023]
Abstract
BACKGROUND Osteomeles schwerinae C. K. Schneid. (Rosaceae, OSSC) is a medicinal plant traditionally used to treat various diseases in Asia. The chemical constituents of OSSC have an inhibitory effect on aldose reductase activity, which has been implicated in the pathogenesis of diabetic complications. However, the protective effects of the pharmacological activity and potential mechanisms in diabetic nephropathy are still not known. OBJECTIVE In the present study, OSSC extracts and major compounds were examined for their effects on binding to the receptors of advanced glycation end products (RAGE) and on transforming growth factor-beta1 (TGF-β1) expression-related signal mechanisms in mouse glomerular mesangial cells (GMCs). MATERIALS AND METHODS A simple, rapid and efficient method was developed for the simultaneous determination of the marker compounds in the ethanol extract of the leaves and twigs of OSSC using HPLC-diode array detector (DAD). In this study, we determined the effects of OSSC extract and hyperoside on AGE and RAGE binding, and studied the mechanism of OSSC extract effects on AGE-bovine serum albumin (BSA)-treated GMCs. GMCs overexpressing human RAGE were cultured in AGE-BSA labeled with Alexa 488, and OSSC extract. AGE/RAGE binding were measured using fluorescence (excitation 485 nm/emission 528 nm). TGF-β1 protein expression levels were determined by western blot analyses. RESULTS OSSC extracts of leaves and twigs inhibited on AGE/RAGE binding and TGF-β1 protein expression in a dose-dependent manner in GMCs. Furthermore, OSSC extracts reduced the effects on AGE-BSA-induced reactive oxidative species (ROS) formation and nuclear translocalization of transcription factor NF-κB. OSSC extracts inhibited phosphorylation of extracellular signal-regulated protein kinases1/2 (ERK1/2), p38 mitogen-activated protein kinases (p38MAPK), and IκB. Hyperoside also inhibited AGE/RAGE binding and ROS formation, and reduced TGF-β1 expression and IkB phosphorylation. CONCLUSIONS OSSC extracts and hyperoside may attenuate AGE/RAGE binding and expression of TGF-β1 by downregulating of pERK1/2, p38MAPK and IκB phosphorylations in GMCs under diabetic condition and retard the development of diabetic complications such as diabetic nephropathy.
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Affiliation(s)
- Young Sook Kim
- Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine (KIOM), Daejeon, South Korea
| | - Dong Ho Jung
- Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine (KIOM), Daejeon, South Korea
| | - Ik-Soo Lee
- Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine (KIOM), Daejeon, South Korea
| | - Bo-Jeong Pyun
- Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine (KIOM), Daejeon, South Korea
| | - Jin Sook Kim
- Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine (KIOM), Daejeon, South Korea.
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Park JH, Li L, Choi JW, Baek KH. The Association of -429T>C and -374T>A Polymorphisms in the RAGE Gene with Polycystic Ovary Syndrome. Int J Med Sci 2016; 13:451-6. [PMID: 27279795 PMCID: PMC4893560 DOI: 10.7150/ijms.15389] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 05/09/2016] [Indexed: 01/02/2023] Open
Abstract
Polycystic ovary syndrome (PCOS) is a complex disorder characterized by hyperandrogenism and insulin resistance. In addition, a number of females with PCOS have ovaries with multiple cysts, an irregular or no menstrual cycle, and an imbalance of female hormones compared to those of normal controls. A variety of genetic factors have been involved in the pathogenesis of PCOS. Among these genetic factors, the receptor for advanced glycation end products (RAGE) that is associated with diabetes and involved in the complications of PCOS, was selected. We aimed to assess the relationship between -429T>C and -374T>A single nucleotide polymorphisms (SNPs) of RAGE gene with the susceptibility to PCOS.128 controls and 265 PCOS patients were used for -374T>A polymorphism and 141 controls and 290 PCOS patients were used for -429T>C polymorphism, respectively. Genotyping of two polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay and statistical analysis was performed. P values for both alleles were higher than 0.05. Frequencies of genotype and allele of two polymorphisms in RAGE gene showed no significant differences between controls and PCOS patients. The initial study on the correlation between RAGE gene and PCOS indicates that the two polymorphisms of RAGE are not associated with the pathogenesis of PCOS. However, further studies regarding the association between RAGE gene and PCOS patients in different ethnic groups are required.
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Affiliation(s)
- Jung-Hyun Park
- 1. Department of Biomedical Science, CHA University, Bundang CHA Hospital, Gyeonggi-Do 463-400, Republic of Korea
| | - Lan Li
- 1. Department of Biomedical Science, CHA University, Bundang CHA Hospital, Gyeonggi-Do 463-400, Republic of Korea
| | - Jin-Woo Choi
- 2. Columbia College of Columbia University, New York, NY 10027, USA
| | - Kwang-Hyun Baek
- 1. Department of Biomedical Science, CHA University, Bundang CHA Hospital, Gyeonggi-Do 463-400, Republic of Korea
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16
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Semba RD, Sun K, Schwartz AV, Varadhan R, Harris TB, Satterfield S, Garcia M, Ferrucci L, Newman AB. Serum carboxymethyl-lysine, an advanced glycation end product, is associated with arterial stiffness in older adults. J Hypertens 2015; 33:797-803; discussion 803. [PMID: 25915884 PMCID: PMC4458067 DOI: 10.1097/hjh.0000000000000460] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
OBJECTIVE The objective of this study is to examine the relationship of serum carboxymethyl-lysine (CML), an advanced glycation end product (AGE), with pulse pressure (PP), aortic pulse wave velocity (aPWV) and hypertension in older adults. BACKGROUND AGEs are bioactive molecules that accumulate in tissues with ageing and can both cross-link collagen and induce inflammation in model systems. The relationship of AGEs with arterial stiffness and hypertension has not been well characterized in community-dwelling older adults. METHODS We measured serum CML and blood pressure in 3044 adults, aged 70-79 years, who participated in the Health, Aging and Body Composition Study, a population-based study of ageing in Pittsburgh, Pennsylvania and Memphis, Tennessee. aPWV was measured in 2468 participants. RESULTS Participants in the highest tertile of serum CML had higher PP (highest tertile: beta = 2.85, SE = 0.82, P = 0.0005; middle tertile: beta = 0.60, SE = 0.80, P = 0.45), and higher aPWV (highest tertile: beta = 51.4, SE = 20.1, P = 0.01; middle tertile: beta = 3.2, SE = 19.8, P = 0.87) than those in the lowest tertile in multivariable linear regression models adjusting for age, sex, race, education, BMI, smoking, alcohol use, total cholesterol, high-density lipoprotein (HDL) cholesterol, diabetes, cardiovascular disease and chronic kidney disease. Participants in the highest and middle tertiles of serum CML had higher odds of hypertension [odds ratio (OR) 1.32, 95% confidence interval (95% CI) 1.06-1.60, P = 0.005; OR 1.27, 95% CI 1.05-1.53, P = 0.01, respectively] than those in the lowest tertile in a multivariable logistic regression model adjusting for the same covariates. CONCLUSION Elevated serum CML was associated with arterial stiffness, as reflected by higher PP and aPWV, in older, community-dwelling adults.
