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Purpose of review Advanced glycation endproducts (AGE) have an important role in the development of chronic complications in diabetes mellitus and in renal failure. Skin autofluorescence (SAF) is a simple noninvasive optical technique to estimate AGE levels in the dermis. SAF increases with age, but rises more rapidly in diabetes and renal failure, and is also associated with, and a predictor of their complications. Recent findings In recent large population studies, SAF is a strong predictor of development of type 2 diabetes (T2D), and in persons with known diabetes of its complications. SAF also predicts new cardiovascular disease (CVD) and mortality not only in individuals with known type 2 diabetes but also in the general population. SAF is a simple, powerful and independent predictor for development of type 2 diabetes (T2D), and also for cardiovascular disease and mortality in both persons with diabetes, and in the general population.

Background: Physical activity (PA) has substantial health benefits and is important in combatting chronic diseases, which have been associated with elevated levels of advanced glycation endproducts (AGEs). AGEs play a role in the aging process, and an association between PA and AGEs has been reported. We aimed to investigate the relationship between PA and AGE accumulation in a general population and in a population with chronic diseases.Methods: This large cross-sectional population study used data from adult participants in the LifeLines project, with participant information drawn from the LifeLines database as well data from patients with diabetes mellitus or renal and/or cardiovascular diseases. Tissue AGE accumulation was assessed non-invasively by skin-autofluorescence (SAF) using an AGE reader (DiagnOptics Technologies BV, Groningen, the Netherlands). PA was assessed using the short questionnaire to assess health-enhancing physical activity (SQUASH). Multivariate linear regression analyses were adjusted for age, body mass index, sex, and smoking status.Results: Data from 63,452 participants (general population n = 59,177, chronic disease n = 4275) were analyzed. The general population was significantly younger (43.58 +/- 11.77 years, mean +/- SD) and had significantly lower SAF (1.90 +/- 0.42 arbitrary units (AU)) compared to the population with chronic disease (age: 55.51 +/- 12.07 years; SAF: 2.27 +/- 0.51 AU). In the group with chronic disease, more hours of moderate to vigorous physical activities per week were associated with lower SAF (beta= -0.002, 95% confidence interval (95%CI): -0.002 to -0.001). For the general population, there was no association between hours of moderate to vigorous activity and SAF (beta= 3.2 x 10(-5), 95%CI: 0.000-0.001, p = 0.742). However, there was an association in the general population between total hours of PA per week and SAF (beta= 4.2 x 10(-4), 95%CI: 0.000-0.001, p < 0.001), but this association was not found in the chronic disease population (beta = -3.2 x 10(-4), 95%CI: -0.001 to 0.000, p = 0.347).Conclusion: Our study demonstrates that an inverse relationship exists between PA and AGE accumulation in the population with chronic disease. More hours of moderate to vigorous activity is associated with a significantly decreased SAF. More PA is associated with a lower SAF, even after adjusting for the established predictors (age, body mass index, smoking status, and sex). Our findings could help to promote health and prolong longevity.

Background: Dicarbonyls are highly reactive compounds and major precursors of advanced glycation end products (AGEs). Both dicarbonyls and AGEs are associated with development of age-related diseases. Dicarbonyls are formed endogenously but also during food processing. To what extent dicarbonyls from the diet contribute to circulating dicarbonyls and AGEs in tissues is unknown.Objectives: To examine cross-sectional associations of dietary dicarbonyl intake with plasma dicarbonyl concentrations and skin AGEs.Methods: In 2566 individuals of the population-based Maastricht Study (age: 60 +/- 8 y, 50% males, 26% with type 2 diabetes), we estimated habitual intake of the dicarbonyls methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG) by combining FFQs with our dietary dicarbonyl database of MGO, GO, and 3-DG concentrations in> 200 commonly consumed food products. Fasting plasma concentrations of MGO, GO, and 3-DG were measured by ultra-performance liquid chromatography-tandem mass spectrometry. Skin AGEs were measured as skin autofluorescence (SAF), using theAGE Reader. Associations of dietary dicarbonyl intake with their respective plasma concentrations and SAF (all standardized) were examined using linear regression models, adjusted for age, sex, potential confounders related to cardiometabolic risk factors, and lifestyle.Results: Median intake of MGO, GO, and 3-DG was 3.6, 3.5, and 17 mg/d, respectively. Coffee was the main dietary source of MGO, whereas this was bread for GO and 3-DG. In the fully adjusted models, dietary MGO was associated with plasma MGO (beta: 0.08; 95% CI: 0.02, 0.13) and SAF (beta: 0.12; 95% CI: 0.07, 0.17). Dietary GO was associated with plasma GO (beta: 0.10; 95% CI: 0.04, 0.16) but not with SAF. 3-DG was not significantly associated with either plasma 3-DG or SAF.Conclusions: Higher habitual intake of dietary MGO and GO, but not 3-DG, was associated with higher corresponding plasma concentrations. Higher intake of MGO was also associated with higher SAF. These results suggest dietary absorption of MGO and GO. Biological implications of dietary absorption of MGO and GO need to be determined. The study has been approved by the institutional medical ethical committee (NL31329.068.10) and the Minister of Health, Welfare and Sports of the Netherlands (Permit 131088-105234-PG).

Background:Arterial stiffening is a hallmark of vascular ageing and a consequence of many diseases including diabetes mellitus. Methylglyoxal (MGO), a highly reactive α-dicarbonyl mainly formed during glycolysis, has emerged as a potential contributor to the development of arterial stiffness. MGO reacts with arginine and lysine residues in proteins to form stable advanced glycation endproducts (AGEs). AGEs may contribute to arterial stiffening by increased cross-linking of collagen within the extracellular matrix (ECM), by altering the vascular structure, and by triggering inflammatory and oxidative pathways. Although arterial stiffness is mainly determined by ECM and vascular smooth muscle cell function, the effects of MGO and MGO-derived AGEs on these structures have not been thoroughly reviewed to date. Methods and results:We conducted a PubMed search without filtering for publication date which resulted in 16 experimental and 22 clinical studies eligible for inclusion. Remarkably, none of the experimental and only three of the clinical studies specifically mentioned MGO-derived AGEs. Almost all studies reported an association between arterial stiffness and AGE accumulation in the arterial wall or increased plasma AGEs. Other studies report reduced arterial stiffness in experimental models upon administration of AGE-breakers. Conclusions:No papers published to date directly show an association between MGO or MGO-derived AGEs and arterial stiffening. The relevance of the various underlying mechanisms is not yet clear, which is particularly due to methodological challenges in the detection of MGO and MGO-derived AGEs at the molecular, intra- and pericellular, and structural levels, as well as in challenges in the assessment of intrinsic arterial wall properties at ECM- and tissue levels.

Background The accumulation of advanced glycation end products (AGEs) occurring in skin tissues can be measured as skin autofluorescence (SAF). Here, we assessed the correlation between SAF values and the complexity and severity of type 2 diabetes mellitus (T2DM) complications. Methods The basic clinical information of 825 patients with T2DM was collected through an electronic system, and SAF was measured by adapting a DM-Scan, a non-invasive optical signal detector. Diabetic complications were diagnosed based on clinical criteria by experienced doctors. Linear regression analysis was used to evaluate the independent determinants of SAF, and multiple logistic regression analysis was performed to assess independent determinants that influence the severity of the complications. Results SAF was significantly associated with the complexity of T2DM complications. Similarly, independent relationships between SAF and age (β = 0.389, P β = − 2.221, P = 0.004), 2-h C-peptide (β = − 0.182, P = 0.017), aminotransferase (ALT, β = − 0.158, P = 0.041), blood creatinine (BCr, β = 0.206, P = 0.009), and fatty liver (β = 0.161, P = 0.026) were observed. With the increasing number of complications, the SAF values increased significantly after adjusting for related risk factors. The SAF values correlated with diabetic retinopathy, diabetic kidney diseases, cardiovascular disease, and diabetic peripheral neuropathy when compared with patients without any T2DM-associated complications. Moreover, the AGE-based diabetic complication risk score for each complication demonstrated a relationship with the presence or absence of certain complications. Conclusion SAF is an independent marker for diabetic retinopathy, diabetic kidney diseases, cardiovascular disease, and diabetic peripheral neuropathy, and it is also a predictor of the complexity of T2DM complications. Moreover, the diabetic complication risk score is capable of predicting the risk of diabetic complications in patients with T2DM.

