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Tanito M, Koyama M. Accelerated Biological Aging in Exfoliation Glaucoma Assessed by Fundus-Derived Predicted Age and Advanced Glycation End Products. Int J Mol Sci 2025; 26:4725. [PMID: 40429867 PMCID: PMC12112260 DOI: 10.3390/ijms26104725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2025] [Revised: 05/09/2025] [Accepted: 05/13/2025] [Indexed: 05/29/2025] Open
Abstract
Glaucoma is an age-related neurodegenerative disease characterized by progressive optic nerve damage. Accelerated biological aging, assessed using predicted age derived from fundus images, may serve as a biomarker for glaucoma progression. This study aimed to examine fundus-derived age acceleration among patients with primary open-angle glaucoma (POAG), exfoliation glaucoma (EXG), and controls, and to explore its biochemical basis through advanced glycation end products (AGEs). Fundus photographs from 237 participants (79 POAG, 79 EXG, and 79 age- and sex-matched controls) were analyzed using a deep learning model (EfficientNet) previously trained to predict biological age. AGE accumulation was assessed by measuring skin autofluorescence (sAF). Multivariate regression analyses were conducted to identify factors influencing predicted age acceleration, with stratification into age tertiles to control for age-related effects. EXG patients demonstrated significant accelerated biological aging compared to controls (p = 0.006), particularly evident in younger and middle-aged tertiles. AGE scores were significantly elevated in EXG relative to both POAG (p = 0.009) and control groups (p = 0.003). Predicted age and AGE scores were more strongly correlated than chronological age and AGEs, especially in the middle tertile (p = 0.002). Accelerated biological aging detected via fundus images occurs prominently in EXG, potentially reflecting underlying AGE accumulation. Fundus-derived predicted age could serve as a non-invasive biomarker for assessing glaucoma progression risk and warrants further exploration in clinical applications.
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Affiliation(s)
- Masaki Tanito
- Department of Ophthalmology, Faculty of Medicine, Shimane University, Enya 89-1, Izumo 693-8501, Shimane, Japan
| | - Makoto Koyama
- Minamikoyasu Eye Clinic, 2-8-30 Minamikoyasu, Kimitsu 299-1162, Chiba, Japan;
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Liu Z, Wang J, Zhao Y, Yuan Z, Zhuang X, Yin J. Associations of Skin Autofluorescence with Diabetic Kidney Disease in Type 2 Diabetes. Biomedicines 2025; 13:764. [PMID: 40299327 PMCID: PMC12025064 DOI: 10.3390/biomedicines13040764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Revised: 02/16/2025] [Accepted: 02/18/2025] [Indexed: 04/30/2025] Open
Abstract
Background: Diabetic kidney disease (DKD), a severe chronic complication of diabetes, significantly impacts the quality of life and life expectancy of affected individuals. Meanwhile, advanced glycation end products (AGEs) are believed to play a central role in the pathogenesis of DKD. Skin autofluorescence (SAF) is a well-validated, noninvasive technique for the estimation of AGE levels in the dermis. Aims: This study aims to evaluate the correlation between SAF and DKD prevalence, as well as the association between SAF and renal function parameters, in patients with Type 2 Diabetes Mellitus (T2DM). Methods: This cross-sectional analysis included 1259 hospitalized T2DM patients. SAF was measured using a spectroscopy device. Logistic regression analysis, p-trend analysis, and restricted cubic spline were performed with the prevalence of DKD as the dependent variable. Multiple linear regression analyses were conducted to investigate the associations of SAF with renal function parameters, specifically the estimated glomerular filtration rate (eGFR) and the log-transformed albumin-to-creatinine ratio (ln(ACR)). Results: The prevalence of DKD was strongly associated with SAF rather than with glycosylated hemoglobin (HbA1c). For each arbitrary unit (AU) increase in SAF, DKD incidence rose by 1.6%. A significant stepwise increase in the odds ratio (OR) of DKD was observed across SAF quartiles. A dose-response relationship existed between SAF and the OR value of DKD. Additionally, SAF showed a linear correlation with eGFR and ln(UACR). For each AU increase in SAF, eGFR decreased by 0.14 mL/min/1.73 m2, while UACR increased by 1.2%. Conclusions: Elevated SAF, rather than HbA1c, is independently associated with increased DKD prevalence and impaired renal function.
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Affiliation(s)
- Ziwei Liu
- Department of Endocrinology and Metabolism, Jinshan Branch of Shanghai Sixth People’s Hospital, Shanghai 201599, China; (Z.L.); (Y.Z.); (Z.Y.)
| | - Jingjie Wang
- Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China;
| | - Yuedong Zhao
- Department of Endocrinology and Metabolism, Jinshan Branch of Shanghai Sixth People’s Hospital, Shanghai 201599, China; (Z.L.); (Y.Z.); (Z.Y.)
| | - Zhu Yuan
- Department of Endocrinology and Metabolism, Jinshan Branch of Shanghai Sixth People’s Hospital, Shanghai 201599, China; (Z.L.); (Y.Z.); (Z.Y.)
| | - Xinjuan Zhuang
- Department of Endocrinology and Metabolism, Jinshan Branch of Shanghai Sixth People’s Hospital, Shanghai 201599, China; (Z.L.); (Y.Z.); (Z.Y.)
| | - Jun Yin
- Department of Endocrinology and Metabolism, Jinshan Branch of Shanghai Sixth People’s Hospital, Shanghai 201599, China; (Z.L.); (Y.Z.); (Z.Y.)
- Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China;
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Martínez-García I, Cavero-Redondo I, Pascual-Morena C, Otero-Luis I, Fenoll-Morate M, Lever-Megina CG, Rodríguez-Gutiérrez E, Saz-Lara A. Reference Values of Skin Autofluorescence by Age Groups in Healthy Spanish Adults: Results from the EVasCu Study, a Systematic Review, and a Meta-Analysis. J Clin Med 2025; 14:474. [PMID: 39860480 PMCID: PMC11766177 DOI: 10.3390/jcm14020474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 01/07/2025] [Accepted: 01/10/2025] [Indexed: 01/27/2025] Open
Abstract
Background/Objectives: Age is a known predictor of skin autofluorescence (SAF) across populations, but age-based reference values are lacking for the Spanish population. This study aims to establish SAF reference values for healthy Spanish adults by age group, compare these with other populations, and estimate optimal SAF cut-off points by age range. Additionally, it aims to analyse the influence of sex, smoking, and skin phototype. Methods: This cross-sectional EVasCu study included 390 healthy subjects aged over 18 years. Participants' age, sex, smoking status, and skin were recorded and categorised into age groups. Advanced glycation end products were measured through the SAF. A systematic review and meta-analysis, including an EVasCu study, was performed to obtain pooled means and standard deviations by age group. Results: The mean SAF Spanish values by age were (95% CI): (i) 18-19 years: 1.34-1.56 arbitrary units (AU); (ii) 20-29 years: 1.56-1.70 AU; (iii) 30-39 years: 1.66-1.84 AU; (iv) 40-49 years: 1.79-1.91 AU; (v) 50-59 years: 2.07-2.21 AU; (vi) ≥60 years: 2.07-2.50 AU. SAF was significantly correlated with age (r = 0.531; p < 0.001), smoking status (r = -0.196; p < 0.001), and skin phototype (r = 0.138; p = 0.007), and SAF was greater in smokers and dark-skinned individuals (p < 0.05). No significant differences were found in the SAF values for sex. The results of the meta-analysis were in line with those of the present study, providing reference values of SAF for the general population. Conclusions: SAF increases linearly with age in healthy individuals, and higher levels of SAF are observed in smokers and dark-skinned individuals.
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Affiliation(s)
- Irene Martínez-García
- CarVasCare Research Group (2023-GRIN-34459), Faculty of Nursing, Universidad de Castilla-La Mancha, 16002 Cuenca, Spain; (I.M.-G.); (I.C.-R.); (I.O.-L.); (M.F.-M.); (C.G.L.-M.); (A.S.-L.)
| | - Iván Cavero-Redondo
- CarVasCare Research Group (2023-GRIN-34459), Faculty of Nursing, Universidad de Castilla-La Mancha, 16002 Cuenca, Spain; (I.M.-G.); (I.C.-R.); (I.O.-L.); (M.F.-M.); (C.G.L.-M.); (A.S.-L.)
| | - Carlos Pascual-Morena
- Health and Social Research Center, Universidad de Castilla-La Mancha, 16002 Cuenca, Spain;
- Facultad de Enfermería de Albacete, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
| | - Iris Otero-Luis
- CarVasCare Research Group (2023-GRIN-34459), Faculty of Nursing, Universidad de Castilla-La Mancha, 16002 Cuenca, Spain; (I.M.-G.); (I.C.-R.); (I.O.-L.); (M.F.-M.); (C.G.L.-M.); (A.S.-L.)
| | - Marta Fenoll-Morate
- CarVasCare Research Group (2023-GRIN-34459), Faculty of Nursing, Universidad de Castilla-La Mancha, 16002 Cuenca, Spain; (I.M.-G.); (I.C.-R.); (I.O.-L.); (M.F.-M.); (C.G.L.-M.); (A.S.-L.)
| | - Carla Geovanna Lever-Megina
- CarVasCare Research Group (2023-GRIN-34459), Faculty of Nursing, Universidad de Castilla-La Mancha, 16002 Cuenca, Spain; (I.M.-G.); (I.C.-R.); (I.O.-L.); (M.F.-M.); (C.G.L.-M.); (A.S.-L.)
| | - Eva Rodríguez-Gutiérrez
- Health and Social Research Center, Universidad de Castilla-La Mancha, 16002 Cuenca, Spain;
- Research Network on Chronicity, Primary Care and Health Promotion (RICAPPS), 16071 Cuenca, Spain
| | - Alicia Saz-Lara
- CarVasCare Research Group (2023-GRIN-34459), Faculty of Nursing, Universidad de Castilla-La Mancha, 16002 Cuenca, Spain; (I.M.-G.); (I.C.-R.); (I.O.-L.); (M.F.-M.); (C.G.L.-M.); (A.S.-L.)