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Affiliation(s)
- Richard D Semba
- aDepartment of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland bDepartment of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California cDivision of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore dLaboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Rockville, Maryland eDepartment of Preventive Medicine, University of Tennessee, Memphis, Tennessee fNational Institute on Aging, Baltimore, Maryland gDepartment of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA
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17
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Prasad K. Low levels of serum soluble receptors for advanced glycation end products, biomarkers for disease state: myth or reality. Int J Angiol 2014; 23:11-6. [PMID: 24627612 DOI: 10.1055/s-0033-1363423] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Abstract
Advanced glycation end products (AGEs) interact with the receptor for AGEs (RAGE) on the membrane and induce deleterious effects via activation of nuclear factor kappa-B, and increased oxidative stress and inflammatory mediators. AGEs also combine with circulating soluble receptors (endogenous secretory RAGE [esRAGE] and soluble receptor for RAGE [sRAGE]) and sequester RAGE ligands and act as a cytoprotective agent. esRAGE is secreted from the cells and is a spliced variant of RAGE. The sRAGE on the other hand is proteolytically cleaved from cell surface receptor via matrix metalloproteinase (MMPs). sRAGE is elevated in type 1 and type 2 diabetes and in patients with decreased renal function. Serum levels of sRAGE are reduced in diseases including coronary artery disease, atherosclerosis, essential hypertension, chronic obstructive lung disease, heart failure, and hypercholesterolemia. Serum levels of AGEs are elevated in patients with coronary artery disease and atherosclerosis. However, the increases in serum AGEs are very high in patients with diabetes and renal disease. There is a positive correlation between serum levels of AGEs and RAGE and sRAGE. The elevated levels of sRAGE in patients with diabetes and impaired renal function may be due to increased levels of MMPs. AGEs increase in the expression and production of MMPs, which would increase the cleavage of sRAGE from cell surface. In conclusion, low level of serum sRAGE is a good biomarker for disease other than diabetes and renal disease. A unified formula that takes into consideration of AGEs, sRAGE, and esRAGE such as AGE/sRAGE or AGEs/esRAGE would be better biomarker than sRAGE or esRAGE for all AGE-RAGE-associated diseases including diabetes and renal disease.
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Affiliation(s)
- Kailash Prasad
- Department of Physiology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
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18
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Semba RD, Cotch MF, Gudnason V, Eiríksdottir G, Harris TB, Sun K, Klein R, Jonasson F, Ferrucci L, Schaumberg DA. Serum carboxymethyllysine, an advanced glycation end product, and age-related macular degeneration: the Age, Gene/Environment Susceptibility-Reykjavik Study. JAMA Ophthalmol 2014; 132:464-70. [PMID: 24481410 PMCID: PMC4169215 DOI: 10.1001/jamaophthalmol.2013.7664] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
IMPORTANCE Advanced glycation end products have been implicated in the pathogenesis of age-related macular degeneration (AMD). OBJECTIVE To investigate the relationship between serum carboxymethyllysine (CML), a major circulating advanced glycation end product, and AMD in older adults. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study of a population-based sample of 4907 older adults (aged ≥66 years) in the Age, Gene/Environment Susceptibility-Reykjavik Study in Iceland. EXPOSURES Serum CML and risk factors for AMD. MAIN OUTCOMES AND MEASURES Early or late AMD, assessed through fundus images taken through dilated pupils using a 45° digital camera and grading for drusen size, type, area, increased retinal pigment, retinal pigment epithelial depigmentation, neovascular lesions, and geographic atrophy using the modified Wisconsin Age-Related Maculopathy Grading System. RESULTS Of the 4907 participants, 1025 (20.9%) had early AMD and 276 (5.6%) had late AMD. Mean (SD) serum CML concentrations among adults with no AMD, early AMD, and late AMD (exudative AMD and pure geographic atrophy) were 618.8 (195.5), 634.2 (206.4), and 638.4 (192.0) ng/mL, respectively (to convert to micromoles per liter, multiply by 0.00489; P = .07). Log serum CML (per 1-SD increase) was not associated with any AMD (early and late AMD) (odds ratio = 0.97; 95% CI, 0.90-1.04; P = .44) or with late AMD (odds ratio = 0.94; 95% CI, 0.82-1.08; P = .36) in respective multivariable logistic regression models adjusting for age, sex, body mass index, smoking, and renal function. CONCLUSIONS AND RELEVANCE Higher serum CML concentration had no significant cross-sectional association with prevalent AMD in this large population-based cohort of older adults in Iceland.
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Affiliation(s)
- Richard D Semba
- Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Mary Frances Cotch
- Division of Epidemiology and Clinical Research, National Eye Institute, Bethesda, Maryland
| | - Vilmundur Gudnason
- Icelandic Heart Association, Reykjavik, Iceland4Department of Medicine, University of Iceland, Reykjavik, Iceland
| | | | - Tamara B Harris
- Laboratory of Epidemiology, Demography, and Biometry, Intramural Research Program, National Institute on Aging, Bethesda, Maryland
| | - Kai Sun
- Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ronald Klein
- Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison
| | - Fridbert Jonasson
- Department of Medicine, University of Iceland, Reykjavik, Iceland7Department of Ophthalmology, Landspitali University Hospital, Reykjavik, Iceland
| | - Luigi Ferrucci
- Longitudinal Studies Section, National Institute on Aging, Baltimore, Maryland
| | - Debra A Schaumberg
- Moran Center for Translational Medicine, Department of Ophthalmology and Visual Sciences, University of Utah School of Medicine, Salt Lake City
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Tripathi AK, Chawla D, Bansal S, Banerjee BD, Madhu SV, Kalra OP. Association of RAGE gene polymorphism with vascular complications in Indian type 2 diabetes mellitus patients. Diabetes Res Clin Pract 2014; 103:474-81. [PMID: 24418399 DOI: 10.1016/j.diabres.2013.12.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Revised: 09/19/2013] [Accepted: 12/18/2013] [Indexed: 10/25/2022]
Abstract
AIMS The study was designed to evaluate the association of -374T/A and -429T/C polymorphism in the promoter region and Gly82Ser polymorphism in exon 3 region of RAGE gene with diabetic vascular complications in Indian population. METHODS We screened 603 subjects which includes 176 healthy controls, 140 type 2 diabetes mellitus (T2DM) subjects without any vascular complications (DM), 152 T2DM subjects with microvascular complications (DM-micro) and 135 T2DM subjects with macrovascular complications (DM-macro) for -374T/A, -429T/C and Gly82Ser polymorphisms of RAGE gene. DNA isolated from the enrolled subjects were genotyped by PCR-RFLP. Logistic regression analysis was used to evaluate the association of single nucleotide polymorphisms (SNPs). RESULTS The -429 T/C and Gly82Ser RAGE polymorphisms were found to be significantly associated with the development of macrovascular and microvascular complications, respectively, in T2DM subjects while -374A allele showed reduced risk towards the development of macrovascular complications. Further, -429T/C, -374T/A and Gly82Ser haplotype analysis revealed association of CTG haplotype with development of macrovascular complications while haplotype TAG was observed to be significantly protective towards development of macrovascular complications in T2DM subjects (OR=0.617, p=0.0202). CONCLUSIONS Our data indicates significant association of RAGE SNPs and haplotypes with vascular complications in North Indian T2DM subjects.
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Affiliation(s)
- Ashok Kumar Tripathi
- Biochemistry and Immunology Laboratory, Department of Biochemistry, University College of Medical Sciences (University of Delhi) and G.T.B. Hospital, Dilshad Garden, Delhi 110095, India.
| | - Diwesh Chawla
- Biochemistry and Immunology Laboratory, Department of Biochemistry, University College of Medical Sciences (University of Delhi) and G.T.B. Hospital, Dilshad Garden, Delhi 110095, India.
| | - Savita Bansal
- Biochemistry and Immunology Laboratory, Department of Biochemistry, University College of Medical Sciences (University of Delhi) and G.T.B. Hospital, Dilshad Garden, Delhi 110095, India.
| | - Basu Dev Banerjee
- Biochemistry and Immunology Laboratory, Department of Biochemistry, University College of Medical Sciences (University of Delhi) and G.T.B. Hospital, Dilshad Garden, Delhi 110095, India.
| | - Sri Venkata Madhu
- Department of Medicine, University College of Medical Sciences (University of Delhi) and G.T.B. Hospital, Dilshad Garden, Delhi 110095, India.
| | - Om Prakash Kalra
- Department of Medicine, University College of Medical Sciences (University of Delhi) and G.T.B. Hospital, Dilshad Garden, Delhi 110095, India.