Stiffening of large arteries, clinically manifesting as increased aortic pulse wave velocity (PWV), is an inevitable outcome of aging. Among other mechanisms, impaired glucose metabolism plays an important role, leading to the deposition of advanced glycation end products (AGEs). This process is counterbalanced by the circulating soluble receptor for AGEs (sRAGE). We investigated the association between arterial stiffness on one side and multiple circulating biomarkers and the degree of skin deposition of AGEs on the other. In a cross-sectional design, 867 participants based on a general population sample (Czech post-MONICA studies) were examined. PWV was measured by SphygmoCor device (AtCor Medical Ltd.), while skin AGEs were measured using a dedicated autofluorescence method (AGE Reader mu®). To quantify the circulating status of AGEs, carboxymethyl lysine (CML) and sRAGE concentrations were assessed by ELISA, along with conventional glucose metabolism indicators. When analyzing the whole sample using multiple linear or logistic regression models and after adjustment for potential covariates, a significant association with PWV was found for fasting glycemia, HbA1c, sRAGE, skin AGEs, and the skin AGE-to-sRAGE ratio. Among these parameters, stepwise models identified the strongest association for the skin AGEs and AGE-to-sRAGE ratio, and this was also true when diabetic subjects were excluded. In contrast, neither CML nor its ratio relative to sRAGE showed any association with arterial stiffness. In conclusion, skin AGEs along with their ratio relative to sRAGE were closely associated with arterial stiffness and is a better indicator of the current status of deposited AGEs than other relevant factors.

Background Accumulation of advanced glycation end-products (AGEs) in skeletal muscle has been implicated in development of sarcopenia. Aim To obtain further insight in the pathophysiology of sarcopenia, we studied its relationship with skin AGEs in the general population. Methods In a cross-sectional analysis, 2744 participants of northern European background, mean age 74.1 years, were included from the Rotterdam Study. Skin AGEs were measured as skin autofluorescence (SAF) using AGE ReaderTM, appendicular skeletal mass index (ASMI) using insight dual-energy X-ray absorptiometry, hand grip strength (HGS) using a hydraulic hand dynamometer, and, in a subgroup, gait speed (GS) measured on an electronic walkway (n = 2080). We defined probable sarcopenia (low HGS) and confirmed sarcopenia (low HGS and low ASMI) based on the European Working Group on Sarcopenia in Older People (EWGSOP2) revised criteria cutoffs. Multivariate linear and logistic regression were performed adjusting for age, sex, body fat percentage, height, renal function, diabetes, and smoking status. Results The prevalence of low ASMI was 7.7%; probable sarcopenia, 24%, slow GS, 3%; and confirmed sarcopenia, 3.5%. SAF was inversely associated with ASMI [β −0.062 (95% CI −0.092, −0.032)], HGS [β −0.051 (95% CI −0.075, −0.026)], and GS [β −0.074 (95% CI −0.116, −0.033)]. A 1-unit increase in SAF was associated with higher odds of probable sarcopenia [odds ratio (OR) 1.36 (95% CI 1.09, 1.68)] and confirmed sarcopenia [OR 2.01 (95% CI 1.33, 3.06)]. Conclusion Higher skin AGEs are associated with higher sarcopenia prevalence. We call for future longitudinal studies to explore the role of SAF as a potential biomarker of sarcopenia.

Background: An autofluorescence (AF) reader can be used to diagnose skin AF non-invasively by measuring local accumulation of advanced glycation end-products. A number of studies have investigated the relationships between skin AF and cardiovascular disease. However, data regarding the usefulness of skin AF as a predictor of chronic heart failure remain limited. This prospective study aimed to elucidate the usefulness of skin AF as a predictor of first heart failure (HF) hospitalization in patients with HF with preserved ejection fraction (HFpEF). Methods: A total of 412 outpatients with HFpEF with no history of HF hospitalization were enrolled. Patients were assigned to either the low (group L; skin AF =¥ 3.0 AU; n = 109) group according to optimal skin AF cut-off levels determined using receiver operating characteristic curves. Clinical parameters and the usefulness of skin AF as a predictor of first HF hospitalization were evaluated. Results: The E/e’ ratio as a marker of left ventricular diastolic function was significantly higher in group H patients than in group L patients at baseline (group H, 11.8 ± 3.8; group L, 10.6 ± 3.3; P = 0.002). During the 72.7-month follow-up period, 43 HF cases were hospitalized (group L, 15 cases; group H, 28 cases; P < 0.001, log-rank test). Multivariate Cox regression analyses revealed that group H exhibited a significantly higher risk of first HF hospitalization than did group L (hazard ratio, 2.26; 95% confidence interval, 1.21 - 3.52; P = 0.014). Conclusions: The present study demonstrated that skin AF can predict the risk of first HF hospitalization in patients with HFpEF. Prospective studies, including intervention therapies, are required to validate our observations. Cardiol Res. 2020;11(4):247-255 doi: https://doi.org/10.14740/cr1097

Introduction An increase over time in skin autofluorescence (SAF), a measure of accumulation of advanced glycation end products (AGE), predicts higher mortality on hemodialysis (HD). However, evidence is lacking regarding factors that contribute to changes in SAF over time in populations on dialysis. We investigated the rate of change in SAF over 1 year and the factors associated with these changes. Methods We enrolled 109 patients on HD and 28 on peritoneal dialysis in a prospective study. SAF was measured at baseline, 3, 6, 9, and 12 months. Rate of change in SAF was calculated using the SLOPE function in Microsoft Excel (Microsoft, Redmond, WA). Participants were then grouped into those with stable SAF or increasing SAF. Dietary AGE intake and nutritional assessments were performed at baseline, 6, and 12 months. Results The mean SAF trend observed was an increase of 0.30 ± 0.63 arbitrary units (AU) per year, but this varied from a decrease of 0.15 ± 0.44 to an increase of 0.76 ± 0.42 AU per year in stable and increasing SAF groups, respectively. Increasing SAF was more common in participants who developed malnutrition during the observation period, whereas those who became well-nourished were more likely to have stable SAF (8 [80%] vs. 14 [42%]; P = 0.02). Development/prevalence of malnutrition over 1 year, HD as first dialysis modality, and current smoking were independent predictors of increasing SAF. Conclusion SAF increases over time in most persons on dialysis. Independent determinants of increasing SAF were development/prevalence of malnutrition, HD as first dialysis modality, and current smoking. Strategies to reduce/prevent the rise in SAF, including prevention/correction of malnutrition, should be investigated in prospective studies., Graphical abstract

Aims/hypothesis Reactive α-dicarbonyl compounds are major precursors of AGEs and may lead to glycation of circulating and/or cell-associated complement regulators. Glycation of complement regulatory proteins can influence their capacity to inhibit complement activation. We investigated, in a human cohort, whether greater dicarbonyl stress was associated with more complement activation. Methods Circulating concentrations of dicarbonyl stress markers, i.e. α-dicarbonyls (methylglyoxal [MGO], glyoxal [GO] and 3-deoxyglucosone [3-DG]), and free AGEs (Nε-(carboxymethyl)lysine [CML], Nε-(carboxyethyl)lysine [CEL] and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine [MG-H1]), and protein-bound AGEs (CML, CEL, pentosidine), as well as the complement activation products C3a and soluble C5b-9 (sC5b-9), were measured in 530 participants (59.5 ± 7.0 years [mean ± SD], 61% men) of the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study. Multiple linear regression analyses were used to investigate the associations between dicarbonyl stress (standardised) and complement activation (standardised) with adjustment of potential confounders, including age, sex, lifestyle, use of medication and markers of obesity. In addition, the associations of two potentially functional polymorphisms (rs1049346, rs2736654) in the gene encoding glyoxalase 1 (GLO1), the rate-limiting detoxifying enzyme for MGO, with C3a and sC5b-9 (all standardized) were evaluated. Results After adjustment for potential confounders, plasma concentration of the dicarbonyl GO was inversely associated with sC5b-9 (β −0.12 [95% CI –0.21, −0.02]) and the protein-bound AGE CEL was inversely associated with C3a (−0.17 [−0.25, −0.08]). In contrast, the protein-bound AGE pentosidine was positively associated with sC5b-9 (0.15 [0.05, 0.24]). No associations were observed for other α-dicarbonyls and other free or protein-bound AGEs with C3a or sC5b-9. Individuals with the AG and AA genotype of rs1049346 had, on average, 0.32 and 0.40 SD lower plasma concentrations of sC5b-9 than those with the GG genotype, while concentrations of C3a did not differ significantly between rs1049346 genotypes. GLO1 rs2736654 was not associated with either C3a or sC5b-9. Conclusions/interpretation Plasma concentrations of dicarbonyl stress markers showed distinct associations with complement activation products: some of them were inversely associated with either C3a or sC5b-9, while protein-bound pentosidine was consistently and positively associated with sC5b-9. This suggests different biological relationships of individual dicarbonyl stress markers with complement activation.