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Pan J, Bao X, Gonçalves I, Jujić A, Engström G. Skin autofluorescence, a measure of tissue accumulation of advanced glycation end products, is associated with subclinical atherosclerosis in coronary and carotid arteries. Atherosclerosis 2022; 345:26-32. [DOI: 10.1016/j.atherosclerosis.2022.02.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 02/02/2022] [Accepted: 02/03/2022] [Indexed: 11/02/2022]
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Schmitt J, Wurm M, Schwab KO, Spiekerkoetter U, Hannibal L, Grünert SC. Glycogen storage disease type I patients with hyperlipidemia have no signs of early vascular dysfunction and premature atherosclerosis. Nutr Metab Cardiovasc Dis 2021; 31:3384-3392. [PMID: 34627694 DOI: 10.1016/j.numecd.2021.08.027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 07/20/2021] [Accepted: 08/02/2021] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND AIMS Glycogen storage disease type I (GSD I) is associated with hyperlipidemia, a known risk factor for premature atherosclerosis. Few studies have addressed endothelial dysfunction in patients with GSD I, and these studies yielded controversial results. METHODS AND RESULTS We investigated vascular dysfunction in a cohort of 32 patients with GSD I (26 GSD Ia, 6 GSD Ib, mean age 20.7 (4.8-47.5) years) compared to 32 age-, gender-, and BMI-matched healthy controls using non-invasive techniques such as quantification of carotid intima media thickness, retinal vessel analysis and 24 h-blood pressure measurements. In addition, early biomarkers of inflammatory and oxidative endothelial stress were assessed in blood. Although GSD I patients had a clearly proatherogenic lipid profile, increased oxidative stress, higher levels of high sensitivity C-reactive protein and increased lipoprotein associated phospholipase A2 activity, functional and structural parameters including carotid intima media thickness and retinal vessel diameters did not indicate premature atherosclerosis in this patient cohort. Blood pressure values and pulse wave velocity were comparable in patients and healthy controls, while central blood pressure and augmentation index were higher in GSD patients. CONCLUSION Our data suggest that GSD I is not associated with early vascular dysfunction up to the age of at least 20 years. Further studies are needed to elucidate the possibly protective mechanisms that prevent early atherosclerosis is GSD I. Longer follow-up studies are required to assess the long-term risk of vascular disease with increased oxidative stress being present in GSD I patients.
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Affiliation(s)
- Johannes Schmitt
- Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center - University of Freiburg, Faculty of Medicine, 79106 Freiburg, Germany
| | - Michael Wurm
- Department of Pediatrics, St. Hedwigs Campus, University Children's Hospital Regensburg, 93049 Regensburg, Germany
| | - K Otfried Schwab
- Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center - University of Freiburg, Faculty of Medicine, 79106 Freiburg, Germany
| | - Ute Spiekerkoetter
- Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center - University of Freiburg, Faculty of Medicine, 79106 Freiburg, Germany
| | - Luciana Hannibal
- Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center - University of Freiburg, Faculty of Medicine, 79106 Freiburg, Germany
| | - Sarah C Grünert
- Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center - University of Freiburg, Faculty of Medicine, 79106 Freiburg, Germany.
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Hansrivijit P, Chen YJ, Lnu K, Trongtorsak A, Puthenpura MM, Thongprayoon C, Bathini T, Mao MA, Cheungpasitporn W. Prediction of mortality among patients with chronic kidney disease: A systematic review. World J Nephrol 2021; 10:59-75. [PMID: 34430385 PMCID: PMC8353601 DOI: 10.5527/wjn.v10.i4.59] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/11/2021] [Accepted: 07/23/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Chronic kidney disease (CKD) is a common medical condition that is increasing in prevalence. Existing published evidence has revealed through regression analyses that several clinical characteristics are associated with mortality in CKD patients. However, the predictive accuracies of these risk factors for mortality have not been clearly demonstrated. AIM To demonstrate the accuracy of mortality predictive factors in CKD patients by utilizing the area under the receiver operating characteristic (ROC) curve (AUC) analysis. METHODS We searched Ovid MEDLINE, EMBASE, and the Cochrane Library for eligible articles through January 2021. Studies were included based on the following criteria: (1) Study nature was observational or conference abstract; (2) Study populations involved patients with non-transplant CKD at any CKD stage severity; and (3) Predictive factors for mortality were presented with AUC analysis and its associated 95% confidence interval (CI). AUC of 0.70-0.79 is considered acceptable, 0.80-0.89 is considered excellent, and more than 0.90 is considered outstanding. RESULTS Of 1759 citations, a total of 18 studies (n = 14579) were included in this systematic review. Eight hundred thirty two patients had non-dialysis CKD, and 13747 patients had dialysis-dependent CKD (2160 patients on hemodialysis, 370 patients on peritoneal dialysis, and 11217 patients on non-differentiated dialysis modality). Of 24 mortality predictive factors, none were deemed outstanding for mortality prediction. A total of seven predictive factors [N-terminal pro-brain natriuretic peptide (NT-proBNP), BNP, soluble urokinase plasminogen activator receptor (suPAR), augmentation index, left atrial reservoir strain, C-reactive protein, and systolic pulmonary artery pressure] were identified as excellent. Seventeen predictive factors were in the acceptable range, which we classified into the following subgroups: predictors for the non-dialysis population, echocardiographic factors, comorbidities, and miscellaneous. CONCLUSION Several factors were found to predict mortality in CKD patients. Echocardiography is an important tool for mortality prognostication in CKD patients by evaluating left atrial reservoir strain, systolic pulmonary artery pressure, diastolic function, and left ventricular mass index.
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Affiliation(s)
- Panupong Hansrivijit
- Department of Internal Medicine, UPMC Pinnacle, Harrisburg, PA 17104, United States
| | - Yi-Ju Chen
- Department of Internal Medicine, UPMC Pinnacle, Harrisburg, PA 17104, United States
| | - Kriti Lnu
- Department of Internal Medicine, UPMC Pinnacle, Harrisburg, PA 17104, United States
| | - Angkawipa Trongtorsak
- Department of Internal Medicine, Amita Health Saint Francis Hospital, Evanston, IL 60202, United States
| | - Max M Puthenpura
- Department of Medicine, Drexel University College of Medicine, Philadelphia, PA 19129, United States
| | - Charat Thongprayoon
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN 55905, United States
| | - Tarun Bathini
- Department of Internal Medicine, University of Arizona, Tucson, AZ 85721, United States
| | - Michael A Mao
- Division of Nephrology and Hypertension, Mayo Clinic, Jacksonville, FL 32224, United States
| | - Wisit Cheungpasitporn
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN 55905, United States
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Brain glycogen serves as a critical glucosamine cache required for protein glycosylation. Cell Metab 2021; 33:1404-1417.e9. [PMID: 34043942 PMCID: PMC8266748 DOI: 10.1016/j.cmet.2021.05.003] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 03/02/2021] [Accepted: 05/03/2021] [Indexed: 02/08/2023]
Abstract
Glycosylation defects are a hallmark of many nervous system diseases. However, the molecular and metabolic basis for this pathology is not fully understood. In this study, we found that N-linked protein glycosylation in the brain is metabolically channeled to glucosamine metabolism through glycogenolysis. We discovered that glucosamine is an abundant constituent of brain glycogen, which functions as a glucosamine reservoir for multiple glycoconjugates. We demonstrated the enzymatic incorporation of glucosamine into glycogen by glycogen synthase, and the release by glycogen phosphorylase by biochemical and structural methodologies, in primary astrocytes, and in vivo by isotopic tracing and mass spectrometry. Using two mouse models of glycogen storage diseases, we showed that disruption of brain glycogen metabolism causes global decreases in free pools of UDP-N-acetylglucosamine and N-linked protein glycosylation. These findings revealed fundamental biological roles of brain glycogen in protein glycosylation with direct relevance to multiple human diseases of the central nervous system.
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Saz-Lara A, Álvarez-Bueno C, Martínez-Vizcaíno V, Notario-Pacheco B, Sequí-Dominguez I, Cavero-Redondo I. Are Advanced Glycation End Products in Skin Associated with Vascular Dysfunction Markers? A Meta-Analysis. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17186936. [PMID: 32972023 PMCID: PMC7559442 DOI: 10.3390/ijerph17186936] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 09/17/2020] [Accepted: 09/20/2020] [Indexed: 12/22/2022]
Abstract
Evidence exists regarding the association between advanced glycation end products and different cardiovascular disease subclinical processes, such as arterial stiffness and atherosclerosis. With this systematic review and meta-analysis, we aimed to provide a synthesis of the evidence regarding the association of arterial stiffness measured by pulse wave velocity and atherosclerosis measured by carotid intima media thickness with skin autofluorescence. A systematic search was performed using: MEDLINE (PubMed), SCOPUS, and Web of Science, until 30 March 2020. Cross-sectional studies or baseline data from prospective longitudinal studies were considered. The DerSimonian and Laird method was used to calculate the pooled estimates of correlation coefficients and the corresponding 95% confidence intervals (CI) for the association of pulse wave velocity and carotid intima media thickness with skin autofluorescence. Twenty-five studies were included in the systematic review and meta-analysis, including 6306 subjects. The pooled correlation coefficient was 0.25 (95% CI: 0.18, 0.31) for pulse wave velocity and skin autofluorescence, and 0.31 (95% CI: 0.25, 0.38) for carotid intima media thickness and skin autofluorescence. This systematic review and meta-analysis provide a synthesis of the evidence showing a positive weak association of pulse wave velocity and carotid intima media thickness with skin autofluorescence.