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Elmhiri G, Barella LF, Vieau D, Camous S, Mathias PCF, Abdennebi-Najar L. Acute exposure to a precursor of advanced glycation end products induces a dual effect on the rat pancreatic islet function. Int J Endocrinol 2014; 2014:378284. [PMID: 25484898 PMCID: PMC4248554 DOI: 10.1155/2014/378284] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Accepted: 10/20/2014] [Indexed: 11/18/2022] Open
Abstract
Aim. Chronic diseases are the leading cause of death worldwide. Advanced glycation end products, known as AGEs, are a major risk factor for diabetes onset and maintenance. Methylglyoxal (MG), a highly reactive metabolite of glucose, is a precursor for the generation of endogenous AGEs. Methods. In this current study we incubated in vitro pancreatic islets from adult rats in absence or presence of MG (10 μmol/l) with different concentrations of glucose and different metabolic components (acetylcholine, epinephrine, potassium, forskolin, and leucine). Results. Different effects of MG on insulin secretion were evidenced. In basal glucose stimulation (5.6 mM), MG induced a significant (P < 0.05) increase of insulin secretion. By contrast, in higher glucose concentrations (8.3 mM and 16.7 mM), MG significantly inhibited insulin secretion (P < 0.05). In the presence of potassium, forskolin, and epinephrine, MG enhanced insulin secretion (P < 0.05), while when it was incubated with acetylcholine and leucine, MG resulted in a decrease of insulin secretion (P < 0.05). Conclusion. We suggest that MG modulates the secretion activity of beta-cell depending on its level of stimulation by other metabolic factors. These results provide insights on a dual acute effect of MG on the pancreatic cells.
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Affiliation(s)
- Ghada Elmhiri
- Institut Polytechnique LaSalle Beauvais, EGEAL-UP 2012.10.101., 19 rue Pierre Waguet, 60026 Beauvais Cedex, France
| | - Luiz Felipe Barella
- Laboratory of Secretion Cell Biology, Department of Biotechnology, Genetics and Cell Biology, State University of Maringá, 87020-900 Maringá, PR, Brazil
| | - Didier Vieau
- Environnement Périnatal et Croissance (EA4489), Equipe Dénutritions Maternelles Périnatales, SN4, Université de Lille 1, 59655 Villeneuve d'Ascq, France
| | - Sylvaine Camous
- INRA, UMR1198, Biologie du Développement et Reproduction, 78352 Jouy en Josas, France
| | - Paulo C. F. Mathias
- Laboratory of Secretion Cell Biology, Department of Biotechnology, Genetics and Cell Biology, State University of Maringá, 87020-900 Maringá, PR, Brazil
| | - Latifa Abdennebi-Najar
- Institut Polytechnique LaSalle Beauvais, EGEAL-UP 2012.10.101., 19 rue Pierre Waguet, 60026 Beauvais Cedex, France
- *Latifa Abdennebi-Najar:
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Gangoiti MV, Anbinder PS, Cortizo AM, McCarthy AD. Morphological changes induced by advanced glycation endproducts in osteoblastic cells: effects of co-incubation with alendronate. Acta Histochem 2013; 115:649-57. [PMID: 23465485 DOI: 10.1016/j.acthis.2013.01.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Revised: 01/21/2013] [Accepted: 01/23/2013] [Indexed: 01/06/2023]
Abstract
Advanced glycation endproducts (AGEs) accumulate with age in various tissues, and are further increased in patients with Diabetes mellitus, in which they are believed to contribute to the development and progression of chronic complications that include a decrease in bone quality. Bisphosphonates are anti-osteoporotic drugs that have been used for the treatment of patients with diabetic bone alterations, although with contradictory results. In the present study, we have evaluated the in vitro alterations on osteoblastic morphology by environmental scanning electron microscopy, in actin cytoskeleton and apoptosis induced by AGEs, as well as the modulation of these effects by alendronate (an N-containing bisphosphonate). Our present results provide evidence for disruption induced by AGEs of the osteoblastic actin cytoskeleton (geodesic domes) and significant alterations in cell morphology with a decrease in cell-substratum interactions leading to an increase in apoptosis of osteoblasts and a decrease in osteoblastic proliferation. High concentrations of alendronate (10(-5)M, such as could be expected in an osteoclastic lacuna) further increase osteoblastic morphological and cytoskeletal alterations. However, low doses of alendronate (10(-8)M, compatible with extracellular fluid levels to which an osteoblast could be exposed for most of its life cycle) do not affect cell morphology, and in addition are able to prevent AGEs-induced alterations and consequently apoptosis of osteoblasts.
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Affiliation(s)
- María Virginia Gangoiti
- LIOMM, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, Calle 47 y 115, CP (1900) La Plata, Argentina.
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Lapidos KA, Sprague SM, Ameer GA. Impact of serum source and inflammatory cytokines on the isolation of endothelial colony-forming cells from peripheral blood. J Tissue Eng Regen Med 2012; 8:747-56. [PMID: 22888041 DOI: 10.1002/term.1580] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2012] [Revised: 05/24/2012] [Accepted: 06/26/2012] [Indexed: 01/26/2023]
Abstract
Endothelial colony-forming cells (ECFCs) isolated from peripheral blood are a highly promising cell source for a wide range of applications, including tissue engineering, in vivo vasculogenesis and anti-cancer therapeutics. Because of the potential for clinical translation, it is increasingly important to isolate and study ECFCs from patient cohorts that may benefit from such technologies. The primary objective of this investigation was to determine whether ECFCs could be obtained from patients with chronic kidney disease and diabetes (CKD-DM), using techniques that can be readily applied in the clinical setting. We also investigated the impact of autologous vs commercially available (i.e. allogeneic) human serum on ECFCs isolation. Surprisingly, the efficacy of ECFCs isolation from the CKD-DM group was comparable to a healthy control group when autologous serum was used. In contrast, substitution of allogeneic serum reduced ECFCs isolation in CKD-DM and control groups. In characterization studies, ECFCs were positive for several endothelial cell markers. ECFCs from the CKD-DM group were sensitive to inflammatory activation but their cellular proliferation was compromised. The concentrations of IL-4 and IL-8 were significantly increased in allogeneic serum, which induced a pro-inflammatory environment, including the release of IL-4, IL-6, IL-8 and MCP-1 into the conditioned media of cell cultures. Taken together, these data support further investigation into the use of autologous serum and cells for ECFC-based therapeutics and underscore the importance of the cytokine content in serum used for ECFCs isolation.
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Affiliation(s)
- Karen A Lapidos
- Biomedical Engineering Department, Northwestern University, Evanston, IL, USA
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Pyridoxamine ameliorates the effects of advanced glycation end products on subtotal nephrectomy induced chronic renal failure rats. J Funct Foods 2012. [DOI: 10.1016/j.jff.2012.04.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Sato E, Nagaoka T, Yokota H, Takahashi A, Yoshida A. Correlation between plasma pentosidine concentrations and retinal hemodynamics in patients with type 2 diabetes. Am J Ophthalmol 2012; 153:903-909.e1. [PMID: 22265156 DOI: 10.1016/j.ajo.2011.10.020] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2011] [Revised: 10/17/2011] [Accepted: 10/17/2011] [Indexed: 11/24/2022]
Abstract
PURPOSE To investigate whether plasma pentosidine, a well-defined advanced glycation end product, is associated with retinal hemodynamic abnormalities in patients with type 2 diabetes. DESIGN Prospective cross-sectional study. METHODS Forty-two eyes with type 2 diabetes mellitus were evaluated. The type 2 diabetic eyes were divided into 2 groups: 22 eyes (22 patients; mean age, 61 years) with nondiabetic retinopathy (NDR) and 20 eyes (20 patients; mean age, 61 years) with mild nonproliferative diabetic retinopathy (NPDR). We used a retinal laser Doppler system to measure the arterial diameter, velocity, and blood flow in the major temporal retinal arteries. The pulsatility ratio, a resistive index expressed as the peak systolic to the end diastolic velocity ratio, was calculated from the blood velocity traces. Plasma pentosidine was measured in 42 patients with diabetes using a commercially available competitive enzyme-linked immunosorbent assay. RESULTS The pulsatility ratio significantly increased in patients with NPDR (4.8 ± 1.5) compared with patients with NDR (3.7 ± 0.8) (P = .0061). No differences in velocity, diameter, or blood flow were seen between the 2 groups. Plasma pentosidine levels also increased significantly (P = .0085) in patients with NPDR (0.057 ± 0.015) compared to patients with NDR (0.047 ± 0.012). The pulsatility ratio was correlated positively with the plasma pentosidine levels in patients with NPDR (Pearson correlation, r = 0.45, P = .044). Multiple regression analysis showed that the plasma pentosidine level was significantly associated with the pulsatility ratio (standardized coefficient, 0.62; P = .009). CONCLUSIONS The vascular rigidity of the retinal arteries may increase with increasing plasma pentosidine in patients with type 2 diabetes with retinopathy.