Aim To determine the relationship between bone microarchitecture, as measured by trabecular bone score, and advanced glycation end-product accumulation, as assessed by skin autofluorescence. Methods This was a cross-sectional study. Participants were 64 post-menopausal women with type 2 diabetes and 175 post-menopausal women without diabetes. Trabecular bone score and skin autofluorescence data were obtained at time of bone density measurement. Results Trabecular bone score and skin autofluorescence were inversely correlated in women with type 2 diabetes (r = -0.34, P = 0.006); no correlation was seen in post-menopausal women without diabetes (r = -0.029, P = 0.707). After adjustment, neither skin autofluorescence nor a diagnosis of diabetes were associated with trabecular bone score, but HbA1c and waist circumference were independently associated with trabecular bone score. Conclusion Skin autofluorescence did not predict trabecular bone score. In contrast, glycaemia, as reflected by HbA1c , and visceral adiposity, as reflected by waist circumference, were independently associated with trabecular bone score.

Objective This study aimed to evaluate the influence of advanced glycation end-product (AGE) accumulation on the prevalence and severity of overactive bladder (OAB) in community-dwelling elderly adults. Methods We conducted a cross-sectional study involving 269 Japanese community dwellers aged ≥75 years in 2015. AGE accumulation was non-invasively measured via skin autofluorescence (SAF) values using AGE Reader. The primary and secondary outcomes were the presence and severity of OAB evaluated using the Overactive Bladder Symptom Score (OABSS). Individuals with an urgency score of ≥2 and sum score of ≥3 were considered to have OAB. The associations of SAF with the prevalence and severity of OAB were assessed using logistic and linear regression models, respectively, adjusted for clinically important confounders. Results The median age of participants was 78 years. Of 269 participants, 110 (40.9%) were men and 75 (27.9%) had OAB. The median SAF was 2.2 AU (arbitrary units). Increasing median SAF was observed with increasing age. Multivariable analysis revealed that SAF was not associated with either the likelihood of having OAB (odds ratio per 1 AU = 0.77, 95% confidence interval: 0.37–1.62) or the natural log-transformed OABSS (β per 1 AU = −0.07, 95% confidence interval: −0.26–0.12). Conclusions In this study, AGE accumulation, as assessed by SAF, was not associated with the prevalence and severity of OAB in Japanese community-dwelling elderly people aged ≥75 years.

Advanced glycation end-products (AGEs), which bind to type 1 collagen in bone and skin, have been implicated in reduced bone quality. The AGE reader™ measures skin autofluorescence (SAF), which might be regarded as a marker of long-term accumulation of AGEs in tissues. We investigated the association of SAF with bone mineral density (BMD) and fractures in the general population. We studied 2853 individuals from the Rotterdam Study with available SAF measurements (median age, 74.1 years) and with data on prevalent major osteoporotic (MOFs: hip, humerus, wrist, clinical vertebral) and vertebral fractures (VFs: clinical + radiographic Genant’s grade 2 and 3). Radiographs were assessed 4 to 5 years before SAF. Multivariate regression models were performed adjusted for age, sex, BMI, creatinine, smoking status, and presence of diabetes and additionally for BMD with interaction terms to test for effect modification. Prevalence of MOFs was 8.5% and of VFs 7%. SAF had a curvilinear association with prevalent MOFs and VFs and therefore, age-adjusted, sex stratified SAF quartiles were used. The odds ratio (OR) (95% confidence interval [CI]) of the second, third and fourth quartiles of SAF for MOFs were as follows: OR 1.60 (95% CI, 1.08–2.35; p = .02); OR 1.30 (95% CI, 0.89–1.97; p = .20), and OR 1.40 (95% CI, 0.95–2.10; p = .09), respectively, with first (lowest) quartile as reference. For VFs the ORs were as follows: OR 1.69 (95% CI, 1.08–2.64; p = .02), OR 1.74(95% CI, 1.11–2.71; p = .01), and OR 1.73 (95% CI, 1.12–2.73; p = .02) for second, third, and fourth quartiles, respectively. When comparing the top three quartiles combined with the first quartile, the OR (95% CI) for MOFs was 1.43 (95% CI, 1.04–2.00; p = .03) and for VFs was 1.72 (95% CI, 1.18–2.53; p = .005). Additional adjustment for BMD did not change the associations. In conclusion, there is evidence of presence of a threshold of skin AGEs below which there is distinctly lower prevalence of fractures. Longitudinal analyses are needed to confirm our cross-sectional findings. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Skin autofluorescence (sAF) represents tissue accumulation of advanced glycation end products (AGEs) and correlates with cardiovas-cular morbidity and diabetes risk.To assess sAF in Polish children without diabetes and to investigate whether sAF values in children with chronic diseases (but without glucose metabolism disorders) differ from sAF in healthy children.Children without diseases known to influence sAF results (diabetes, renal failure) and with HbA1c5.7% (39 mmol/mol) were includ-ed, and the total study group was divided into two subgroups: with and without chronic conditions. Skin autofluorescence was meas-ured with an AGE Reader (Diagnoptics BV, Groningen, Netherlands). Data were presented as medians; Mann-Whitney U-test, Kruskall Wallis test, and Spearman's correlation coefficients were used in statistical analyses.The study group included 86 children (41 girls; mean age 10.1 ±4.2 years). Median sAF was 1.20 AU (25th-75th centile: 1.06-1.30). There was a positive correlation between sAF and age (R = 0.37, p = 0.0005). Skin autofluorescence values were higher in children with chronic diseases than in healthy children (1.23 AU [25th-75th centile: 1.10-1.40], n = 51 vs. 1.16 AU [1.06-1.26], n = 36, p = 0.0272).To our knowledge we present the first data on sAF values in Polish children without glucose metabolism disorders. We suggest that larger, homogenous populations of different ages should be studied to determine if and which diseases affect sAF measurements, and to develop pediatric reference values for sAF. This will allow a wider use of sAF measurement in the assessment of cardiovascular risk in the paediatric population.Autofluorescencja skóry (skin autofluorescence – sAF) odzwierciedla zawartość końcowych produktów zaawansowanej glikacji (ad-vanced glycation end products – AGEs) w organizmie i wyniki jej pomiaru korelują z obecnością i nasileniem zaburzeń metabolizmu glukozy i z występowaniem chorób sercowo-naczyniowych.Ocena sAF u polskich dzieci oraz zbadanie, czy wartości sAF u dzieci z chorobami przewlekłymi (ale bez zaburzeń metabolizmu gluko-zy) różnią się od wartości sAF u dzieci zdrowych.Badaniami objęto dzieci z prawidłowym stężeniem hemoglobiny glikowanej [HbA1c5,7% (39 mmol/mol)]. Grupę badaną podzielono na dwie podgrupy: dzieci z chorobami przewlekłymi (z wykluczeniem chorób o znanym wpływie na sAF – cukrzyca, niewydolność nerek) oraz dzieci zdrowych. Pomiar sAF wykonywano w sposób nieinwazyjny, za pomocą urządzenia AGE Reader (Diagnoptics BV, Groningen, Holandia). Wyniki przedstawiono jako mediany; w analizie statystycznej wykorzystano test U Manna-Whitneya, test Kru-skalla Wallisa oraz współczynniki korelacji Spearmana.Grupę badaną stanowiło 86 dzieci (41 dziewczynek i 45 chłopców; średni wiek 10,1 ±4,2 roku) – 36 dzieci zdrowych i 51 ze schorze-niami przewlekłymi (u większości rozpoznano choroby alergiczne, choroby krwi, choroby tarczycy). Mediana sAF wynosiła 1,20 AU (25.–75. centyl: 1,06–1,30). Stwierdzono dodatnią korelację między sAF a wiekiem (R = 0,37, p = 0,0005). Wartości sAF były wyższe u dzieci z chorobami przewlekłymi niż u dzieci zdrowych [1,23 AU (25.–75. centyl: 1,10–1,40) vs 1,16 AU (1,06–1,26) p = 0,0272].Zgodnie z wiedzą autorów jest to pierwsze podsumowanie prezentujące wartości sAF u polskich dzieci w różnym wieku, bez zaburzeń metabolizmu glukozy. Wskazane są dalsze badania obejmujące większe, jednorodne populacje, które pozwolą ocenić, czy i jakie choroby wpływają na wyniki pomiaru sAF i umożliwią opracowanie wartości referencyjnych sAF dla polskiej populacji pediatrycznej. Pozwoli to na szersze zastosowanie pomiarów sAF w ocenie ryzyka sercowo-naczyniowego u dzieci.