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Affiliation(s)
- Alicia Saz-Lara
- Health and Social Research Center, Universidad de Castilla-La Mancha, 16171 Cuenca, Spain; (A.S.-L.); (V.M.-V.); (B.N.-P.); (I.S.-D.); (I.C.-R.)
| | - Celia Álvarez-Bueno
- Health and Social Research Center, Universidad de Castilla-La Mancha, 16171 Cuenca, Spain; (A.S.-L.); (V.M.-V.); (B.N.-P.); (I.S.-D.); (I.C.-R.)
- Universidad Politécnica y Artística del Paraguay, 001518 Asuncion, Paraguay
- Correspondence:
| | - Vicente Martínez-Vizcaíno
- Health and Social Research Center, Universidad de Castilla-La Mancha, 16171 Cuenca, Spain; (A.S.-L.); (V.M.-V.); (B.N.-P.); (I.S.-D.); (I.C.-R.)
- Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, 3460000 Talca, Chile
| | - Blanca Notario-Pacheco
- Health and Social Research Center, Universidad de Castilla-La Mancha, 16171 Cuenca, Spain; (A.S.-L.); (V.M.-V.); (B.N.-P.); (I.S.-D.); (I.C.-R.)
| | - Irene Sequí-Dominguez
- Health and Social Research Center, Universidad de Castilla-La Mancha, 16171 Cuenca, Spain; (A.S.-L.); (V.M.-V.); (B.N.-P.); (I.S.-D.); (I.C.-R.)
| | - Iván Cavero-Redondo
- Health and Social Research Center, Universidad de Castilla-La Mancha, 16171 Cuenca, Spain; (A.S.-L.); (V.M.-V.); (B.N.-P.); (I.S.-D.); (I.C.-R.)
- Universidad Politécnica y Artística del Paraguay, 001518 Asuncion, Paraguay
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Shirakami T, Yamanaka M, Fujihara J, Matsuoka Y, Gohto Y, Obana A, Tanito M. Advanced Glycation End Product Accumulation in Subjects with Open-Angle Glaucoma with and without Exfoliation. Antioxidants (Basel) 2020; 9:E755. [PMID: 32824189 PMCID: PMC7465686 DOI: 10.3390/antiox9080755] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 08/11/2020] [Accepted: 08/14/2020] [Indexed: 11/16/2022] Open
Abstract
Advanced glycation end products (AGEs), which are the products of a non-enzymatic reaction between reducing sugars and other macromolecules, are critical in aging, as well as metabolic and degenerative diseases. To assess the involvement of AGEs in glaucoma, skin autofluorescence (sAF) level, which is a measurement of AGEs' accumulation, was compared among Japanese patients with glaucoma (316 with primary open-angle glaucoma (PG) and 127 exfoliation syndrome and glaucoma (EG)) and controls (133 nonglaucomatous controls) (mean age 71.6 ± 12.8 years, 254 men and 322 women). The sAF values were estimated from the middle fingertip using a 365 nm light-emitting diode for excitation and detection at 440 nm emission light. The estimated AGE values (arbitrary unit) were 0.56 ± 0.15, 0.56 ± 0.11, and 0.61 ± 0.11 in the control, PG, and EG groups, respectively (p < 0.0001, analysis of variance); and were significantly higher in the EG group than the control (p = 0.0007) and PG (p < 0.0001) groups. After adjustment for various demographic parameters by multivariate analyses, male sex (standard β = 0.23), EG (0.19), and diabetes (0.09) were associated with higher AGE levels; PG (-0.18) and smoking (-0.19) were associated with lower AGE levels. Age, visual acuity, intraocular pressure, glaucoma medications, lens status, and systemic hypertension were not associated with AGEs. The high AGE level in EG suggested that specific oxidation and glycation mechanisms underlie the glaucoma pathogenesis associated with pseudoexfoliation syndrome.
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Affiliation(s)
- Tomoki Shirakami
- Department of Ophthalmology, Shimane University Faculty of Medicine, Izumo 693-8501, Japan;
| | - Mikihiro Yamanaka
- Laboratory of Food and Regulation Biology, School of Agriculture, Tokai University, Kumamoto 862-8652, Japan;
| | - Jo Fujihara
- Division of Ophthalmology, Matsue Red Cross Hospital, Matsue 690-8506, Japan; (J.F.); (Y.M.)
| | - Yotaro Matsuoka
- Division of Ophthalmology, Matsue Red Cross Hospital, Matsue 690-8506, Japan; (J.F.); (Y.M.)
| | - Yuko Gohto
- Department of Ophthalmology, Seirei Hamamatsu General Hospital, Hamamatsu 430-8558, Japan; (Y.G.); (A.O.)
| | - Akira Obana
- Department of Ophthalmology, Seirei Hamamatsu General Hospital, Hamamatsu 430-8558, Japan; (Y.G.); (A.O.)
| | - Masaki Tanito
- Department of Ophthalmology, Shimane University Faculty of Medicine, Izumo 693-8501, Japan;
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Mukai H, Svedberg O, Lindholm B, Dai L, Heimbürger O, Barany P, Anderstam B, Stenvinkel P, Qureshi AR. Skin autofluorescence, arterial stiffness and Framingham risk score as predictors of clinical outcome in chronic kidney disease patients: a cohort study. Nephrol Dial Transplant 2019; 34:442-448. [PMID: 29378035 DOI: 10.1093/ndt/gfx371] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Accepted: 12/18/2017] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND The risk of cardiovascular disease (CVD) is predicted by Framingham's CVD risk scores (FRS) but the high CVD-related mortality in patients with chronic kidney disease (CKD) is only partially explained by traditional CVD risk markers. Therefore, there is a need to explore whether other CVD risk markers may improve risk prediction. Although arterial stiffness measured by augmentation index (AIx) and tissue content of advanced glycation end-products (AGEs) measured by skin autofluorescence (SAF) are two biomarkers that associate with CVD and mortality in CKD, it is not known how they compare with FRS. We evaluated associations between SAF, AIx and FRS, and their associations with CVD and mortality in CKD patients. METHODS SAF (AGE Reader) and AIx (SphygmoCor; adjusted for 75 heart beats per minute) were measured in 261 clinically stable and extensively phenotyped patients with CKD Stage 5 (median age 56 years, 66% male, 20% diabetes; 130 non-dialysed, 93 patients on peritoneal dialysis and 38 patients on haemodialysis). Multivariate receiver operator characteristics (ROC) curve analysis and multivariate Cox models followed by C-statistics were used to evaluate CVD-related and all-cause mortality risk associated with SAF, AIx and FRS during follow-up for median 25 months with 46 deaths. RESULTS In multivariate regression analysis, SAF associated with FRS, haemoglobin, fat body mass index and CVD, and inversely with per cent handgrip strength (HGS). AIx associated with FRS, and inversely with per cent HGS. Associations of SAF and AIx with high-sensitivity C-reactive protein (hsCRP), serum albumin, statin therapy and renal replacement therapy were not statistically significant. In ROC analysis, area under the curve (AUC) for CVD mortality ranged from AUC = 0.72 (AIx and FRS, respectively) to AUC = 0.78 (FRS + AIx), and for all-cause mortality from AUC = 0.70 (AIx) to AUC = 0.79 (FRS + AIx). In multivariate Cox analysis, after adjusting for 1-standard deviation (1-SD) of FRS, 1-SD increase of SAF associated with all-cause mortality and 1-SD increase of AIx associated with CVD mortality and all-cause mortality. After further adjustments for hsCRP, albumin and presence of CVD, AIx (but not SAF) remained independently associated with CVD mortality, hazard ratio (HR) 2.14 [95% confidence interval (95% CI) 1.18-3.89] and all-cause mortality, HR 1.74 (95% CI 1.16-2.60). CONCLUSIONS In patients with CKD Stage 5, SAF and aortic stiffness associated with mortality, independently of FRS. After adjusting for additional confounders including inflammation, aortic stiffness remained as an independent predictor of outcome. Since the contribution of SAF and aortic stiffness compared with FRS in ROC curve analysis was relatively modest, this underlines the importance of traditional CVD risk factors in CKD.
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Affiliation(s)
- Hideyuki Mukai
- Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Campus Flemingsberg, Stockholm, Sweden
| | - Oskar Svedberg
- Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Campus Flemingsberg, Stockholm, Sweden
| | - Bengt Lindholm
- Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Campus Flemingsberg, Stockholm, Sweden
| | - Lu Dai
- Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Campus Flemingsberg, Stockholm, Sweden
| | - Olof Heimbürger
- Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Campus Flemingsberg, Stockholm, Sweden
| | - Peter Barany
- Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Campus Flemingsberg, Stockholm, Sweden
| | - Björn Anderstam
- Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Campus Flemingsberg, Stockholm, Sweden
| | - Peter Stenvinkel
- Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Campus Flemingsberg, Stockholm, Sweden
| | - Abdul Rashid Qureshi
- Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Campus Flemingsberg, Stockholm, Sweden
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11
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Chen JH, Lin X, Bu C, Zhang X. Role of advanced glycation end products in mobility and considerations in possible dietary and nutritional intervention strategies. Nutr Metab (Lond) 2018; 15:72. [PMID: 30337945 PMCID: PMC6180645 DOI: 10.1186/s12986-018-0306-7] [Citation(s) in RCA: 119] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 09/21/2018] [Indexed: 02/08/2023] Open
Abstract
Advanced glycation end products (AGEs), a group of compounds that are formed by non-enzymatic reactions between carbonyl groups of reducing sugars and free amino groups of proteins, lipids or nucleic acids, can be obtained exogenously from diet or formed endogenously within the body. AGEs accumulate intracellularly and extracellularly in all tissues and body fluids and can cross-link with other proteins and thus affect their normal functions. Furthermore, AGEs can interact with specific cell surface receptors and hence alter cell intracellular signaling, gene expression, the production of reactive oxygen species and the activation of several inflammatory pathways. High levels of AGEs in diet as well as in tissues and the circulation are pathogenic to a wide range of diseases. With respect to mobility, AGEs accumulate in bones, joints and skeletal muscles, playing important roles in the development of osteoporosis, osteoarthritis, and sarcopenia with aging. This report covered the related pathological mechanisms and the potential pharmaceutical and dietary intervention strategies in reducing systemic AGEs. More prospective studies are needed to determine whether elevated serum AGEs and/or skin autofluorescence predict a decline in measures of mobility. In addition, human intervention studies are required to investigate the beneficial effects of exogenous AGEs inhibitors on mobility outcomes.