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Jung DH, Kim YS, Kim JS. Screening System of Blocking Agents of the Receptor for Advanced Glycation Endproducts in Cells Using Fluorescence. Biol Pharm Bull 2012; 35:1826-30. [DOI: 10.1248/bpb.b12-00361] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Dong Ho Jung
- Korean Medicine-Based Herbal Drug Research Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine (KIOM)
| | - Young Sook Kim
- Korean Medicine-Based Herbal Drug Research Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine (KIOM)
| | - Jin Sook Kim
- Korean Medicine-Based Herbal Drug Research Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine (KIOM)
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26
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Advanced glycation end products enhance reactive oxygen and nitrogen species generation in neutrophils in vitro. Mol Cell Biochem 2011; 361:289-96. [DOI: 10.1007/s11010-011-1114-9] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2011] [Accepted: 10/07/2011] [Indexed: 10/16/2022]
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Yamagishi SI, Matsui T. Advanced glycation end products, oxidative stress and diabetic nephropathy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2010. [PMID: 20716934 PMCID: PMC2952094 DOI: 10.4161/oxim.3.2.4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
About 246 million people worldwide had diabetes in 2007. The global figure of people with diabetes is projected to increase to 370 million in 2030. As the prevalence of diabetes has risen to epidemic proportions worldwide, diabetic nephropathy has become one of the most challenging health problems. Therapeutic options such as strict blood glucose and blood pressure controls are effective for preventing diabetic nephropathy, but are far from satisfactory, and the number of diabetic patients on end-stage renal disease is still increasing. Therefore, a novel therapeutic strategy that could halt the progression of diabetic nephropathy should be developed. There is accumulating evidence that advanced glycation end products (AGEs), senescent macroprotein derivatives formed at an accelerated rate under diabetes, play a role in diabetic nephropathy via oxidative stress generation. In this paper, we review the pathophysiological role of AGEs and their receptor (RAGE)-oxidative stress system in diabetic nephropathy.
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Affiliation(s)
- Sho-Ichi Yamagishi
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan.
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Semba RD, Beck J, Sun K, Egan JM, Carlson OD, Varadhan R, Ferrucci L. Relationship of a dominant advanced glycation end product, serum carboxymethyl-lysine, and abnormal glucose metabolism in adults: the Baltimore Longitudinal Study of Aging. J Nutr Health Aging 2010; 14:507-13. [PMID: 20818463 PMCID: PMC3435097 DOI: 10.1007/s12603-010-0105-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
BACKGROUND AND OBJECTIVES Although hyperglycemia is thought to increase the generation of advanced glycation end products (AGEs), studies have not shown a consistent relationship between abnormal glucose metabolism and serum AGEs. We investigated the relationship between a dominant serum AGE, N-carboxymethyl-lysine (CML), and glucose metabolism. SUBJECTS AND METHODS Serum CML, fasting plasma glucose, and glucose tolerance were measured in 755 adults in the Baltimore Longitudinal Study of Aging. Fasting plasma glucose was categorized as normal (< or = 99 mg/dL), impaired (100-125 mg/dL), and diabetic (> 125 mg/dL). Two-hour plasma glucose on oral glucose tolerance testing was categorized as normal (< or = 139 mg/dL), impaired (140-199 mg/dL), and diabetic (> or = 200 mg/dL). RESULTS The proportion of adults with normal, impaired, and diabetic fasting plasma glucose was 73.8%, 22.9%, and 2.9%, respectively, and the proportion with normal, impaired, and diabetic 2-hour plasma glucose was 73.1%, 19.2%, and 7.7%, respectively. Serum CML (microg/mL) was not associated with abnormal fasting plasma glucose (Odds Ratio [O.R.] 0.60, 95% Confidence Interval [C.I.] 0.15-2.36, P = 0.47) in a multivariate, ordered logistic regression model, adjusting for age, race, gender, body mass index, and chronic diseases. Serum CML (microg/mL) was associated with abnormal 2-hour plasma glucose on glucose tolerance testing (O.R. 0.15, 95% C.I. 0.04-0.63, P = 0.009) in a multivariate, ordered logistic regression model, adjusting for the same covariates. CONCLUSIONS Elevated CML, a dominant AGE, was not associated with elevated fasting plasma glucose and was associated with a reduced odds of abnormal glucose tolerance in older community-dwelling adults.
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Affiliation(s)
- R D Semba
- Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
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29
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Chabroux S, Canouï-Poitrine F, Reffet S, Mills-Joncour G, Morelon E, Colin C, Thivolet C. Advanced glycation end products assessed by skin autofluorescence in type 1 diabetics are associated with nephropathy, but not retinopathy. DIABETES & METABOLISM 2010; 36:152-7. [DOI: 10.1016/j.diabet.2009.11.003] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/28/2009] [Revised: 11/03/2009] [Accepted: 11/08/2009] [Indexed: 11/26/2022]
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Yamagishi SI, Matsui T. Advanced glycation end products, oxidative stress and diabetic nephropathy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2010; 3:101-8. [PMID: 20716934 PMCID: PMC2952094 DOI: 10.4161/oxim.3.2.11148] [Citation(s) in RCA: 283] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/05/2010] [Revised: 01/07/2010] [Accepted: 01/07/2010] [Indexed: 12/28/2022]
Abstract
About 246 million people worldwide have diabetes in 2007. The global figure of people with diabetes is projected to increase to 370 million in 2030. As the prevalence of diabetes has risen to epidemic proportions worldwide, diabetic nephropathy has become one of the most challenging health problems. Therapeutic options such as strict blood glucose and blood pressure controls are effective for preventing diabetic nephropathy, but are far from satisfactory, and the number of diabetic patients on end-stage renal disease is still increasing. Therefore, a novel therapeutic strategy that could halt the progression of diabetic nephropathy should be developed. There is accumulating evidence that advanced glycation end products (AGEs), senescent macroprotein derivatives formed at an accelerated rate under diabetes, play a role in diabetic nephropathy via oxidative stress generation. In this paper, we review the pathophysiological role of AGEs and their receptor (RAGE)-oxidative stress system in diabetic nephropathy.
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Affiliation(s)
- Sho-Ichi Yamagishi
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan.
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31
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Polymorphism in exon 7 of the endothelial nitric oxide synthase gene is associated with low incidence of microvascular damage in type 1 diabetic neuropathy. Open Life Sci 2009. [DOI: 10.2478/s11535-009-0051-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
AbstractMicrovascular complications associated with type 1 diabetes mellitus (T1DM) are caused in part by endothelial dysfunction. We aimed to determine the association between polymorphisms in endothelial nitric oxide synthase (eNOS) gene (894G>T, 4ab) and T1DM-associated microvascular disorders, and the roles of nitrite/nitrate products (NOx) and low molecular weight-AGEs (LMW-AGEs) levels in this relationship. We carried out a case-control study (328 subjects) and determined genotypes by PCR. The rare-type TT of eNOS 894G>T was significantly overrepresented in patients without microvascular disorders as compared with control (OR=3.64; 95% C.I.=1.02–12.73; P=0.039). The prevalence of neuropathy was high among 894GG homozygotes (OR=0.5; 95% C.I.=0.29–0.86; P=0.012) who had high levels of triglycerides, elevated systolic BP, increased NOx, and LMW-AGEs. Decreased NOx levels were associated with 894TT genotype (beta=−0.65; P=0.043) in diabetic patients prone to microvascular complications. Multiple regression analysis indicated a negative correlation between eNOS 894G>T and diabetic neuropathy (P=0.025). The distribution of eNOS 4aa genotype was high (P=0.042) in patients with T1DM; however, it does not represent a risk factor for neuropathy. The overrepresentation of eNOS 894TT genotype in diabetic patients is associated with low risk for neuropathy. Decreased NOx and LMW-AGEs levels and lower lipid profile are the main features of patients carrying the eNOS 894T allele. These data suggest that the eNOS 894TT genotype may play a protective role by preventing microvascular disorders.