Background/aim: Obesity, diabetes mellitus, and metabolic syndrome (MetS) are associated with increased accumulated skin advanced glycation end products. We aimed to evaluate the association of MetS components with skin autofluorescence (SAF) in patients with morbid obesity. Material and methods: Eight hundred and one patients with morbid obesity and 94 age-matched controls with normal body mass index (BMI) and normal glucose metabolism were included. Advanced glycation end products (AGEs) were measured using SAF in the forearm, with an AGE reader. Results: The prevalence of MetS in patients with morbid obesity was 65.5% (n = 525). Type 2 diabetes mellitus (type 2 DM) and hypertension were present in 40.9% (n = 328) and 43.7% (n = 357). Patients with morbid obesity and those with MetS had higher SAF measurements compared with the control group, 1.85 ± 0.44 arbitrary unit (AU) and 1.86 ± 0.43 AU vs. 1.72 ± 0.30 AU, respectively (p = 0.016). There was no difference in SAF levels between patients with and without MetS. SAF measurements of patients without MetS were not statistically different from the control group (p = 0.076). Patients with five MetS criteria had higher SAF measurements compared with patients with fewer MetS components (p = 0.019). There was no difference in SAF levels between patients with type 2 DM, impaired glucose metabolism, and patients with normal glucose metabolism (p = 0.513). Conclusion: Although MetS and type 2 DM are known as factors related to increased SAF levels, obesity can cause elevated SAF measurements in different ways independent of concomitant comorbid diseases. Larger studies with longer follow-ups are needed to enlighten the underlying mechanism.

Background: Advanced glycation end products (AGE), one of the main factors causing diabetic end-organ damage, accumulate in long half-life proteins, such as skin and cartilage collagen. AGE measurement may offer additional evidence to predict diabetic vascular complications. Skin autofluorescence (SAF) is suggested as a non-invasive, quick, and reliable method to measure tissue AGE level. The aim of this study was to review and evaluate evidence on the clinical validation of SAF measurement in diabetes mellitus (DM) patients. Methods: In this systematic review and meta-analysis, we searched ''PubMed'' (MEDLINE) and ''Cochrane'' databases from their inception to 10 August 2021 for observational studies concerning SAF measurement in diabetic patients. The following key terms were used in advanced searching: “Diabetes”, “Diabetes Mellitus”,” DM”, “Glycation “, “Advanced Glycation End product”, “AGE”, “skin autofluorescence”, “SAF”. Published studies that included DM patients and estimated their AGE using SAF were considered eligible for meta-analysis. Articles that were editorials, study proposals, congress posters, or case reports and were not on human subjects were excluded. We used a random-effect models for meta-analyzing the clinical validation of SAF in DM with particular emphasis on chronic diabetes complications. Findings: We identified 881 records and twenty-nine records fulfilled our eligibility criteria and were included in the systematic review and meta-analysis. A statistically significant correlation was found between SAF and diabetes last HbA1c 0.21(0.13,0.28) in studies with substantial heterogeneity (I2=77.99%, p

Background and aims Advanced glycation end products (AGEs) are reported to be correlated with diabetic vascular complications. This study aimed to investigate the association between AGEs and carotid atherosclerosis (CAS) as a surrogate marker of cardiovascular disease (CVD). Methods and results A total of 1006 patients with type 2 diabetes were included. CAS was defined as the presence of carotid arterial atherosclerotic plaque in any of bilateral carotid artery segments measured by ultrasonography. AGEs were measured by the noninvasive skin autofluorescence method. AGEage index was calculated as AGEs × age/100. Patients with CAS showed a significantly higher AGEage (P Conclusion AGEage, the noninvasive measurement of AGEs combined with age is a promising approach for triaging patients at high risk of CVDs.

Aims To investigate association between skin autofluorescence (SAF) and cardiovascular events (CVE) and assess its predictive value in Chinese adults with type 2 diabetes (T2D). Materials and methods SAF was measured non-invasively in 3806 Chinese adults with T2D between 2016 and 2019 with CVE as primary endpoint and individual components as secondary endpoints. Cox proportional hazard models were used to examine associations between SAF and endpoints with adjustment for conventional risk factors. C-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI) were performed to evaluate SAF's predictive value. Results During a median 1.8 (interquartile range, 1.2–3.1) years of follow-up, 172 individuals experienced CVE. Multivariate Cox model showed that SAF was independently associated with CVE (HR 1.18 per SD, 95% CI [1.02, 1.37]), coronary heart disease (HR 1.29 per SD, 95% CI [1.02, 1.63]), and congestive heart failure (HR 1.53 per SD, 95% CI [1.14, 2.05]). SAF yielded additional value on CVE risk stratification with enhanced IDI (95% CI) (0.023 [0.001, 0.057]) and continuous NRI (0.377 [0.002, 0.558]) over traditional risk factors. Conclusions Higher SAF was independently associated with CVE in Chinese adults with T2D and yielded incremental predictive information for CVE. SAF has potential as a prognostic maker for CVE.

Background: Skin autofluorescence has been used to assess longer term glycemic control and risk of complications. There is however no agreed site at which autofluorescence should be measured. This study evaluated the within- and between-site agreement in measurement of skin autofluorescence using a noninvasive advanced glycation end product (AGE) reader. Methods: Overall, 132 participants were included: 16 with diabetes-related foot ulcers (DFU), 63 with diabetes but without foot ulcers (DMC), 53 without diabetes or foot ulcers (HC). Skin autofluorescence was measured using the AGE Reader (DiagnOptics technologies BV, the Netherlands). Three consecutive skin autofluorescence measurements were each performed at six different body sites: the volar surfaces of both forearms (arms), dorsal surfaces of both calves (legs), and plantar surfaces of both feet (feet). Within- and between-site agreements were analyzed with concordance correlation coefficients (CCC) and 95% confidence intervals (95% CI), absolute mean differences (±standard deviation), and Bland-Altman limits of agreement. Results: The agreement between repeat assessments at the same site was almost perfect (CCC [95% CI] ranging from 0.94 [0.91-0.96] for assessments in the right foot to 0.99 [0.99-0.99] for assessments in the left arm). The limits of agreement were narrow within ±0.5 arbitrary units for all sites. The between-site agreement in measurements was poor (CCC < 0.65) with large maximum absolute mean differences (±SD) in arbitrary units (DFU = 3.40 [±2.04]; DMC = 3.15 [±2.45]; HC = 2.72 [±1.83]) and wide limits of agreement. Conclusions: Skin autofluorescence measurements can be repeated at the same site with adequate repeatability but measurements at different sites in the same patient have marked differences. The reason for this variation across sites and whether this has any role in diabetes-related complications needs further investigation.