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Affiliation(s)
- Jie-Hua Chen
- Science and Technology Centre, By-Health Co. Ltd, No. 3 Kehui 3rd Street, No. 99 Kexue Avenue Central, Science City, Luogang District, Guangzhou, 510000 China
| | - Xu Lin
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031 China
| | - Cuihong Bu
- Science and Technology Centre, By-Health Co. Ltd, No. 3 Kehui 3rd Street, No. 99 Kexue Avenue Central, Science City, Luogang District, Guangzhou, 510000 China
| | - Xuguang Zhang
- Science and Technology Centre, By-Health Co. Ltd, No. 3 Kehui 3rd Street, No. 99 Kexue Avenue Central, Science City, Luogang District, Guangzhou, 510000 China
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12
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Yozgatli K, Lefrandt JD, Noordzij MJ, Oomen PHN, Brouwer T, Jager J, Castro Cabezas M, Smit AJ. Accumulation of advanced glycation end products is associated with macrovascular events and glycaemic control with microvascular complications in Type 2 diabetes mellitus. Diabet Med 2018; 35:1242-1248. [PMID: 29687658 DOI: 10.1111/dme.13651] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/17/2018] [Indexed: 01/08/2023]
Abstract
AIM The United Kingdom Prospective Diabetes Study (UKPDS) study showed that glycaemic control (HbA1c ) can predict vascular complications in Type 2 diabetes mellitus. The Diabetes Control and Complications Trial (DCCT) study showed that accumulation of advanced glycation end products (AGEs) from skin biopsies predicts vascular complications in Type 1 diabetes. Previously, we showed that tissue AGEs can be measured non-invasively using skin autofluorescence (SAF). The aim of this study was to compare the predictive value of HbA1c and SAF for new macrovascular events and microvascular complications in people with Type 2 diabetes. METHODS A prospective cohort study of 563 participants, median age 64 years [interquartile range (IQR) 57-72], diabetes duration of 13 years, from five Dutch hospitals was performed. RESULTS After a median follow-up of 5.1 (IQR 4.3-5.9) years, 79 (15%) participants had died and 49 (9%) were lost to follow-up. Some 133 (26%) developed a microvascular complication and 189 (37%) a macrovascular event. Tertiles of HbA1c were significantly associated with development of microvascular complications (log rank P = 0.022), but not with macrovascular events. Tertiles of SAF were significantly associated with macrovascular events (log rank P = 0.003). Cox regression analysis showed SAF was associated with macrovascular events: crude hazard ratio (HR) 1.53 (P < 0.001) per unit increase, HR 1.28 (P = 0.03) after correction for UKPDS score. HbA1c was predictive for microvascular complications: crude HR 1.20 (P = 0.004), HR 1.20 (P = 0.004) after correction for UKPDS score. CONCLUSION This study shows that tissue accumulation of AGEs, assessed by SAF, is associated with development of macrovascular events in people with Type 2 diabetes, whereas HbA1c is associated with the development of microvascular complications.
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Affiliation(s)
- K Yozgatli
- Department of Internal Medicine, University of Groningen, University Medical Centre Groningen
| | - J D Lefrandt
- Department of Internal Medicine, University of Groningen, University Medical Centre Groningen
| | - M J Noordzij
- Department of Internal Medicine, University of Groningen, University Medical Centre Groningen
| | - P H N Oomen
- Department of Internal Medicine, Medical Centre Leeuwarden
| | - T Brouwer
- Department of Internal Medicine, Onze Lieve Vrouwe Gasthuis, Amsterdam
| | - J Jager
- Department of Internal Medicine, Het Diakonessenhuis, Meppel
| | - M Castro Cabezas
- Department of Internal Medicine, Sint Franciscus Gasthuis Rotterdam, The Netherlands
| | - A J Smit
- Department of Internal Medicine, University of Groningen, University Medical Centre Groningen
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13
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The association between skin auto-fluorescence of palmoplantar sites and microvascular complications in Asian patients with type 2 diabetes mellitus. Sci Rep 2018; 8:6309. [PMID: 29679014 PMCID: PMC5910431 DOI: 10.1038/s41598-018-24707-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Accepted: 04/09/2018] [Indexed: 12/17/2022] Open
Abstract
Skin auto-fluorescence (SAF) has generated broad interest about the prospects for non-invasive advanced glycation end product assessment and its direct interplay with the development of microvascular complications, but clinical application of the existing SAF measuring of non-palmoplantar sites in non-Caucasian subjects with dark skin type is still controversial. Here, we tested the diabetic complication screening performance of a novel SAF measuring system in Asian type 2 diabetes mellitus (T2DM) subjects. A total of 166 Korean patients with T2DM were enrolled in this study and palmoplantar SAF was measured by a newly developed transmission-geometry noninvasive optical system. We found that transmitted SAF values of palmoplantar sites, 1st dorsal interossei muscles of the hand, in a complication group were significantly higher than in a non-complication group while no differences were observed between the two groups in reflected SAF of non-palmoplantar sites. The transmitted SAF values of palmoplantar sites were dramatically increased in subjects with multiple complications and were tightly correlated with the duration of microvascular complications. In conclusion, the SAF measurement in the palmoplantar sites with a non-invasive transmission-geometry optical system provided better microvascular complication screening performance compared to the SAF measurement of non-palmoplantar sites specifically in Asian T2DM subjects.
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14
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Da Moura Semedo C, Webb M, Waller H, Khunti K, Davies M. Skin autofluorescence, a non-invasive marker of advanced glycation end products: clinical relevance and limitations. Postgrad Med J 2017; 93:289-294. [PMID: 28143896 DOI: 10.1136/postgradmedj-2016-134579] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Revised: 12/20/2016] [Accepted: 01/08/2017] [Indexed: 11/03/2022]
Abstract
Advanced glycation end products (AGEs) are protein-bound compounds derived from glycaemic and oxidative stress that contain fluorescent properties, which can be non-invasively measured as skin autofluorescence (SAF) by the AGE Reader. SAF has been demonstrated to be a biomarker of cumulative skin AGEs and potentially may be a better predictor for the development of chronic complications and mortality in diabetes than glycated haemoglobin A1c. However, there are several confounding factors that should be assessed prior to its broader application: these include presence of other fluorescent compounds in the skin that might be measured (eg, fluorophores), skin pigmentation and use of skin creams. The aim of this article is to provide a theoretical background of this newly developed method, evaluate its clinical relevance and discuss the potential confounding factors that need further analysis.