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Halushka MK, Selvin E, Lu J, Macgregor AM, Cornish TC. Use of human vascular tissue microarrays for measurement of advanced glycation endproducts. J Histochem Cytochem 2009; 57:559-66. [PMID: 19223295 PMCID: PMC2690436 DOI: 10.1369/jhc.2009.953273] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2008] [Accepted: 01/27/2009] [Indexed: 11/22/2022] Open
Abstract
Advanced glycation endproducts (AGEs) are present in the vasculature and are associated with vascular disease. We determined levels of AGEs in eight distinct adult vascular tissues using tissue microarray (TMA) technology and associated these levels with clinical characteristics. Medium-to-large caliber blood vessels were harvested from 100 adult autopsies to create 17 TMAs. AGE levels were evaluated by IHC using a polyclonal anti-AGE antibody on over 700 unique blood vessels. Slides were digitally scanned, and quantitative analysis was performed using a color deconvolution image analysis technique. Medial AGE staining was strongly correlated between all eight blood vessels. In the media, AGE staining levels were significantly higher at older ages (p=0.009), in white subjects (p<0.001) and with longer postmortem interval (PMI; p<0.0001). These associations remained significant after simultaneous adjustment for age, race/ethnicity, PMI, and diabetes status. Diabetes was associated with elevated AGE levels but only after adjustment for confounding by clinical variables including race/ethnicity, hypertension, and kidney function. This extensive vascular study shows that AGE accumulation in the macrovasculature is a global process affecting atherosclerosis-prone and -resistant vessels. It also suggests ethnicity has a previously undescribed role in vascular tissue AGE levels. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.
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Affiliation(s)
- Marc K Halushka
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
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Ray A, Huisman MV, Tamsma JT, van Asten J, Bingen BO, Broeders EABJ, Hoogeveen ES, van Hout F, Kwee VA, Laman B, Malgo F, Mohammadi M, Nijenhuis M, Rijkée M, van Tellingen MM, Tromp M, Tummers Q, de Vries L. The role of inflammation on atherosclerosis, intermediate and clinical cardiovascular endpoints in type 2 diabetes mellitus. Eur J Intern Med 2009; 20:253-60. [PMID: 19393492 DOI: 10.1016/j.ejim.2008.07.008] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2007] [Revised: 06/23/2008] [Accepted: 07/07/2008] [Indexed: 02/07/2023]
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) is associated with increased cardiovascular morbidity and mortality. Sub-clinical systemic inflammation is often present in T2DM patients. Systemic inflammation has also been implicated in the pathophysiology of atherosclerosis. This review investigates the direct evidence present in literature for the effect of inflammation on atherosclerosis, specifically in the setting of T2DM. Special emphasis is given to the pathogenesis of atherosclerosis as well as intermediate and clinical cardiovascular endpoints. The important role of deteriorated endothelial function in T2DM was excluded from the analysis. METHODS Extensive literature searches were performed using the PubMed and Web of Science databases. Articles were identified, retrieved and accepted or excluded based on predefined criteria. RESULTS Substantial evidence was found for an important inflammatory component in the pathogenesis of atherosclerosis in T2DM, demonstrated by inflammatory changes in plaque characteristics and macrophage infiltration. Most epidemiologic studies found a correlation between inflammation markers and intermediate cardiovascular endpoints, especially intima-media thickness. Several, but not all clinical trials in T2DM found that reducing sub-clinical inflammation had a beneficial effect on intermediate endpoints. When regarding cardiovascular events however, current literature consistently indicates a strong relationship between inflammation and clinical endpoints in subjects with T2DM. CONCLUSION Current literature provides direct evidence for a contribution of inflammatory responses to the pathogenesis of atherosclerosis in T2DM. The most consistent relation was observed between inflammation and clinical endpoints.
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Affiliation(s)
- A Ray
- Vascular Medicine, Department of General Internal Medicine & Endocrinology, Leiden University Medical Centre, Leiden, The Netherlands.
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Xanthis A, Hatzitolios A, Fidani S, Befani C, Giannakoulas G, Koliakos G. Receptor of Advanced Glycation End Products (RAGE) Positively Regulates CD36 Expression and Reactive Oxygen Species Production in Human Monocytes in Diabetes. Angiology 2009; 60:772-9. [DOI: 10.1177/0003319708328569] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Introduction: Advanced glycation end products (AGEs) engagement of a monocyte surface receptor (RAGE) induces atherosclerosis. AGEs also act as CD36 ligands. We studied reactive oxygen species (ROS) and CD36 expression after siRNA inhibition of RAGE expression in human monocytes. Methods: We isolated monocytes from: a) 10 type 2 diabetics, and b) 5 age- and sex-matched healthy individuals. CD36 expression and ROS production were evaluated before and after RAGE knockdown. Results: After incubation of monocytes with AGE + bovine serum albumin (BSA), CD36 expression and intracellular ROS increased significantly in all groups. In RAGE-knockdown monocytes, AGE-induced CD36 expression and ROS generation were also significantly inhibited. Conclusions: Blocking RAGE expression using siRNA in human monocytes led to a significant inhibition of CD36 expression and ROS production, suggesting a positive interaction between RAGE, CD36 expression and ROS generation in monocytes.
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Affiliation(s)
- A. Xanthis
- First Propedeutic Internal Medicine Clinic, AHEPA Hospital, Aristotle University of Thessaloniki, Greece,
| | - A. Hatzitolios
- First Propedeutic Internal Medicine Clinic, AHEPA Hospital, Aristotle University of Thessaloniki, Greece
| | - S. Fidani
- Laboratory of General Biology, Medical School, Aristotle University of Thessaloniki, Greece
| | - C. Befani
- Laboratory of Biological Chemistry, Medical School, Aristotle University of Thessaloniki, Greece
| | - G. Giannakoulas
- Laboratory of Biological Chemistry, Medical School, Aristotle University of Thessaloniki, Greece
| | - G. Koliakos
- 1st Cardiology Dept, Medical School, Aristotle University of Thessaloniki, Greece
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Persson F, Rossing P, Hovind P, Stehouwer CDA, Schalkwijk CG, Tarnow L, Parving HH. Endothelial dysfunction and inflammation predict development of diabetic nephropathy in the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA 2) study. Scandinavian Journal of Clinical and Laboratory Investigation 2009; 68:731-8. [PMID: 18609080 DOI: 10.1080/00365510802187226] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To evaluate risk factors for progression from persistent microalbuminuria to diabetic nephropathy in the Irbesartan in Patients with Type 2 diabetes and Microalbuminuria (IRMA 2) study, including biomarkers of endothelial dysfunction, chronic low-grade inflammation, growth factors and advanced glycation end products (AGE peptides). METHODS IRMA 2 was a 2-year multicentre, randomized, double-blind trial comparing irbesartan (150 and 300 mg once daily) versus placebo. The primary end-point was time to onset of diabetic nephropathy. Samples from a subgroup from the placebo and the 300 mg irbesartan treatment group were used in this post-hoc analysis (n = 269, 68 %). Nine biomarkers were analysed: high sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), fibrinogen, von Willebrand Factor (vWf), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular cell adhesion molecule-1 (sICAM-1), sE-selectin, transforming growth factor-beta (TGF-beta) and AGE peptides. Mean standard deviation scores (Z-scores) were used to combine biomarker information. RESULTS In a Cox enter model with combined Z-scores for biomarkers of endothelial dysfunction (vWf, sVCAM-1, sICAM-1, sE-selectin) and for biomarkers of inflammation (hs-CRP, IL-6, fibrinogen), endothelial dysfunction (hazard ratio for a 28 % increase ( = 1 SD) in Z-score) 3.20 (1.56 to 6.56), p = 0.001) and UAER (HR for a 75 % increase ( = 1 SD) in UAER) 2.61 (1.30 to 5.23), p = 0.007) were found as independent predictors. Independently, IL-6 and vWf predicted the end-point. In addition, endothelial Z-score was associated with progression of albuminuria (p = 0.038). CONCLUSION Endothelial dysfunction and possibly inflammation are novel predictors of progression to diabetic nephropathy in patients with type 2 diabetes and microalbuminuria independently of traditional risk factors. ClinicalTrials.gov ID: NCT00317915.