Background Recent clinical studies have demonstrated the importance of skin autofluorescence as a cardiovascular risk factor. However, data regarding the relationship between skin autofluorescence and atrial fibrillation are limited. The aim of this study was to clarify the clinical significance of skin autofluorescence in elderly patients with long-standing persistent atrial fibrillation. Methods This cross-sectional study enrolled 112 elderly patients with long-standing persistent atrial fibrillation who were treated medically (46 men and 66 women; mean age, 81 ± 9 years). The association between skin autofluorescence and various clinical parameters was examined. Results Significant relationships were observed between skin autofluorescence and CHADS2 score (r = 0.53, P < 0.001), high-sensitivity cardiac troponin T level (r = 0.43, P < 0.001), reactive oxygen metabolite levels (r = 0.52, P < 0.001), and whole blood passage time (r = 0.45, P < 0.001). Furthermore, multiple regression analyses showed that these clinical parameters were independent variables when skin autofluorescence was used as a subordinate factor. Receiver-operating characteristic curve analysis indicated that the risk values of skin autofluorescence for high CHADS2 scores (≥ 2) or elevated high-sensitivity cardiac troponin T levels (> 0.014ng/mL) were 2.6 arbitrary units (AU) and 2.7 AU, respectively. Conclusions The findings of this study indicated that skin autofluorescence may be a prognostic factor in elderly patients with long-standing persistent atrial fibrillation. The risk value of skin autofluorescence was considered as 2.6 AU or 2.7 AU.

Background Recent clinical studies have indicated the importance of low blood testosterone concentration or whole blood passage time (WBPT) which reflects blood rheology as a cardiovascular risk factor. On the contrary, there are no reports regarding the association of blood testosterone concentrations and WBPT. This cross-sectional study aimed to elucidate the clinical significance of low blood testosterone concentration in men as a cardiovascular risk factor from the perspective of blood rheology using WBPT. Methods In total, 382 male patients with traditional cardiovascular risk factor and no history of cardiovascular disease (age (mean ± standard deviation (SD)), 64 ± 10 years) were enrolled. Serum total testosterone concentration (T-T) was measured as a marker of testosterone level in vivo, and WBPT was also measured using microchannel array flow analyzer as a commercial device. The relationship between T-T and WBPT was evaluated. Results There was a significantly negative correlation between T-T and WBPT (r = -0.45; P < 0.001). Furthermore, multiple regression analysis revealed that T-T (β = -0.25; P < 0.001) could be selected as an independent variable when WBPT was used as a subordinate factor. According to receiver operating characteristic curve analysis and the result of the previous report that determined WBPT of > 72.4 s as a risk for incidence of primary cardiovascular disease, T-T of < 551.4 ng/dL is the optimal cut-off point for discriminating high WBPT. Conclusions The study results showed that T-T is independently and inversely associated with WBPT in male patients with traditional cardiovascular risk factor and no history of cardiovascular disease. In addition, this study suggests that the incidence of primary cardiovascular events can be prevented by maintaining T-T at approximately ≥ 550 ng/dL from the perspective of blood rheology.

AIM To evaluate the association between skin advanced glycation end products and insulin resistance in Type 1 diabetes. METHODS The study group consisted of 476 people with Type 1 diabetes (247 men) with a median (interquartile range) age of 42 (33-53) years, disease duration of 24 (19-32) years and HbA1c concentration of 63 (55-74) mmol/mol [7.9 (7.2-8.9)%]. Insulin resistance was assessed according to estimated glucose disposal rate. Advanced glycation product accumulation in the skin was measured by autofluorescence using an AGE Reader. The group was divided into three subgroups based on estimated glucose disposal rate tertiles ( 9.5 mg/kg/min, respectively). The higher the estimated glucose disposal rate, the lower the insulin resistance. RESULTS Skin autofluoresence level decreased with increasing estimated glucose disposal rate; comparing people below the lower tertile, with those between the first and third tertiles, and with those above the third tertile, the median autofluoresences were, respectively: 2.5 (2.2-2.9) vs 2.3 (2.0-2.7) vs 2.1 (1.9-2.5) AU (P

AIM: Advanced glycation end-products (AGEs) have been involved in the atherogenic process in the high-risk population. The goal of this study was to demonstrate that AGEs are related to subclinical atheromatous disease in subjects with low to moderate vascular risk. METHODS: A cross-sectional study in which 2,568 non-diabetic subjects of both sexes without cardiovascular disease were included. Subcutaneous content of AGEs was assessed by skin autofluorescence (SAF) and subclinical atheromatous disease was measured by assessing the atheromatous plaque burden in carotid and femoral regions using ultrasonography. In addition, serum pentosidine, carboxymethyl-lysine (CML) and AGE receptors (RAGE) were assessed in a nested case-control study with 41 subjects without plaque and 41 individuals subjects with generalized disease. RESULTS: Patients with atheromatous plaque had a higher SAF than those with no plaque (1.9 [1.7 to 2.3] vs. 1.8 [1.6 to 2.1] arbitrary units (AU), p＜0.001). The SAF correlated with the total number of affected regions (r= 0.171, p＜0.001), increasing progressively from 1.8 [1.6 to 2.1] AU in those without atheromatous disease to 2.3 [1.9 to 2.7] AU in patients with ≥ 8 plaques (p＜0.001). A correlation was also observed between SAF and the total plaque area (r=0.113, p＜0.001). The area under the Receiver Operating Characteristic curve was 0.65 (0.61 to 0.68) for identifying male subjects with atheromatous disease. The multivariable logistic regression model showed a significant and independent association between SAF and the presence of atheromatous disease. However, no significant differences in serum pentosidine, CML, and RAGE were observed. CONCLUSIONS: Increased subcutaneous content of AGEs is associated with augmented atheromatous plaque burden. Our results suggest that SAF may provide clinically relevant information to the current strategies for the evaluation of cardiovascular risk, especially among the male population. This work was supported by grants from the Diputació de Lleida, Instituto de Salud Carlos III (Action Plan II14//00008), Fundación de la Sociedad Española de Endocrinología y Nutrición (FSEEN), Esteve Laboratory, Generalitat de Catalunya (2017SGR696 and SLT0021600250), IRBLleida Biobank (B.0000682) and Plataforma Biobancos PT13/0010/0014. CIBER de Diabetes y Enfermedades Metabólicas Asociadas and CIBER de Enfermedades Respiratorias are initiatives of the Instituto de Salud Carlos III. These organizations had no role in study design, the collection, analysis and interpretation of data, report writing, or the decision to submit the article for publication. The authors declare that there are no relationships with industry relevant to this manuscript.

Aim: The level of accumulated advanced glycation end-products (AGEs) in the skin has been shown to predict the risk of complications in patients with diabetes mellitus (DM). Recently, the level of accumulated fluorescent AGEs in the skin has become measurable as skin autofluorescence (skin AF) using a non-invasive apparatus, autofluorescence reader. The purpose of this study was to evaluate the association between skin AF and the subclinical atherosclerosis markers, especially endothelial dysfunction, in patients with DM. Methods: We enrolled 140 Japanese subjects with DM who attended Osaka University Hospital, and measured the skin level of AGEs by skin AF and three subclinical atherosclerosis markers: endothelial function by flow-mediated vasodilation, FMD; carotid intima-media thickness, IMT; and brachial-ankle pulse wave velocity, baPWV. Results: FMD was significantly associated with skin AF (r = −0.259, p = 0.002). Furthermore, a stepwise multivariate regression analysis revealed that skin AF was an independent determinant of FMD (β = −0.180, p = 0.038). Although there were significant associations between skin AF and maximum carotid intima-media thickness (max-IMT)(r = 0.298, p < 0.001) as well as baPWV (r = 0.284, p = 0.001) in univariate analysis, skin AF was not an independent determinant of either carotid max-IMT or baPWV after adjustment for conventional cardiovascular risk factors. Receiver-operating characteristic curve analysis revealed that skin AF can identify the subjects whose FMD, max-IMT, and baPWV were completely within the normal range (C-statistics, 0.73; 95% confidence interval, 0.61–0.84; p < 0.001). Conclusions: Skin AF was independently associated with FMD as an indicator of endothelial dysfunction, and can be utilized as a screening marker of atherosclerosis in Japanese patients with DM.