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Affiliation(s)
- Cidila Da Moura Semedo
- The Leicester Diabetes Centre, University Hospitals of Leicester NHS Trust, Leicester General Hospital, Leicester, UK
| | - M'Balu Webb
- The Leicester Diabetes Centre, University Hospitals of Leicester NHS Trust, Leicester General Hospital, Leicester, UK.,NIHR Leicester-Loughborough Diet, Lifestyle and Physical Activity Biomedical Research Unit, University Hospitals of Leicester, Leicester General Hospital, Leicester, UK
| | - Helen Waller
- Diabetes Research Centre, University of Leicester, Leicester General Hospital, Leicester, UK
| | - Kamlesh Khunti
- The Leicester Diabetes Centre, University Hospitals of Leicester NHS Trust, Leicester General Hospital, Leicester, UK.,NIHR Leicester-Loughborough Diet, Lifestyle and Physical Activity Biomedical Research Unit, University Hospitals of Leicester, Leicester General Hospital, Leicester, UK.,Diabetes Research Centre, University of Leicester, Leicester General Hospital, Leicester, UK
| | - Melanie Davies
- The Leicester Diabetes Centre, University Hospitals of Leicester NHS Trust, Leicester General Hospital, Leicester, UK.,NIHR Leicester-Loughborough Diet, Lifestyle and Physical Activity Biomedical Research Unit, University Hospitals of Leicester, Leicester General Hospital, Leicester, UK.,Diabetes Research Centre, University of Leicester, Leicester General Hospital, Leicester, UK
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15
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The Course of Skin and Serum Biomarkers of Advanced Glycation Endproducts and Its Association with Oxidative Stress, Inflammation, Disease Severity, and Mortality during ICU Admission in Critically Ill Patients: Results from a Prospective Pilot Study. PLoS One 2016; 11:e0160893. [PMID: 27529340 PMCID: PMC4986948 DOI: 10.1371/journal.pone.0160893] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 07/26/2016] [Indexed: 12/31/2022] Open
Abstract
Background Advanced glycation end products (AGEs) have been implicated in multiple organ failure, predominantly via their cellular receptor (RAGE) in preclinical studies. Little is known about the time course and prognostic relevance of AGEs in critically ill human patients, including those with severe sepsis. Objective 1) To explore the reliability of Skin Autofluorescence (AF) as an index of tissue AGEs in ICU patients, 2) to compare its levels to healthy controls, 3) to describe the time course of AGEs and influencing factors during ICU admission, and 4) to explore their association with disease severity, outcome, and markers of oxidative stress and inflammation. Methods Skin AF, serum N"-(carboxyethyl)lysine (CEL), N"-(carboxymethyl)lysine (CML), and soluble RAGE (sRAGE) were serially measured for a maximum of 7 days in critically ill ICU patients with multiple organ failure and compared to age-matched healthy controls. Correlations with (changes in) clinical parameters of disease severity, LDL dienes, and CRP were studied and survival analysis for in-hospital mortality was performed. Results Forty-five ICU patients (age: 59±15 years; 60% male), and 37 healthy controls (59±14; 68%) were included. Skin AF measurements in ICU patients were reproducible (CV right-left arm: 13%, day-to-day: 10%), with confounding effects of skin reflectance and plasma bilirubin levels. Skin AF was higher in ICU patients vs healthy controls (2.7±0.7 vs 1.8±0.3 au; p<0.001). Serum CEL (23±10 vs, 16±3 nmol/gr protein; p<0.001), LDL dienes (19 (15–23) vs. 9 (8–11) μmol/mmol cholesterol; <0.001), and sRAGE (1547 (998–2496) vs. 1042 (824–1388) pg/ml; p = 0.003) were significantly higher in ICU patients compared to healthy controls, while CML was not different (27 (20–39) vs 29 (25–33) nmol/gr protein). While CRP and LDL dienes decreased significantly, Skin AF and serum AGEs and sRAGE did not change significantly during the first 7 days of ICU admission. CML and CEL were strongly correlated with SOFA scores and CML above the median at baseline was associated with increased risk for mortality (Hazard ratio 3.3 (1.3–8.3); p = 0.01). All other markers did not correlate with disease severity and did not predict mortality. Conclusions This study demonstrates that markers for the AGE-RAGE axis are elevated in critically ill patients compared to healthy controls but remain stable for at least 7 days despite clearly fading inflammation and oxidative stress. Circulating AGEs may be associated with disease severity and outcome. Further research should be conducted to elucidate the role of the AGE-RAGE axis in the exaggerated inflammatory response leading to multiple organ failure and death, and whether or not this may be a target for treatment.
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16
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Fokkens BT, Smit AJ. Skin fluorescence as a clinical tool for non-invasive assessment of advanced glycation and long-term complications of diabetes. Glycoconj J 2016; 33:527-35. [PMID: 27287226 PMCID: PMC4975757 DOI: 10.1007/s10719-016-9683-1] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Revised: 04/28/2016] [Accepted: 05/24/2016] [Indexed: 11/29/2022]
Abstract
Glycation is important in the development of complications of diabetes mellitus and may have a central role in the well-described glycaemic memory effect in developing these complications. Skin fluorescence has emerged over the last decade as a non-invasive method for assessing accumulation of advanced glycation endproducts. Skin fluorescence is independently related to micro- and macrovascular complications in both type 1 and type 2 diabetes mellitus and is associated with mortality in type 2 diabetes. The relation between skin fluorescence and cardiovascular disease also extends to other conditions with increased tissue AGE levels, such as renal failure. Besides cardiovascular complications, skin fluorescence has been associated, more recently, with other prevalent conditions in diabetes, such as brain atrophy and depression. Furthermore, skin fluorescence is related to past long-term glycaemic control and clinical markers of cardiovascular disease. This review will discuss the technique of skin fluorescence, its validation as a marker of tissue AGE accumulation, and its use as a clinical tool for the prediction of long-term complications in diabetes mellitus.
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Affiliation(s)
- Bernardina T Fokkens
- Department of Internal Medicine, University Medical Center Groningen (UMCG), Hanzeplein 1, 9713 GZ, Groningen, the Netherlands. .,Research Institute GUIDE, Graduate School of Medical Sciences, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, the Netherlands.
| | - Andries J Smit
- Department of Internal Medicine, University Medical Center Groningen (UMCG), Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.,Research Institute GUIDE, Graduate School of Medical Sciences, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, the Netherlands
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17
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Ahmad MS, Damanhouri ZA, Kimhofer T, Mosli HH, Holmes E. A new gender-specific model for skin autofluorescence risk stratification. Sci Rep 2015; 5:10198. [PMID: 25974028 PMCID: PMC4431468 DOI: 10.1038/srep10198] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Accepted: 04/07/2015] [Indexed: 11/08/2022] Open
Abstract
Advanced glycation endproducts (AGEs) are believed to play a significant role in the pathophysiology of a variety of diseases including diabetes and cardiovascular diseases. Non-invasive skin autofluorescence (SAF) measurement serves as a proxy for tissue accumulation of AGEs. We assessed reference SAF and skin reflectance (SR) values in a Saudi population (n = 1,999) and evaluated the existing risk stratification scale. The mean SAF of the study cohort was 2.06 (SD = 0.57) arbitrary units (AU), which is considerably higher than the values reported for other populations. We show a previously unreported and significant difference in SAF values between men and women, with median (range) values of 1.77 AU (0.79-4.84 AU) and 2.20 AU (0.75-4.59 AU) respectively (p-value « 0.01). Age, presence of diabetes and BMI were the most influential variables in determining SAF values in men, whilst in female participants, SR was also highly correlated with SAF. Diabetes, hypertension and obesity all showed strong association with SAF, particularly when gender differences were taken into account. We propose an adjusted, gender-specific disease risk stratification scheme for Middle Eastern populations. SAF is a potentially valuable clinical screening tool for cardiovascular risk assessment but risk scores should take gender and ethnicity into consideration for accurate diagnosis.
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Affiliation(s)
- Muhammad S. Ahmad
- Drug Metabolism Unit, King Fahad Medical Research Center, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
| | - Zoheir A. Damanhouri
- Drug Metabolism Unit, King Fahad Medical Research Center, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
- Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
| | - Torben Kimhofer
- Section of Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, SW7 2AZ, United Kingdom
| | - Hala H. Mosli
- Department of Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
| | - Elaine Holmes
- Drug Metabolism Unit, King Fahad Medical Research Center, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
- Section of Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, SW7 2AZ, United Kingdom
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18
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Kanufre VC, Soares RD, Alves MRA, Aguiar MJ, Starling ALP, Norton RC. Metabolic syndrome in children and adolescents with phenylketonuria. JORNAL DE PEDIATRIA (VERSÃO EM PORTUGUÊS) 2015. [DOI: 10.1016/j.jpedp.2014.06.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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19
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Kanufre VC, Soares RDL, Alves MRA, Aguiar MJB, Starling ALP, Norton RC. Metabolic syndrome in children and adolescents with phenylketonuria. J Pediatr (Rio J) 2015; 91:98-103. [PMID: 25458873 DOI: 10.1016/j.jped.2014.06.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2014] [Revised: 05/18/2014] [Accepted: 06/05/2014] [Indexed: 11/18/2022] Open
Abstract
OBJECTIVE This study aimed to identify markers of metabolic syndrome (MS) in patients with phenylketonuria (PKU). METHODS This was a cross-sectional study consisting of 58 PKU patients (ages of 4-15 years): 29 patients with excess weight, and 29 with normal weight. The biochemical variables assessed were phenylalanine (phe), total cholesterol, HDL-c, triglycerides, glucose, and basal insulin. The patients had Homeostasis Model Assessment (HOMA) and waist circumference assessed. RESULTS No inter-group difference was found for phe. Overweight patients had higher levels of triglycerides, basal insulin, and HOMA, but lower concentrations of HDL-cholesterol, when compared to the eutrophic patients. Total cholesterol/HDL-c was significantly higher in the overweight group. A positive correlation between basal insulin level and HOMA with waist circumference was found only in the overweight group. CONCLUSION The results of this study suggest that patients with PKU and excess weight are potentially vulnerable to the development of metabolic syndrome. Therefore, it is necessary to conduct clinical and laboratory monitoring, aiming to prevent metabolic changes, as well as excessive weight gain and its consequences, particularly cardiovascular risk.