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Piwowar A, Knapik-Kordecka M, Szczecińska J, Warwas M. Plasma glycooxidation protein products in type 2 diabetic patients with nephropathy. Diabetes Metab Res Rev 2008; 24:549-53. [PMID: 18613218 DOI: 10.1002/dmrr.885] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND In diabetes mellitus, hyperglycaemia accelerates non-enzymatic glycation and oxidative stress leading to damage of macromolecules, among others proteins. This manifests in the increased levels of advanced glycation end products (AGE) and advanced oxidation protein products (AOPP). OBJECTIVES To assess the plasma levels of AGE and AOPP in the patients with type 2 diabetes mellitus (T2DM) and to estimate its relation and connection with the degree of nephropathy. MATERIAL AND METHODS In 121 diabetic patients and 22 healthy people plasma levels of AGE and AOPP were determined with fluorimetric and spectrophotometric methods, respectively. To estimate nephropathy stage, albumin/creatinine ratio was calculated on the basis of albumin and creatinine concentrations in early morning urine samples. RESULTS Diabetic patients had significantly higher levels of AGE and AOPP in comparison to healthy people. Both parameters were increasing progressively from normoalbuminuria, through microalbuminuria to macroalbuminuria. Statistically, the most significant differences were observed in AOPP concentration between separated groups. AGE fluorescence was significantly different on the same low, statistical level between patients with normoalbuminuria when compared to those with micro- and macroalbuminuria. Plasma AGE correlated significantly with urinary albumin/creatinine ratio whereas AOPP correlated with plasma creatinine level. CONCLUSIONS The connection between plasma levels of both glycooxidation protein products-AGE and AOPP with nephropathy severity, measured by the degree of albuminuria, in T2DM patients was observed. We can suggest that the AOPP better reflect the progression of kidney damage than AGE in examined diabetic patients.
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Affiliation(s)
- Agnieszka Piwowar
- Department of Pharmaceutical Biochemistry, Wroclaw Medical University, Poland.
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Correlation of low molecular weight advanced glycation end products and nitric oxide metabolites with chronic complications in type 1 diabetic patients. Open Life Sci 2008. [DOI: 10.2478/s11535-008-0019-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
AbstractAdvanced glycation end products (AGEs) are involved in the occurrence of vascular complications in diabetes. The present study was undertaken to investigate the level of low-molecular weight products of AGEs (LMW-AGEs) in relation to microvascular complications in type 1 diabetes, and the possible relationship with nitric oxide (NO) as a marker of endothelial function. Patients with normal renal function (NRF) were classified into two groups: (1) without, and (2) with diabetic neuropathy; and patients with renal impairment also into two groups: (3) diabetic renal disease, and (4) end-stage renal disease. The fluorescence of LMW-AGEs and measurement of NO metabolites was assessed in 277 serum samples. In addition, multiple regression analysis was performed. In group 1, LMW-AGEs level (9.3±1.1 AF%) was higher than in the control group (2.4±0.3 AF%). A trend in the increase of LMW-AGEs with neuropathy (29.7±5.5 AF%, group 2), and further with renal impairment (47.0±8.0, group 3 and 137.8±25.5 AF%, group 4), was observed. In multivariate regression analysis LMW-AGEs were associated with NO metabolites in group 2. In NRF patients, diabetic neuropathy was significantly correlated with LMW-AGEs and NO metabolites, independently of serum creatinine and duration of diabetes. This relationship suggests that the NO and LMW-AGEs’ actions (possibly synergistic) in endothelial activation possess a role in the initiation and development of diabetic microvascular complications.
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Barbosa JHP, Oliveira SL, Seara LTE. O papel dos produtos finais da glicação avançada (AGEs) no desencadeamento das complicações vasculares do diabetes. ACTA ACUST UNITED AC 2008; 52:940-50. [DOI: 10.1590/s0004-27302008000600005] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2007] [Accepted: 03/28/2008] [Indexed: 01/12/2023]
Abstract
Os produtos finais da glicação avançada (AGEs [do inglês, Advanced Glycation End-products]) constituem uma classe de moléculas heterogêneas formadas a partir de reações aminocarbonilo de natureza não-enzimática, que ocorrem aceleradamente no estado hiperglicêmico do diabetes. Considerados importantes mediadores patogênicos das complicações diabéticas, os AGEs são capazes de modificar, irreversivelmente, as propriedades químicas e funcionais das mais diversas estruturas biológicas. Na presente revisão, são apresentados os dados recentes da literatura que descrevem as vias de formação de AGEs, seu metabolismo, os principais mecanismos de ação dessas substâncias no desencadeamento dos processos patológicos, bem como os métodos de determinação de AGEs em amostras biológicas. Este artigo aponta, ainda, novas perspectivas de terapias anti-AGEs, a exemplo de estudos envolvendo a ação de compostos naturais dos alimentos, que podem oferecer potencial terapêutico para os portadores de diabetes ou de outras patologias associadas ao acúmulo degenerativo de AGEs.
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Stirban AO, Tschoepe D. Cardiovascular complications in diabetes: targets and interventions. Diabetes Care 2008; 31 Suppl 2:S215-21. [PMID: 18227488 DOI: 10.2337/dc08-s257] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Cardiovascular complications are mainly responsible for the high morbidity and mortality in people with diabetes. The awareness of physicians for the importance of primary prevention increased lately and numerous strategies have been developed. The spectrum ranges from pharmacologic treatment to vitamins and dietetic interventions. Some interesting concepts such as focusing on exogenous advanced glycation end products have emerged, but definitive results on their clinical relevance are still lacking. A major problem of the primary prevention is the choice of the method applied for screening, the criteria used to classify risk patients, as well as the choice of therapy. Guidelines provide goals to be achieved and offer alternatives for treatment, but the medical decision has to be made on an individualized basis. In this overview, we will comprehensively focus on the most important pathomechanisms and clinically relevant approaches, aiming at the early diagnosis and treatment of diabetes along with coronary heart disease. When primary prevention fails, we advocate a more aggressive treatment of critically ill patients, followed by optimal secondary prevention meeting on-target goals precisely.
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Affiliation(s)
- Alin O Stirban
- Heart and Diabetes Center, Ruhr-University Bochum, Bad Oeynhausen, Germany
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40
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S Januszewski A, C Thomas M, S Karschimkus C, S Chung J, G Rowley K, L Nelson C, N O’Neal D, Dragicevic G, A Harper C, D Best J, J Jenkins A. Longitudinal analysis of low-molecular weight fluorophores in type 1 diabetes mellitus. THE JOURNAL OF MEDICAL INVESTIGATION 2008; 55:29-36. [DOI: 10.2152/jmi.55.29] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Affiliation(s)
| | | | | | - Jasmine S Chung
- University of Melbourne, Department of Medicine, St Vincent’s Hospital
| | - Kevin G Rowley
- University of Melbourne, Department of Medicine, St Vincent’s Hospital
| | - Craig L Nelson
- University of Melbourne, Department of Medicine, St Vincent’s Hospital
| | - David N O’Neal
- University of Melbourne, Department of Medicine, St Vincent’s Hospital
| | - George Dragicevic
- University of Melbourne, Department of Medicine, St Vincent’s Hospital
| | | | - James D Best
- University of Melbourne, Department of Medicine, St Vincent’s Hospital
| | - Alicia J Jenkins
- University of Melbourne, Department of Medicine, St Vincent’s Hospital
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Lapolla A, Brancia FL, Bereszczak J, Fedele D, Baccarin L, Seraglia R, Traldi P. Off-line liquid chromatography-MALDI by with various matrices and tandem mass spectrometry for analysis of glycated human serum albumin tryptic peptides. Mol Nutr Food Res 2007; 51:456-61. [PMID: 17357982 DOI: 10.1002/mnfr.200600291] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Advanced glycation end-product (AGE)/peptides, arising from in vivo digestion of glycated proteins, are biologically important compounds, due to their reactivity against circulating and tissue proteins. For information on their possible structure, in vitro glycation of HSA and its further enzymatic digestion were performed. The resulting digestion product mixture was analysed directly by MALDI MS with various matrices [2,5-dihydroxy benzoic acid (DHB) and alpha-cyano-4-hydroxy cinnamic acid (CHCA)]. Alternatively, offline microbore LC prior to MALDI analysis was used, and showed that 63% of the free amino groups prone to glycation are modified, indicating the contemporary presence of unglycated peptides. This result proves that, regardless of the high glucose concentration employed for HSA incubation, glycation does not go to completion. Further studies showed that the collisionally activated decomposition of singly charged glycated peptides leads to specific fragmentation pathways, all related to the condensed glucose molecule. These unique product ions can be used as effective markers to establish the presence of a glucose molecule within a peptide ion.