Background: Decline in physical activity and functioning is commonly observed in the older population and might be associated with biomarkers such as advanced glycation end products (AGEs). AGEs contribute to age-related decline in the function of cells and tissues in normal aging and have been found to be associated with motor function decline. The aim of this study is to investigate the association between the levels of AGEs, as assessed by skin autofluorescence, and the amount of physical activity and loss of physical functioning in older participants.Methods: Cross-sectional data of 5,624 participants aged 65 years and older from the LifeLines Cohort Study were used. Linear regression analyses were utilized to study the associations between skin autofluorescence/AGE levels (AGE Reader), the number of physically active days (SQUASH), and physical functioning (RAND-36). A logistic regression analysis was used to study the associations between AGE levels and the compliance with the Dutch physical activity guidelines (SQUASH).Results: A statistical significant association between AGE levels and the number of physically active days (beta = -0.21, 95% confidence interval: -0.35 to -0.07,p = .004), physical functioning (beta = -1.60, 95% confidence interval: -2.64 to -0.54, p = .003), and compliance with the Dutch physical activity guidelines (odds ratio = 0.76, 95% confidence interval: 0.62 to 0.94, p = .010) was revealed.Conclusions: This study indicates that high AGE levels may be a contributing factor as well as a biomarker for lower levels of physical activity and functioning in the older population.

Background: The cardio-ankle vascular index (CAVI) is a physiological indicator of arterial elasticity. However, limited information regarding the clinical significance of the CAVI in patients with hypercholesterolemia is available. This cross-sectional study aimed to elucidate the clinical significance of the CAVI for the primary prevention of cardiovascular disease (CVD) among postmenopausal women with hypercholesterolemia. Methods: A total of 168 untreated postmenopausal hypercholesterolemic women (low-density lipoprotein cholesterol levels ? 140 mg/dL, mean age ± standard deviation, 63 ± 10 years) with no history of CVD events were enrolled. The CAVI was measured using commercial devices, after which, its relationships with various clinical parameters, such as carotid artery ultrasonography findings and CVD biomarkers, were examined. Results: A significant positive correlation was observed between the CAVI and maximum intima-media thickness of the common carotid artery (max-C-IMT), which was evaluated using carotid artery ultrasonography (r = 0.49, P < 0.001). Regarding CVD biomarkers, the CAVI was significantly correlated with estimated glomerular filtration rate (r = -0.18, P < 0.001), high-sensitivity C-reactive protein (r = 0.36, P < 0.001), whole blood passage time as a marker of blood rheology (r = 0.41, P < 0.001), and skin autofluorescence as a marker of advanced glycation end products in tissues (r = 0.46, P < 0.001), although no significant correlation was noted between serum lipid parameters and the CAVI. Multiple regression analysis identified max-C-IMT (? = 0.35, P < 0.001), whole blood passage time (? = 0.18, P = 0.007), skin autofluorescence (? = 0.17, P = 0.011), and age (? = 0.16, P = 0.018) as variables independently associated with CAVI. Conclusion: The present study indicated that the CAVI is an essential CVD risk factor among postmenopausal women with hypercholesterolemia. Moreover, impaired blood rheology and increase of skin autofluorescence were associated with elevated CAVI in such patients. J Clin Med Res. 2021;13(5):276-282 doi: https://doi.org/10.14740/jocmr4509

Catestatin (CST) is a pleiotropic peptide involved in cardiovascular protection with its antihypertensive and angiogenic effects. Considering that patients with end-stage renal disease (ESRD) who are undergoing hemodialysis (HD) are associated with higher cardiovascular risk, the aim of this study was to investigate plasma CST levels in HD patients, compare them to healthy controls and evaluate possible CST associations with advanced glycation end products (AGEs) and laboratory, anthropometric and clinical parameters. The study included 91 patients on HD and 70 healthy controls. Plasma CST levels were determined by an enzyme-linked immunosorbent assay in a commercially available diagnostic kit, while AGEs were determined using skin autofluorescence. Plasma CST levels were significantly higher in the HD group compared to the controls (32.85 ± 20.18 vs. 5.39 ± 1.24 ng/mL, p &lt, 0.001) and there was a significant positive correlation between CST and AGEs (r = 0.492, p &lt, 0.001). Furthermore, there was a significant positive correlation between plasma CST levels with both the Dialysis Malnutrition Score (r = 0.295, p = 0.004) and Malnutrition-Inflammation Score (r = 0.290, p = 0.005). These results suggest that CST could be playing a role in the complex pathophysiology of ESRD/HD and that it could affect the higher cardiovascular risk of patients on HD.

Background Advanced glycation end-products are proteins that become glycated after contact with sugars and are implicated in endothelial dysfunction and arterial stiffening. We aimed to investigate the relationships between advanced glycation end-products, measured as skin autofluorescence, and vascular stiffness in various glycemic strata. Methods We performed a cross-sectional analysis within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort, comprising n = 3535 participants (median age 67 years, 60% women). Advanced glycation end-products were measured as skin autofluorescence with AGE-Reader™, vascular stiffness was measured as pulse wave velocity, augmentation index and ankle-brachial index with Vascular Explorer™. A subset of 1348 participants underwent an oral glucose tolerance test. Participants were sub-phenotyped into normoglycemic, prediabetes and diabetes groups. Associations between skin autofluorescence and various indices of vascular stiffness were assessed by multivariable regression analyses and were adjusted for age, sex, measures of adiposity and lifestyle, blood pressure, prevalent conditions, medication use and blood biomarkers. Results Skin autofluorescence associated with pulse wave velocity, augmentation index and ankle-brachial index, adjusted beta coefficients (95% CI) per unit skin autofluorescence increase: 0.38 (0.21; 0.55) for carotid-femoral pulse wave velocity, 0.25 (0.14; 0.37) for aortic pulse wave velocity, 1.00 (0.29; 1.70) for aortic augmentation index, 4.12 (2.24; 6.00) for brachial augmentation index and − 0.04 (− 0.05; − 0.02) for ankle-brachial index. The associations were strongest in men, younger individuals and were consistent across all glycemic strata: for carotid-femoral pulse wave velocity 0.36 (0.12; 0.60) in normoglycemic, 0.33 (− 0.01; 0.67) in prediabetes and 0.45 (0.09; 0.80) in diabetes groups; with similar estimates for aortic pulse wave velocity. Augmentation index was associated with skin autofluorescence only in normoglycemic and diabetes groups. Ankle-brachial index inversely associated with skin autofluorescence across all sex, age and glycemic strata. Conclusions Our findings indicate that advanced glycation end-products measured as skin autofluorescence might be involved in vascular stiffening independent of age and other cardiometabolic risk factors not only in individuals with diabetes but also in normoglycemic and prediabetic conditions. Skin autofluorescence might prove as a rapid and non-invasive method for assessment of macrovascular disease progression across all glycemic strata.

Background Skin autofluorescence (SAF) is a non-invasive marker of tissue accumulation of advanced glycation endproducts (AGE). Recently, we demonstrated in the general population that elevated SAF levels predict the development of type 2 diabetes (T2D), cardiovascular disease (CVD) and mortality. We evaluated whether elevated SAF may predict the development of CVD and mortality in individuals with T2D. Methods We included 2349 people with T2D, available baseline SAF measurements (measured with the AGE reader) and follow-up data from the Lifelines Cohort Study. Of them, 2071 had no clinical CVD at baseline. 60% were already diagnosed with diabetes (median duration 5, IQR 2–9 years), while 40% were detected during the baseline examination by elevated fasting blood glucose ≥7.0 mmol/l) and/or HbA1c ≥6.5% (48 mmol/mol). Results Mean (±SD) age was 57 ± 12 yrs., BMI 30.2 ± 5.4 kg/m2. 11% of participants with known T2D were treated with diet, the others used oral glucose-lowering medication, with or without insulin; 6% was using insulin alone. Participants with known T2D had higher SAF than those with newly-detected T2D (SAF Z-score 0.56 ± 0.99 vs 0.34 ± 0.89 AU, p p p p Conclusions Measuring SAF can assist in prediction of incident cardiovascular disease and mortality in individuals with T2D. SAF showed a stronger association with future CVD events and mortality than cholesterol or blood pressure levels.