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Affiliation(s)
- Viviane C Kanufre
- Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil; Hospital das Clínicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil; Núcleo de Ações e Pesquisa em Apoio Diagnóstico (NUPAD), Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil.
| | - Rosângelis D L Soares
- Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil; Hospital das Clínicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil; Núcleo de Ações e Pesquisa em Apoio Diagnóstico (NUPAD), Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Michelle Rosa A Alves
- Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil; Núcleo de Ações e Pesquisa em Apoio Diagnóstico (NUPAD), Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil; Pontifícia Universidade Católica de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Marcos J B Aguiar
- Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil; Hospital das Clínicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil; Núcleo de Ações e Pesquisa em Apoio Diagnóstico (NUPAD), Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Ana Lúcia P Starling
- Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil; Hospital das Clínicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil; Núcleo de Ações e Pesquisa em Apoio Diagnóstico (NUPAD), Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Rocksane C Norton
- Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil; Hospital das Clínicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil; Núcleo de Ações e Pesquisa em Apoio Diagnóstico (NUPAD), Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
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Tiessen AH, Jager W, ter Bogt NCW, Beltman FW, van der Meer K, Broer J, Smit AJ. Skin autofluorescence as proxy of tissue AGE accumulation is dissociated from SCORE cardiovascular risk score, and remains so after 3 years. Clin Chem Lab Med 2014; 52:121-7. [PMID: 23612547 DOI: 10.1515/cclm-2012-0825] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2012] [Accepted: 03/07/2013] [Indexed: 11/15/2022]
Abstract
BACKGROUND Skin autofluorescence (SAF), as a proxy of AGE accumulation, is predictive of cardiovascular (CVD) complications in i.a. type 2 diabetes mellitus and renal failure, independently of most conventional CVD risk factors. The present exploratory substudy of the Groningen Overweight and Lifestyle (GOAL)-project addresses whether SAF is related to Systematic COronary Risk Evaluation (SCORE) risk estimation (% 10-year CVD-mortality risk) in overweight/obese persons in primary care, without diabetes/renal disease, and if after 3-year treatment of risk factors (change in, Δ) SAF is related to ΔSCORE. METHODS In a sample of 65 participants from the GOAL study, with a body mass index (BMI) >25-40 kg/m2, hypertension and/or dyslipidemia, but without diabetes/renal disease, SAF and CVD risk factors were measured at baseline, and after 3 years of lifestyle and pharmaceutical treatment. RESULTS At baseline, the mean SCORE risk estimation was 3.1±2.6%, mean SAF 2.04±0.5AU. In multivariate analysis SAF was strongly related to age, but not to other risk factors/SCORE. After 3 years ΔSAF was 0.34±0.45 AU (p<0.001). ΔSAF was negatively related to Δbodyweight but not to ΔSCORE%, or its components. At follow-up, SAF was higher in 11 patients with a history of CVD compared to 54 persons without CVD (p=0.002). CONCLUSIONS Baseline and 3-year-Δ SAF are not related to (Δ)SCORE, or its components, except age, in the studied population. ΔSAF was negatively related to Δweight. As 3-year SAF was higher in persons with CVD, these results support a larger study on SAF to assess its contribution to conventional risk factors/SCORE in predicting CVD in overweight persons with low-intermediate cardiovascular risk.
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Arsov S, Graaff R, van Oeveren W, Stegmayr B, Sikole A, Rakhorst G, Smit AJ. Advanced glycation end-products and skin autofluorescence in end-stage renal disease: a review. Clin Chem Lab Med 2014; 52:11-20. [DOI: 10.1515/cclm-2012-0832] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2012] [Accepted: 03/08/2013] [Indexed: 11/15/2022]
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den Dekker MAM, Zwiers M, van den Heuvel ER, de Vos LC, Smit AJ, Zeebregts CJ, Oudkerk M, Vliegenthart R, Lefrandt JD, Mulder DJ. Skin autofluorescence, a non-invasive marker for AGE accumulation, is associated with the degree of atherosclerosis. PLoS One 2013; 8:e83084. [PMID: 24376641 PMCID: PMC3871581 DOI: 10.1371/journal.pone.0083084] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2013] [Accepted: 10/25/2013] [Indexed: 12/17/2022] Open
Abstract
Introduction Advanced glycation endproducts (AGEs) may be involved in the development of atherosclerosis, beyond diabetes and renal disease. Skin autofluorescence (AF) is a non-invasive marker for AGEs. We examined whether skin AF is increased in (subclinical) atherosclerosis and associated with the degree of atherosclerosis independent of diabetes and renal function. Methods A cross-sectional study of 223 patients referred for primary (n = 163) or secondary (n = 60) prevention between 2006 and 2012 was performed. Skin AF was measured using the AGE-Reader. Ultrasonography was used to assess plaques in carotid and femoral arteries and computed tomography for the calculation of the coronary artery calcium score (CACS; in primary prevention only). Primary prevention patients were divided into a group with subclinical atherosclerosis defined as >1 plaque or CACS>100 (n = 67; age 53 year [interquartile range 48–56]; 49% male) and without (controls; 96; 43 [38–51]; 55%). Secondary prevention were patients with peripheral arterial disease (60; 64 [58–70]; 73%). Results Skin AF was higher in subclinical and clinical atherosclerosis compared with controls (skin AF 2.11 [interquartile range 1.83–2.46] and 2.71 [2.15–3.27] vs. 1.87 [1.68–2.12] respectively; P = 0.005 and <0.001). In a multivariate analysis, the association of skin AF with the atherosclerosis categories was independent of age, sex, diabetes, presence of the metabolic syndrome, Framingham Risk Score, and renal function. Skin AF correlated with most cardiovascular risk factors, Framingham risk score, and IMT and CACS. Conclusions Skin AF is increased in documented subclinical and clinical atherosclerosis, independent of known risk factors such as diabetes and renal disease. These data suggest that AGEs may be associated with the burden of atherosclerosis and warrant a prospective study to investigate its clinical usability as a risk assessment tool for primary prevention.
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Affiliation(s)
- Martijn A. M. den Dekker
- Center for Medical Imaging – North East Netherlands, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Radiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Marjan Zwiers
- Department of Internal Medicine, Division of Vascular Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Edwin R. van den Heuvel
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Lisanne C. de Vos
- Department of Internal Medicine, Division of Vascular Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Andries J. Smit
- Department of Internal Medicine, Division of Vascular Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Clark J. Zeebregts
- Department of Surgery, Division of Vascular Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Matthijs Oudkerk
- Center for Medical Imaging – North East Netherlands, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Rozemarijn Vliegenthart
- Center for Medical Imaging – North East Netherlands, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Radiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Joop D. Lefrandt
- Department of Internal Medicine, Division of Vascular Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Douwe J. Mulder
- Department of Internal Medicine, Division of Vascular Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- * E-mail:
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Kasapkara ÇS, Tümer L, Biberoglu G, Kasapkara A, Hasanoğlu A. Asymmetric dimethylarginine (ADMA) and L-arginine levels in children with glycogen storage disease type I. J Pediatr Endocrinol Metab 2013; 26:427-31. [PMID: 23412857 DOI: 10.1515/jpem-2012-0306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2012] [Accepted: 12/16/2012] [Indexed: 11/15/2022]
Abstract
Patients with glycogen storage disease type I (GSD-I) often have marked hyperlipidemia with abnormal lipoprotein profiles. This metabolic abnormality improves, but is not fully corrected, with dietary therapy; therefore, these patients may be at high risk for the development of atherosclerosis. A recently discussed cardiovascular risk factor, asymmetric dimethylarginine (ADMA), a naturally occuring product of asymmetric methylation of proteins, is an endogenous inhibitor of endothelial nitric oxide synthase. ADMA causes endothelial dysfunction, vasoconstriction, blood pressure elevation, atherosclerosis, and kidney disease progression. A high prevalence of elevated plasma ADMA levels is observed in adults with hypercholesterolemia, hypertension, chronic kidney disease, diabetes mellitus, peripheral arterial disease, coronary artery disease, preeclampsia, heart failure, liver disease, stroke, and many other clinical disorders. Therefore, we aimed to evaluate the endothelial function in patients with GSD-I by using ADMA levels. High-performance liquid chromatography - based method was used for measuring ADMA and L-arginine levels in plasma. The ADMA level was similar between children with GSD-I and the age-matched healthy control group (0.9±0.28 vs. 1.1±0.45 μmol/L; p=0.18). The L-arginine plasma levels in patients with GSD-I were found to be 55.7±41.3 and 91.6±50.2 μmol/L in healthy controls. The preservation of normal endothelial function may result from diminished platelet aggregation, increased levels of apolipoprotein E, decreased susceptibility of low-density lipoprotein to oxidation (possibly related to the altered lipoprotein fatty acid profile in GSD-I), and increased antioxidative defenses in plasma protecting against lipid peroxidation.
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Affiliation(s)
- Çiğdem Seher Kasapkara
- Pediatric Metabolic Unit, Gazi University Medical School, Besevler, Ankara 06500, Turkey.
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Rocha JC, van Spronsen FJ, Almeida MF, Soares G, Quelhas D, Ramos E, Guimarães JT, Borges N. Dietary treatment in phenylketonuria does not lead to increased risk of obesity or metabolic syndrome. Mol Genet Metab 2012; 107:659-63. [PMID: 23137570 DOI: 10.1016/j.ymgme.2012.10.006] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2012] [Accepted: 10/09/2012] [Indexed: 01/10/2023]
Abstract
BACKGROUND Little is known about the consequences of the special energy enriched diet used to treat patients with phenylketonuria (PKU) in terms of obesity and metabolic syndrome (MetSyn) development. OBJECTIVE To investigate the prevalence of overweight and obesity, and its consequences in terms of body composition and MetSyn in early treated patients with PKU compared to controls. DESIGN A sample of 89 patients with PKU (3-30 y; 14.4±6.6 y) and 79 controls (3-47 y; 16.3±7.9 y) were studied. In the fasted state, anthropometric, body composition, blood pressure and analytical parameters [amino acids, glucose, insulin, total and HDL-cholesterol (HDL-c), triglycerides (TG), high sensitivity c-reactive protein and uric acid] were performed. Data on dietary intake was collected. BMI was classified using WHO criteria, while the definition from International Diabetes Federation (IDF) was used for MetSyn. RESULTS Prevalence of overweight and obesity (32.6% vs. 24.1%; p=0.293), body fat percentage (22% vs. 23.1%, p=0.581) and central obesity (36.9% vs. 36.4%, p=0.999) were comparable to controls. Patients revealed a higher TG/HDL-c (p<0.001). The prevalence of MetSyn was 1.5% and 6.1% in patients and controls, respectively. Patients and not controls with central obesity revealed a further significant increase in TG/HDL-c compared with those without central obesity (p=0.023). CONCLUSION Patients and controls were similar in terms of overweight and obesity, body composition and MetSyn. However, the dyslipidemia in patients with PKU in relation to overweight and obesity may help us trying to understand the course and the etiology of MetSyn not only in PKU but also in the general population.