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Affiliation(s)
- Annunziata Lapolla
- Dipartimento di Scienze Mediche e Chirurgiche, Università di Padova, Italy.
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42
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Lutgers HL, Graaff R, Links TP, Ubink-Veltmaat LJ, Bilo HJ, Gans RO, Smit AJ. Skin autofluorescence as a noninvasive marker of vascular damage in patients with type 2 diabetes. Diabetes Care 2006; 29:2654-9. [PMID: 17130200 DOI: 10.2337/dc05-2173] [Citation(s) in RCA: 193] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Advanced glycation end products (AGEs) are thought to have a role in the pathogenesis of diabetes complications. We recently reported the association between skin autofluorescence, as a measure of tissue AGE accumulation, and diabetic neuropathy in a selected diabetic population. In this study, we investigated the relation between skin autofluorescence and clinical variables including micro- and macrovascular complications in a type 2 diabetes primary care population. RESEARCH DESIGN AND METHODS Clinical data and skin autofluorescence were obtained in the type 2 diabetes group (n = 973) and in a control group (n = 231). Skin autofluorescence was assessed by illumination of the lower arm with a fluorescent tube (peak intensity approximately 370 nm). RESULTS Skin autofluorescence was significantly higher in type 2 diabetic patients compared with control subjects in each age category. Multiple regression analysis showed significant correlation of skin autofluorescence with age, sex, diabetes duration, BMI, smoking, HbA1c, plasma creatinine, HDL cholesterol, and albumin-to-creatinine ratio in the type 2 diabetes group (R2 = 25%) and with age and smoking in the control group (R2 = 46%). Skin autofluorescence was significantly higher in the type 2 diabetes group, with both micro- and macrovascular disease, compared with the group without complications and the group with only microvascular complications. CONCLUSIONS This study confirms in a large group of type 2 diabetic patients that skin autofluorescence is higher compared with age-matched control subjects and is associated with the severity of diabetes-related complications. Skin autofluorescence reflecting vascular damage might be a rapid and helpful tool in the diabetes outpatient clinic for identifying diabetic patients who are at risk for developing complications.
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Affiliation(s)
- Helen L Lutgers
- Department of Medicine U3.129, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, Netherlands.
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Brancia FL, Bereszczak JZ, Lapolla A, Fedele D, Baccarin L, Seraglia R, Traldi P. Comprehensive analysis of glycated human serum albumin tryptic peptides by off-line liquid chromatography followed by MALDI analysis on a time-of-flight/curved field reflectron tandem mass spectrometer. JOURNAL OF MASS SPECTROMETRY : JMS 2006; 41:1179-85. [PMID: 16924599 DOI: 10.1002/jms.1083] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
Glycated peptides arising from in vivo digestion of glycated proteins, usually called advanced glycation end (AGE) product peptides, are biologically relevant compounds due to their reactivity towards circulating and tissue proteins. To investigate their structures, in vitro glycation of human serum albumin (HSA) has been performed and followed by enzymatic digestion. Using different MALDI based approaches the digestion products obtained have been compared with those arising from enzymatic digestion of the protein. Results obtained using 2,5-dihydroxybenzoic acid (DHB) indicate this as the most effective matrix, leading to an increase in the coverage of the glycated protein. Off-line microbore liquid chromatography prior to MALDI analysis reveals that 63% of the free amino groups amenable to glycation are modified. In addition, the same approach shows the co-presence of underivatised peptides. This indicates that, regardless of the high glucose concentration employed for HSA incubation, glycation does not go to completion. Tandem mass spectrometric data suggest that the collision induced dissociation of singly charged glycated peptides leads to specific fragmentation pathways related to the condensed glucose molecule. The specific neutral losses derived from the activated glycated peptides can be used as signature for establishing the occurrence of glycation processes.
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Lapolla A, Fedele D, Seraglia R, Traldi P. The role of mass spectrometry in the study of non-enzymatic protein glycation in diabetes: an update. MASS SPECTROMETRY REVIEWS 2006; 25:775-97. [PMID: 16625652 DOI: 10.1002/mas.20090] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Abstract
Recent studies on non-enzymatic protein glycation are reviewed, and results are critically discussed. Advanced glycation end products (AGE) levels in the body reflect a balance between their formation and catabolism. AGE proteolysis leads to the formation of low-molecular-weight AGE (AGE peptides) that are normally excreted in urine. In the case of diabetic disease and/or renal failure, AGE peptides accumulate in plasma. Because of their high reactivity, these compounds have been thought to play a role in the progression of chronic complications. The structural identification of these compounds is particularly important, and a strategy has been designed for their possible definition. A series of experiments has been devoted to the study of the enzymatic degradation products of in vitro glycated human serum albumin (HSA). This approach, based on different MS methods (LC/ESI/MS, LC/ESI/FTMS, MALDI), led to the detection of the glycated peptides generated by digestion of HSA. A further study was devoted to the possible identification of the peptides identified in the glycated HSA digestion products in the plasma of diabetic and nephropatic subjects. No glycated HSA digestion products were found in plasma samples of the subjects under investigation even if clear differences were found among the LC runs from populations of healthy, diabetic, and nephropatic subjects. Parallel investigations were devoted to the evaluation of glyoxal and methylglyoxal-dicarbonyl compounds that originate at the intermediate stage of the Maillard reaction. This evaluation was performed in diabetic patients, before and after the achievement of good metabolic control, and in nephropatic patients subjected to peritoneal dialysis (PD). In the latter case, results indicated that these dicarbonyl compounds, already present in the dialysis fluids, show a decrease in plasma and in dialysis fluids; those data suggested their reaction at peritoneal membrane level.
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Affiliation(s)
- Annunziata Lapolla
- Dipartimento di Scienze Mediche e Chirurgiche, Cattedra di Malattie del Metabolismo, Università di Padova, Padova, Italy
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Huebschmann AG, Regensteiner JG, Vlassara H, Reusch JEB. Diabetes and advanced glycoxidation end products. Diabetes Care 2006; 29:1420-32. [PMID: 16732039 DOI: 10.2337/dc05-2096] [Citation(s) in RCA: 196] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Amy G Huebschmann
- Division of General Internal Medicine, Department of Medicine, University of Colorado Denver and Health Sciences Center, Mailstop F-729, Aurora, CO 80045, USA.
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Monnier VM, Sell DR, Genuth S. Glycation Products as Markers and Predictors of the Progression of Diabetic Complications. Ann N Y Acad Sci 2006; 1043:567-81. [PMID: 16037280 DOI: 10.1196/annals.1333.065] [Citation(s) in RCA: 123] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The structure of a growing number of glycation and advanced glycation end products has been elucidated. Measuring these products can be used to assess cumulative glycemic and glycoxidative damage in diabetes and other chronic conditions. The predictive power of a given glycation product can be tested in large prospective studies that evaluate the risk of developing diabetic micro- and macrovascular disease over years following the quantitative determination of that marker. This article provides a comprehensive review of the field, comparing the merits of each marker, whether in skin, serum, or other tissue. Several conclusions are drawn, one of which identifies skin glycation products as powerful predictors of the risk of developing diabetic complications.