Introduction: Offspring born to women with type 1 diabetes pregnancies have an elevated risk for early-onset obesity and type 2 diabetes compared with offspring born to women without diabetes. Skin autofluorescence (SAF) is a marker of accumulated advanced glycation end products (AGEs) and it has been shown to predict type 2 diabetes, cardiovascular disease, and mortality in the general population. The aim of this study was to evaluate whether maternal type 1 diabetes influences the SAF value in young adult offspring. Methods: This cross-sectional case-control study included 78 offspring of women with type 1 diabetes (cases) and 85 control participants (controls). All study participants, aged 18-23 years, were invited to participate in a clinical assessment including laboratory tests and questionnaires. SAF was assessed using the AGE reader from the dominant forearm of each participant. Results: The mean SAF value did not differ between the cases (1.61 [standard deviation (SD) 0.37]) arbitrary units [AU]) and the controls (1.64 [SD 0.41] AU) (p = 0.69). After adjusting for glycated hemoglobin A(1c), body fat percentage, smoking, and season the mean SAF value did not differ between the cases and the controls (p = 0.49) but differed between men and women (p = 0.008), without any interaction observed (p = 0.78). Conclusion: SAF values did not differ between the young adult offspring of women with type 1 diabetes and offspring born to mothers without diabetes. Surprisingly, young adult women showed higher SAF values than men in both case and control groups.

AIM: To measure skin autofluorescence in youth (

Background and objectives: Chronic obstructive pulmonary disease (COPD) is associated with systemic inflammation and oxidative stress. These physiological processes can lead to increased formation and accumulation of advanced glycation end-products (AGEs), that can play a role in vascular complications. In this crosssectional study, we determined the association between skin AGEs and microvascular health in patients with COPD.Methods: Clinical characteristics and cardiovascular parameters, including pulmonary function, metabolic and inflammatory parameters, and blood pressure, were obtained in this observational study with patients with COPD. Skin concentrations of AGEs were assessed non-invasively by measuring skin autofluorescence (AF). Retinal vessel analysis was used as a marker of microvascular health.Results: 62 patients with COPD (52% males; mean age: 64.4 +/- 8.4 years; mean FEV1: 45.0 +/- 20.7%pred.) were analysed. Mean skin AF was 2.75 +/- 0.64 arbitrary units. Skin AF in patients with COPD was negatively associated with retinal arteriolar diameter (beta -0.021, 95% CI -0.040 to -0.002; p = 0.031) and arteriole-to-venular ratio (beta -7.233, 95% CI -9.732 to -4.734; p Conclusion: We document for the first time that skin AF in patients with COPD is independently associated with retinal arteriolar and venular vessel diameters, biological indicators for microvascular health. This adds to the evidence that AGEs are an accessible marker of microvascular health.

Advanced glycation end products (AGEs) were reported to be associated with diabetes development and diabetes related complications when accumulated in high levels. This study investigated the association between AGEs and diabetic retinopathy (DR).A total of 1,471 patients with type 2 diabetes were enrolled. Fundus radiography was used for DR measurement. AGEs were detected through non-invasive skin autofluorescence method.Patients with more advanced DR showed a much higher AGEs, and the prevalence of DR (based on the severity) increase with ascending AGEs quartiles (all P for trend 0.001). The multivariable-adjusted odds ratios of any DR across AGEs quartiles were 1.00, 1.69 (95% confidence interval [CI] 1.16-2.47), 1.58 (95%CI 1.06-2.37) and 1.60 (95%CI 1.05-2.44) (P for trend = 0.044), respectively. Similar results were found in vision-threatening DR (VTDR) subgroup (P for trend = 0.009). When AGEs was considered as a continuous variable by using restricted cubic splines, a graded positive association of AGEs with the odds of any presence of DR was observed (P for trend 0.001). Further, we found that AGEs presented the similar predictive value for any DR with glycated hemoglobin ANon-invasive measured skin AGEs, associated with the prevalence of all stages of DR, might be a more suitable indicator than HbA

Advanced glycation end products (AGEs) are thought to play important roles in the pathogenesis of diabetic microangiopathy, particularly in the progression of diabetic retinopathy (DR). We assessed the levels of skin autofluorescence (sAF) to assess the association between AGEs and DR stages. A total of 394 eyes of 394 Japanese subjects (172 men, 222 women, mean age &plusmn, standard deviation [SD], 68.4 &plusmn, 13.7 years) comprised the study population, i.e., subjects with diabetes mellitus (DM) (n = 229) and non-diabetic controls (n = 165). The patients with DM were divided into those without DR (NDR, n = 101) and DR (n = 128). DR included simple (SDR, n = 36), pre-proliferative (PPDR, n = 25), and PDR (n = 67). Compared to controls (0.52 &plusmn, 0.12), the AGE scores were significantly higher in patients with DM (0.59 &plusmn, 0.17, p &lt, 0.0001), NDR (0.58 &plusmn, 0.16, p = 0.0012), and DR (0.60 &plusmn, 0.18, p &lt, 0.0001). The proportion of patients with PDR was significantly higher in the highest quartile of AGE scores than the other quartiles (p &lt, 0.0001). Compared to those without PDR (SDR and PPDR), those with PDR were younger (p = 0.0006), more were pseudophakic (p &lt, 0.0001), had worse visual acuity (VA) (p &lt, 0.0001), had higher intraocular pressure (IOP) (p &lt, 0.0001), and had higher AGE scores (p = 0.0016). Multivariate models also suggested that younger age, male gender, pseudophakia, worse VA, higher IOP, and higher AGE scores were risk factors for PDR. The results suggested that AGE scores were higher in patients with DM and were independently associated with progression of DR. In addition, more PDR was seen in the highest quartile of AGE scores. This study highlights the clinical use of the AGE score as a non-invasive, reliable marker to identity patients at risk of sight-threatening DR.

Background Advanced glycation end products (AGEs) are associated with aging, diabetes mellitus (DM), and other chronic diseases. Recently, the accumulation of AGEs can be evaluated by skin autofluorescence (SAF). However, the relationship between SAF levels and exercise capacity in patients with cardiovascular disease (CVD) remains unclear. This study aimed to investigate the association between the tissue accumulation of AGEs and clinical characteristics, including exercise capacity, in patients with CVD. Methods We enrolled 319 consecutive CVD patients aged ≥40 years who underwent early phase II cardiac rehabilitation (CR) at our university hospital between November 2015 and September 2017. Patient background, clinical data, and the accumulation of AGEs assessed by SAF were recorded at the beginning of CR. Characteristics were compared between two patient groups divided according to the median SAF level (High SAF and Low SAF). Results The High SAF group was significantly older and exhibited a higher prevalence of DM than the Low SAF group. The sex ratio did not differ between the two groups. AGE levels showed significant negative correlations with peak oxygen uptake and ventilator efficiency (both P P P = 0.02). Conclusion High levels of tissue accumulated AGEs, as assessed by SAF, were significantly and independently associated with reduced exercise capacity. These data suggest that measuring the tissue accumulation of AGEs may be useful in patients who have undergone CR, irrespective of whether they have DM.