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Affiliation(s)
- Júlio C Rocha
- Center of Medical Genetics Jacinto de Magalhães-INSA, IP, Porto, Portugal.
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25
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Jiang J, Chen P, Chen J, Yu X, Xie D, Mei C, Xiong F, Shi W, Zhou W, Liu X, Sun S, Zhang P, Yang X, Zhang Y, Zhang Y, Liang X, Zhang Z, Lin Q, Yu Y, Miyata T, Tian J, Liang M, Luo W, Xu X, Hou F. Accumulation of tissue advanced glycation end products correlated with glucose exposure dose and associated with cardiovascular morbidity in patients on peritoneal dialysis. Atherosclerosis 2012; 224:187-94. [PMID: 22857897 DOI: 10.1016/j.atherosclerosis.2012.06.022] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2012] [Revised: 06/08/2012] [Accepted: 06/12/2012] [Indexed: 12/23/2022]
Abstract
OBJECTIVES Accumulation of tissue advanced glycation end products (AGEs) is a marker of cumulative glycemic and/or oxidative stress. Cutaneous AGEs levels measured by skin autofluorescence correlate well with cardiovascular outcomes in diabetes and hemodialysis (HD) patients. The present study aimed to compare tissue AGEs levels with peritoneal dialysis (PD) and HD patients and to evaluate the relationship between skin autofluorescence and cardiovascular morbidity in patients on PD. METHODS A total of 2388 maintenance dialysis patients (613 PD and 1775 HD) were enrolled in this cross-sectional study. Skin autofluorescence was measured non-invasively with an autofluorescence reader. Cardiovascular morbidity was defined as clinically diagnosed ischemic heart disease, heart failure, stroke or peripheral vascular disease from initiation of dialysis. RESULTS More than 90% of patients on both PD and HD had met current dialysis adequacy targets. Compared to HD group, PD patients receiving conventional glucose-containing dialyzate had significantly higher skin autofluorescence values in each category of age and dialysis duration, irrespective of the presence or absence of diabetes. In PD patients, skin autofluorescence values were strongly correlated with the duration of PD and glucose exposure dose and independently associated with cardiovascular morbidity. Multivariate analysis revealed that glucose exposure dose and skin autofluorescence were the strongest risk factors for cardiovascular morbidity in PD patients after adjustment by age, gender, and other classic- or uremic-related risk factors. CONCLUSIONS Accumulation of tissue AGEs provides a potential link between PD exposure of metabolic stress and progression of cardiovascular disease in patients on PD.
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Affiliation(s)
- Jianping Jiang
- Division of Nephrology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, China
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Yue X, Hu H, Koetsier M, Graaff R, Han C. Reference values for the Chinese population of skin autofluorescence as a marker of advanced glycation end products accumulated in tissue. Diabet Med 2011; 28:818-23. [PMID: 21204956 DOI: 10.1111/j.1464-5491.2010.03217.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
AIM Advanced glycation end products play an important role in the pathophysiology of several chronic and age-related diseases, especially diabetes mellitus. Skin autofluorescence is a non-invasive method for assessing levels of tissue advanced glycation end products. This study aims to establish the normal reference value of advanced glycation end products accumulated in tissue measured by the advanced glycation end product reader--skin autofluorescence--and discusses some factors influencing it. METHODS The values of autofluorescence in healthy individuals in China were determined by the advanced glycation end product reader; age, gender, skin reflectance, smoking habits and alcohol consumption of the subjects were also recorded. RESULTS The mean reference values of autofluorescence in healthy Chinese subjects are (95% confidence interval) 20-29 years: 1.54-1.62 arbitrary units; 30-39 years: 1.66-1.75; 40-49 years: 1.78-1.89; 50-59 years: 1.87-2.03; 60-69 years: 1.86-2.09; 70-79 years: 1.97-2.31. The value of autofluorescence is strongly related to age, but no significant difference between males and females were found (all P > 0.05). Autofluorescence was higher in smokers than in non-smokers (P < 0.05). In persons with low skin reflectance (< 10%), skin autofluorescence was dependent on skin colour, but was still related to age. CONCLUSIONS The mean reference values of autofluorescence we established could be used for a Chinese population in a clinical setting and are agreement with those in a Caucasian population. Future developments are needed to make the advanced glycation end product reader reliable for lower skin reflections as well, independently of the skin colour.
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Affiliation(s)
- X Yue
- Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China
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Bhattacharya K. Dietary dilemmas in the management of glycogen storage disease type I. J Inherit Metab Dis 2011; 34:621-9. [PMID: 21491105 DOI: 10.1007/s10545-011-9322-8] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2011] [Revised: 03/16/2011] [Accepted: 03/21/2011] [Indexed: 10/18/2022]
Abstract
Over the last 50 years, understanding the biochemical bases of glycogen storage disease type I has led to vastly improved survival and health outcomes but the management still centres around an extremely intensive dietary regimen. Patients' metabolic profiles are really determined by the whole of the diet and it can be very difficult to adjust therapy accordingly. In an iso-energetic diet with reference total energy intake, high carbohydrate intake could compromise other macro- and micro-nutrients; if carbohydrates are not restricted then total energy intake is excessive. The quality of the macronutrient such as the glycemic index of carbohydrate, the type of sugar and the proportion of medium-chain triglyceride and essential fatty acids also has a bearing on an individual's long-term metabolic control with potential clinical correlates. These factors as well as the different requirements between individuals and within individuals as they get older mean that the management of glycogen storage disease type I is particularly fraught. Regular clinical and dietary review is imperative as patients grow, ensuring adequate but not excessive low glycaemic index carbohydrate intake, appropriate dynamic biochemical profiles and suitable age appropriate eating patterns. Without diligent management, and education that empowers the patient, these individuals can struggle in adult life.
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Mulder DJ, de Boer JF, Graaff R, de Vries R, Annema W, Lefrandt JD, Smit AJ, Tietge UJF, Dullaart RPF. Skin autofluorescence is inversely related to HDL anti-oxidative capacity in type 2 diabetes mellitus. Atherosclerosis 2011; 218:102-6. [PMID: 21665206 DOI: 10.1016/j.atherosclerosis.2011.05.011] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2011] [Revised: 04/19/2011] [Accepted: 05/09/2011] [Indexed: 11/25/2022]
Abstract
OBJECTIVE High density lipoprotein (HDL) particles protect apolipoprotein B-containing lipoproteins from oxidative modification. An impaired anti-oxidative functionality of HDL in type 2 diabetes mellitus (T2DM) may contribute to enhanced formation of oxidative stress products, such as Advanced Glycation Endproducts (AGEs). We tested whether in T2DM the HDL anti-oxidative capacity is related to the accumulation of AGEs in the skin. METHODS Skin autofluorescence (AF), a non-invasive read-out for AGEs, and HDL anti-oxidative capacity, i.e. the ability of HDL to protect against LDL oxidation in vitro, were assessed in 67 non-smoking T2DM patients without complications (median age: 60 (53-65), 60% males, 6.5 (5.2-8.5) years of diabetes duration). RESULTS In univariate analysis, skin AF correlated inversely with HDL anti-oxidative capacity (r=-0.305, P<0.02), but not with HDL cholesterol or apolipoprotein A-I. HDL anti-oxidative capacity correlated inversely with glucose, HbA(1c), triglycerides, and insulin resistance (homeostasis model assessment) (P<0.05 to P ≤ 0.001). Multiple linear regression showed that skin AF remained inversely related to HDL anti-oxidative capacity (partial r=-0.314, P=0.015) taking account of age, plasma glucose, non-HDL cholesterol, triglycerides, HOMA(ir), and CRP. CONCLUSION These findings suggest that skin AF is inversely related to the HDL anti-oxidative capacity rather than to the HDL cholesterol concentration in T2DM. Impaired anti-oxidative functionality of HDL could contribute to tissue accumulation of AGEs.
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Affiliation(s)
- Douwe J Mulder
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
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Lutgers HL, Graaff R, de Vries R, Smit AJ, Dullaart RPF. Carotid artery intima media thickness associates with skin autofluoresence in non-diabetic subjects without clinically manifest cardiovascular disease. Eur J Clin Invest 2010; 40:812-7. [PMID: 20597962 DOI: 10.1111/j.1365-2362.2010.02329.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND Skin autofluorescence (skin AF) is determined in part by accumulation of advanced glycation end products. Increased skin AF was shown previously to predict cardiovascular events independently of conventional risk factors. We determined the association of carotid artery intima media thickness (IMT), a marker of subclinical cardiovascular disease, with skin AF in subjects without diabetes or clinically manifest cardiovascular disease. METHODS In a cross-sectional observational study, IMT, skin AF, lipids and apolipoproteins, C-reactive protein (CRP), insulin resistance and paraoxonase-1 activity were measured in 59 non-smoking, non-obese subjects without diabetes mellitus and cardiovascular disease (32 women; 12 subjects with metabolic syndrome (MetS)). RESULTS In univariate analyses, skin AF was correlated with IMT (r = 0.265, P = 0.042), but not significantly with clinical factors, (apo)lipoproteins, CRP, insulin resistance and paraoxonase-1. In multiple linear regression analyses, IMT was determined independently by age (beta = 0.549, P < 0.001), apo B (beta = 0.236, P = 0.022) and skin AF (beta = 0.216, P = 0.035). IMT was also associated with skin AF (beta = 0.213, P = 0.046) in a model which included the presence of MetS. CONCLUSIONS IMT is positively related to skin AF, independently of clinical factors, (apo)lipoproteins and MetS, suggesting that skin AF represents a determinant of subclinical atherosclerosis. Increased skin AF may reflect early abnormalities in processes involved in atherosclerosis development.