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Affiliation(s)
- Vincent M Monnier
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
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Stam F, Schalkwijk CG, van Guldener C, ter Wee PM, Stehouwer CDA. Advanced glycation end-product peptides are associated with impaired renal function, but not with biochemical markers of endothelial dysfunction and inflammation, in non-diabetic individuals. Nephrol Dial Transplant 2005; 21:677-82. [PMID: 16330467 DOI: 10.1093/ndt/gfi309] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Patients with end-stage renal disease as well as mild renal impairment have an increased risk for the development of cardiovascular disease. It has been suggested that advanced glycation end-products (AGEs) are involved in atherogenesis, possibly through induction of endothelial dysfunction and low-grade inflammation. METHODS In a cross-sectional, single-centre study, we investigated four groups of 20 non-diabetic subjects with a creatinine clearance ranging from normal (> 90 ml/min/1.73 m2) to < 31 ml/min/1.73 m2. We measured AGE-peptides, markers of endothelial dysfunction (von Willebrand factor, soluble E-selectin, plasminogen activator inhibitor-1, tissue-type plasminogen activator, soluble vascular cell adhesion molecule-1) and markers of inflammatory activity (soluble intercellular adhesion molecule-1, C-reactive protein, secretory phospholipase A2). We constructed composite endothelial dysfunction and inflammatory activity Z-scores using these markers. RESULTS AGE-peptides were independently related to creatinine clearance (standardized beta -0.55, 95% confidence interval (CI) -0.77 to -0.34, P < 0.001). AGE-peptides were not independently related to the individual markers of endothelial dysfunction and inflammation, nor to the composite endothelial dysfunction Z-score (standardized beta 0.08, 95% CI -0.14 to -0.30, P = 0.48) or the inflammatory activity Z-score (standardized beta -0.05, 95% CI -0.25 to -0.16, P = 0.66). CONCLUSIONS Plasma concentrations of AGE-peptides are associated with creatinine clearance but not with biochemical markers of endothelial dysfunction and inflammatory activity in non-diabetic patients over a wide range of renal function. This suggests that the atherogenic effects of AGE-peptides in individuals with renal functional impairment are not mediated by endothelial dysfunction or inflammatory activity as estimated by the markers used.
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Affiliation(s)
- Frank Stam
- Department of Internal Medicine, VU University Medical Centre, Amsterdam, The Netherlands.
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Schalkwijk CG, Ter Wee PM, Stehouwer CDA. Plasma levels of AGE peptides in type 1 diabetic patients are associated with serum creatinine and not with albumin excretion rate: possible role of AGE peptide-associated endothelial dysfunction. Ann N Y Acad Sci 2005; 1043:662-70. [PMID: 16037290 DOI: 10.1196/annals.1333.075] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Patients with renal impairment have an increased risk for cardiovascular disease, which may be the result of advanced glycation end products (AGEs). The aim of this study was to investigate the levels of AGE peptides in relation to kidney function and to study the relationship of AGE peptides with endothelial function and inflammation in type 1 diabetic patients. We measured plasma levels of AGE peptides with a simple fluorescent analytical procedure in patients with end-stage renal disease with or without diabetes and in 60 type 1 diabetic patients categorized as having normo-, micro-, or macroalbuminuria. Using enzyme-linked immunosorbent assays, we determined vascular cell adhesion molecule 1 (sVCAM-1), sE-selectin, plasminogen activator inhibitor 1 (PAI-1), tissue type-specific plasminogen activator (tPA), von Willebrand factor (vWF), and soluble thrombomodulin (sTM) to be markers of endothelial function and determined C-reactive protein (CRP) to be a marker of inflammation. AGE peptides were increased approximately fivefold in patients with end-stage renal disease, without difference between patients with or without diabetes. In type 1 diabetic patients, the increase of AGE peptides across the groups normo-, micro-, and macroalbuminuria (with medians [range] of 12.6% [7.8-27.2%], 12.1% [7.8-162%], and 46.5% [9.0-248.9%]) was associated with serum creatinine level and not with albumin excretion rate (AER). The relationship with serum creatinine decreased but remained significant after adjusting for age, sex, diabetes duration, hemoglobin A1c (HbA1c), AER, systolic and diastolic blood pressure (BP), and CRP in multiple linear-regression analysis. AGE peptide levels were significantly associated with sVCAM-1 and sTM, independently of serum creatinine. However, these relationships were no longer significant after adjusting for age, sex, diabetes duration, HbA1c, AER, systolic and diastolic BP, and CRP. This study shows that plasma levels of AGE peptides rise with renal impairment, as determined by serum creatinine. AGE peptides are associated with some markers of endothelial activation, which may suggest an involvement of AGE peptides in the acceleration of cardiovascular complications in type 1 diabetic patients with renal impairment.
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Affiliation(s)
- Casper G Schalkwijk
- Department of Clinical Chemistry, University Medical Center, Amsterdam, the Netherlands.
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Januszewski AS, Thomas MC, Chung SJ, Karschimkus CS, Rowley KG, Nelson C, O'Neal D, Wang Z, Best JD, Jenkins AJ. Plasma low-molecular weight fluorescence in type 1 diabetes mellitus. Ann N Y Acad Sci 2005; 1043:655-61. [PMID: 16037289 DOI: 10.1196/annals.1333.074] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Characteristic tissue fluorescence is associated with advanced glycation end product (AGE) accumulation in experimental diabetes models, but its utility in patients with type 1 diabetes remains to be established. We studied 148 patients with type 1 diabetes and 77 healthy age-matched control subjects. Low-molecular weight (LMW) fluorophore levels were estimated in plasma samples obtained after an overnight fast. Intra- and interassay coefficients of variation were 4.7% and 6.4%, respectively. LMW fluorophore levels were significantly higher in patients with diabetes than in control subjects (6.3 +/- 0.6 AU/mL vs. 4.1 +/- 0.3; P = 0.007). However, all of this difference came from patients with microvascular complications (n = 67, 7.5 +/- 1.3). There was no significant difference in LMW fluorescence between complication-free patients (4.4 +/- 0.2) and control subjects (P > 0.05). On multivariate analysis, LMW fluorophores correlated with measures of renal function (P < 0.05) but not with diabetes per se. In addition, there was no correlation between LMW fluorophores and the markers of oxidative stress or systemic inflammation. Longitudinal and interventional studies are required to determine whether the association between LMW fluorophores and nephropathy is cause or effect.
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Affiliation(s)
- A S Januszewski
- University of Melbourne, Department of Medicine, St. Vincent's Hospital, Princes & Regent Streets, Fitzroy, 3065 Melbourne, Australia
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Thomas MC, Forbes JM, MacIsaac R, Jerums G, Cooper ME. Low-molecular weight advanced glycation end products: markers of tissue AGE accumulation and more? Ann N Y Acad Sci 2005; 1043:644-54. [PMID: 16037288 DOI: 10.1196/annals.1333.073] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Incomplete digestion of advanced glycation end product (AGE)-modified protein results in the formation of low-molecular weight degradation products incorporating AGE modifications (LMW-AGEs). In addition to being biomarkers of AGE modification, LMW-AGEs may have a high toxic potential, being free to interact with AGE receptors at distant sites via the circulation. Several free AGEs have been identified, including pentosidine, N(epsilon)-(carboxymethyl)lysine (CML), and free-imidazole AGEs. In addition, fluorescence (370 nm [excitation]/440 nm [emission]) in the LMW phase of serum correlates with tissue fluorescence, an established marker for AGE modification. In experimental diabetes, LMW fluorescence increases with duration of disease and is normalized with the AGE inhibitor aminoguanidine. LMW fluorescence is also higher in patients with diabetes, in whom it is associated with glomerular filtration rate and hemoglobin. Patients with hyperfiltration have lower LMW fluorescence than those with normal renal function, which may protect them from AGE accumulation in the short term. These findings provide clinical support for the association between AGEs and progressive renal injury in diabetes.
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Affiliation(s)
- Merlin C Thomas
- The Baker Heart Research Institute, P.O. Box 6492, St. Kilda Rd. Central, Melbourne, Victoria, Australia.
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