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Affiliation(s)
- Helen L Lutgers
- Department of Endocrinology and Metabolism, University Medical Centre Groningen and University of Groningen, Groningen, The Netherlands.
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Coffeng SM, Blaauw J, Souwer ET, Rakhorst G, Smit AJ, Graaff R, van Doormaal JJ, Aarnoudse JG, Faas MM, van Pampus MG. Skin Autofluorescence as Marker of Tissue Advanced Glycation End-Products Accumulation in Formerly Preeclamptic Women. Hypertens Pregnancy 2010; 30:231-42. [DOI: 10.3109/10641955.2010.484085] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Koetsier M, Nur E, Chunmao H, Lutgers HL, Links TP, Smit AJ, Rakhorst G, Graaff R. Skin color independent assessment of aging using skin autofluorescence. OPTICS EXPRESS 2010; 18:14416-14429. [PMID: 20639927 DOI: 10.1364/oe.18.014416] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2023]
Abstract
Skin autofluorescence (AF) for the non-invasive assessment of the amount of accumulated tissue Advanced Glycation Endproducts (AGEs) increases with aging. In subjects with darker skin colors, measurements typically result in lower AF values than in subjects with fair skin colors, e.g. due to selective absorption by skin compounds. Our aim was to provide a new method for calculating skin AF, yielding values that are independent of skin color. The deviation of skin AF of healthy subjects with various darker skin types (N = 99) compared to reference values from Caucasians showed to be a function of various parameters that were derived from reflectance and emission spectra in the UV and visible range (adjusted R(2) = 80%). Validation of the new algorithm, based on these findings, in a separate dataset (N = 141) showed that results of skin AF can now be obtained to assess skin AGEs independently of skin color.
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Affiliation(s)
- M Koetsier
- Department of BioMedical Engineering, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands
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Koetsier M, Lutgers HL, de Jonge C, Links TP, Smit AJ, Graaff R. Reference values of skin autofluorescence. Diabetes Technol Ther 2010; 12:399-403. [PMID: 20388050 DOI: 10.1089/dia.2009.0113] [Citation(s) in RCA: 142] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
BACKGROUND Skin autofluorescence (AF) as measured with the AGE Reader (DiagnOptics Technologies, Groningen, The Netherlands) is a noninvasive prognostic marker in diabetes mellitus and other diseases with increased cardiovascular risk. This study provides reference values of healthy Caucasian control subjects as a function of age, tobacco smoking, and gender. METHODS The results of skin AF measured in 428 healthy Caucasian control subjects by the AGE Reader (n = 211) and its nonautomated but otherwise similar predecessor, the Autofluorescence Reader (n = 217), were analyzed. Linear regression analysis was performed to obtain reference values for skin AF as a function of age. Further analysis was performed on the effect of tobacco smoking (n = 96) and gender. RESULTS Skin AF was described by a linear increase with age of approximately 0.023 arbitrary units (AU) per year for subject age up to 70 years. Tobacco smoking was associated with an absolute increase of skin AF by 0.16 AU (P < 0.01), without a significant further increase with age (P = 0.17). Gender had no influence on skin AF in nonsmokers. Among current smokers, female subjects had a 0.2 AU higher skin AF than male subjects (P = 0.02), with no further age-related increase. CONCLUSIONS The present results provide reference values of skin AF for healthy Caucasian control subjects over a broad age range. A major contribution of age and some interaction of smoking and gender were observed, resulting in reference values of skin AF suitable for clinical settings and future studies.
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Affiliation(s)
- M Koetsier
- Department of BioMedical Engineering, University Medical Center Groningen and University of Groningen, The Netherlands
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Koren E, Lipkin J, Klar A, Hershkovitz E, Ginsburg I, Kohen R. Total oxidant-scavenging capacities of plasma from glycogen storage disease type Ia patients as measured by cyclic voltammetry, FRAP and luminescence techniques. J Inherit Metab Dis 2009; 32:651. [PMID: 19728140 DOI: 10.1007/s10545-009-1242-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2009] [Revised: 07/09/2009] [Accepted: 07/13/2009] [Indexed: 12/14/2022]
Abstract
It has been suggested that the very low incidence of atherosclerosis in glycogen storage disease type Ia (GSD Ia) subjects might be attributed to elevated levels of uric acid, one of the potent low molecular- weight antioxidants found in plasma. The present communication describes a use of two analytical methods-cyclic voltammetry and ferric reducing ability of plasma-and also two chemiluminescence methods to evaluate the total oxidant-scavenging capacities (TOSC) of plasma from GSD Ia patients. Our results verified the elevation of TOSC in GSD Ia patients and we propose the inclusion of luminescence and cyclic voltammetry assays as reliable methods for estimating TOSC in a variety of clinical disorders. Our findings with the cyclic voltammetry method add support to the assumption that the elevated uric acid levels might be the main contributor to plasma antioxidant capacity and possible protection against atherosclerosis.
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Affiliation(s)
- E Koren
- Department of Pharmaceutics, School of Pharmacy, Richard and Jean Zarbin Chair in Medical Studies, Hebrew University, Hadassah Faculty of Medicine, Jerusalem, 91120, Israel
| | - J Lipkin
- Department of Pediatrics, Bikur Cholim General Hospital, Jerusalem, Israel
| | - A Klar
- Department of Pediatrics, Bikur Cholim General Hospital, Jerusalem, Israel
| | - E Hershkovitz
- Pediatric Endocrinology & Metabolic Unit, Soroka Medical University Center, Beer Sheva, Israel
| | - I Ginsburg
- Faculty of Dental Medicine, Institute for Dental Sciences, Hebrew University, Hadassah Medical Center, Jerusalem, Israel
| | - R Kohen
- Department of Pharmaceutics, School of Pharmacy, Richard and Jean Zarbin Chair in Medical Studies, Hebrew University, Hadassah Faculty of Medicine, Jerusalem, 91120, Israel.
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Lutgers HL, Gerrits EG, Graaff R, Links TP, Sluiter WJ, Gans RO, Bilo HJ, Smit AJ. Skin autofluorescence provides additional information to the UK Prospective Diabetes Study (UKPDS) risk score for the estimation of cardiovascular prognosis in type 2 diabetes mellitus. Diabetologia 2009; 52:789-97. [PMID: 19274450 DOI: 10.1007/s00125-009-1308-9] [Citation(s) in RCA: 137] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2008] [Accepted: 01/30/2009] [Indexed: 12/22/2022]
Abstract
AIMS/HYPOTHESIS The UK Prospective Diabetes Study (UKPDS) risk engine has become a standard for cardiovascular risk assessment in type 2 diabetes mellitus. Skin autofluorescence was recently introduced as an alternative tool for cardiovascular risk assessment in diabetes. We investigated the prognostic value of skin autofluorescence for cardiovascular events in combination with the UKPDS risk engine in a cohort of patients with type 2 diabetes managed in primary care. METHODS Clinical, UKPDS risk engine and skin autofluorescence data were obtained at baseline in 2001-2002 in the type 2 diabetes group (n = 973). Follow-up data concerning fatal and non-fatal cardiovascular events (primary endpoint) were obtained till 2005. Patients were classified as 'low risk' when their 10 year UKPDS risk score for fatal cardiovascular events was <10%, and 'high risk' if >10%. Skin autofluorescence was measured non-invasively with an autofluorescence reader. Skin autofluorescence was classified by the median (i.e. low risk < median, high risk > median). RESULTS The incidence of cardiovascular events was 119 (44 fatal, 75 non-fatal). In multivariate analysis, skin autofluorescence, age, sex and diabetes duration were predictors for the primary endpoint. Addition of skin autofluorescence information to that from the UKPDS risk engine resulted in re-classification of 55 of 203 patients from the low-risk to the high-risk group. The 10 year cardiovascular event rate was higher in patients with a UKPDS score >10% when skin autofluorescence was above the median (55.8% vs 38.9%). CONCLUSIONS/INTERPRETATION Skin autofluorescence provides additional information to the UKPDS risk engine which can result in risk re-classification of a substantial number of patients. It furthermore identifies patients who have a particularly high risk for developing cardiovascular events.
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Affiliation(s)
- H L Lutgers
- Department of Internal Medicine, University Medical Center Groningen, Groningen, the Netherlands.
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Koetsier M, Lutgers H, Smit AJ, Links TP, Vries RD, Gans RO, Rakhorst G, Graaff R. Skin autofluorescence for the risk assessment of chronic complications in diabetes: a broad excitation range is sufficient. OPTICS EXPRESS 2009; 17:509-19. [PMID: 19158862 DOI: 10.1364/oe.17.000509] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
Skin autofluorescence (AF) is becoming an accepted clinical method for assessing the risk of chronic complications in diabetes mellitus (DM). In this study, the role of the excitation wavelength in the recognition of increased risk of diabetes-related chronic complications was investigated. An Excitation Emission Matrix Scanner (EEMS) was used to perform noninvasive measurements in four age-matched groups of patients with type 1 and type 2 DM, with and without chronic complications, as well as in a control group (N=97 in total). AF was calculated for excitation wavelengths in the range 355 - 405 nm. Mean spectra were assessed per group. AF values in both type 1 and type 2 DM patients with complications were increased compared to the control subjects (p < 0:01); this ratio remained practically constant, independent of the excitation wavelength. No emission peaks were distinctive for specific patient groups. We conclude that in these groups, no characteristic fluorophores dictate the use of a specific wavelength or set of wavelengths. The results show the validity of applying a broad excitation wavelength range for risk assessment of chronic complications in diabetes.
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Affiliation(s)
- M Koetsier
- Department of BioMedical Engineering, University Medical Center Groningen and University of Groningen,Groningen, The Netherlands
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