Background. The aim of our study was to estimate the association of lipid fractions and skin autofluorescence (AF), measured with experimental sample of fiber optic spectrometer FOS-1, in patients with diabetes mellitus (DM). Methods. We included in the study 44 type 1 DM patients (median age 29.5 (24.0; 36.0) and 23 type 2 DM patients, median age 58.0 (47.0; 61.0). Blood lipids and glycosylated hemoglobin (HbA1c) were analyzed. Skin AF was measured with fluorescence–reflection spectrometer FOS-1 at a wavelength of 460 nm with excitation of 365 nm. Ratio of fluorescent signal to signal of reflection in excitation region was used as measured parameter to reduce the effect of skin pigmentation. The measurements were carried out at 5 points on the skin area of forearms. Results. Type 1 DM group was divided to 13 dyslipidemic and 31 normolipidemic patients, subgroups were comparable by age, DM duration and HbA1c level. AF level in dyslipidemic and normolipidemic patients was 0.95 (0.82; 1.16) arb. units and 0.86 (0.79; 0.91) arb. units respectively, p=0.016. In type 1 DM group we found significant positive correlation between skin AF and total cholesterol level (R=0.45, р

Advanced glycation end products (AGEs) comprise a heterogeneous group of stable end-products of the non-enzymatic glycation reactions described by Maillard in 1912, in which reduced sugars irreparably modify proteins, lipids and DNA. This is a slow physiological process and accumulation of AGEs is part of normal ageing. Under conditions of hyperglycaemia and oxidative stress, a much faster and more substantial generation of AGEs is induced. The myriad of pathogenic signals AGEs can induce and the fact that enhanced AGE accumulation accompanies a broad spectrum of age-associated chronic inflammatory diseases [1] form the basis of the Maillard theory of ageing [2]., The relationship between SAF and FEV1, DLCO and X5, independent of COPD or diabetes. Will individuals with raised SAF and subclinical lung function alterations develop disease? What mechanisms underlie parenchymal alterations indicated by SAF? https://bit.ly/2YTtdkL

Macrosomia is one of the most frequent complications in women with hyperglycemia in pregnancy, and advanced glycation end products (AGEs) may play a role in fetus growth. We were very interested by the article by Foussard et al. (1) reporting a positive association in women with pregestational diabetes or hyperglycemia in pregnancy between maternal skin autofluorescence (sAF), an estimate of AGE accumulation, and large-for-gestational-age (LGA) newborns or infants with birth weight >4,000 g. This association remained significant after adjustment for HbA1c, suggesting that, besides hyperglycemia, other factors might be involved in the relation between sAF and macrosomia. We had the opportunity to explore the relationship between sAF and …

We were interested in the comment from Cosson et al. (1) on our recent report about high skin autofluorescence (sAF) in hyperglycemic mothers of large-for-gestational-age (LGA) newborns (2). Several reasons can explain why Cosson et al., and previously de Ranitz-Greven et al. (3), failed to detect a relationship between sAF and macrosomia. The first explanation is the low number of participants, 100 in de Ranitz-Greven et al. (3) and 148 in Cosson et al. (1), which can lead to an underpowered study and a lack of statistical power, versus 343 …

Introduction Intensive glycemic control minimizes the risks of microvascular complications in diabetes. A1C is a convenient estimate of mean blood glucose, but is not the only marker available. The practical use and limitations of alternative markers and continuous glucose monitors are the focus of this review. Methods PubMed and the Cochrane Library were searched for studies concerning applications or limitations of A1C, fructosamine, glycated albumin, 1,5-anhydroglucitol, skin autofluorescence, and continuous glucose monitoring. Papers reporting on strengths, limitations, or comparisons of these methods were reviewed for inclusion. Results A1C reflects three months of glycemic control and is not an ideal marker in all patient populations. Fructosamine and glycated albumin reflect mean blood glucose over three weeks. 1,5-Anhydroglucitol can measure hyperglycemic excursions in days to weeks. Continuous glucose monitors provide immediate feedback for timely intervention to reduce glycemic excursions and can assess glycemic variability. Current barriers to continuous glucose monitor use include inexperience, cost, discomfort, and medication interference. Conclusions Many promising alternative glycemic markers exist. The main limitations for all alternative methods of glycemic monitoring are a lack of standardization for clinically useful cut-offs or guidelines, and a lack of long-term data on their association with complications, particularly in varied patient populations.

Background Advanced glycation end products (AGEs) accumulate in tissues with age and in conditions such as diabetes mellitus and chronic kidney disease (CKD), and they may be involved in age-related diseases. Skin AGEs measured as skin autofluorescence (SAF) are a noninvasive reflection of long-term AGE accumulation in tissues. Whether AGEs present in the diet (dAGEs) contribute to tissue AGEs is unclear. Objectives Our aim was to investigate the association between dietary and skin AGEs in the Rotterdam Study, a population-based cohort of mainly European ancestry. Methods In 2515 participants, intake of 3 dAGEs [carboxymethyl-lysine (CML), N-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MGH1), and carboxyethyl-lysine (CEL)] was estimated using FFQs and the content of AGEs measured in commonly consumed foods. SAF was measured 5 y (median value) later using an AGE Reader. The association of dAGEs with SAF was analyzed in linear regression models and stratified for diabetes and chronic kidney disease (CKD, defined as estimated glomerular filtration rate ≤60 mL/min) status. Results Mean ± SD intake was 3.40 ±0.89 mg/d for CML, 28.98 ±7.87 mg/d for MGH1, and 3.11 ±0.89 mg/d for CEL. None of them was associated with SAF in the total study population. However, in stratified analyses, CML was positively associated with SAF after excluding both individuals with diabetes and individuals with CKD: 1 SD higher daily CML intake was associated with a 0.03 (95% CI: 0.009, 0.05) arbitrary units higher SAF. MGH1 and CEL intake were not significantly associated with SAF. Nevertheless, the associations were stronger when the time difference between dAGEs and SAF measurements was shorter. Conclusions Higher dietary CML intake was associated with higher SAF only among participants with neither diabetes nor CKD, which may be explained by high AGE formation in diabetes and decreased excretion in CKD or by dietary modifications in these disease groups. The dAGE-SAF associations were also modified by the time difference between measurements. Our results suggest that dAGEs can influence tissue AGE accumulation and possibly thereby age-related diseases. This trial was registered at the Netherlands National Trial Register as NTR6831 (http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=6831) and at the WHO International Clinical Trials Registry Platform as NTR6831 (http://www.who.int/ictrp/network/primary/en/).

IntroductionThe major challenge for diabetes prevention is early identification of individuals at risk to allow for implementation of measures to delay the onset of future disease. Measures such as fasting plasma glucose (FPG), 2-hour plasma glucose (2hPG), and glycosylated hemoglobin (HbA1c) are equally appropriate for identifying pre-diabetes and diabetes, but do not all identify the disease in the same individual. We tested the utility of a diagnostic method combining FPG, 2hPG and HbA1c for early evaluation and easy identification of pre-diabetes.Research design and methods531 subjects underwent skin autofluorescence (SAF) and glycemia analyses. We created two classification groups based on the American Diabetes Association diagnosis guidelines: (1) based on 2hPG and (2) based on a new combination of three glycemia parameters (the three-criteria strategy (3-c)). Logistic regression modeling was used to estimate the associations.ResultsSAF showed high associations for both 3-c definition and 2hPG definition alone. These associations appeared stronger in 3-c than those in 2hPG. The non-invasive SAF measurement outperformed 2hPG in the detection of dysglycemia or pre-diabetes. Stepwise selections identified 1-hour postload glucose (1hPG) as variable identifying pre-diabetes using the 2hPG criterion, and the model based on 1hPG plus SAF appeared to be the best association using the 3-c strategy.Conclusions1hPG coupled with SAF showed a strong association in the evaluation of pre-diabetes using the 3-c method.

Tissue advanced glycation end products (AGEs) are a measure of cumulative metabolic and oxidative stress and cytokine-driven inflammatory reactions. AGEs are thought to contribute to the cardiovascular complications of hemodialysis (HD) patients. Skin autofluorescence (SAF) is related to the tissue accumulation of AGEs and rises with age. SAF is one of the strongest prognostic markers of mortality in these patients. The content of AGEs is high in barbecue food. Due to the location in northern Sweden, there is a short intense barbecue season between June and August. The aim of this study was to investigate if seasonal variations in SAF exist in HD patients, especially during the barbecue season. SAF was measured noninvasively with an AGE Reader in 34 HD-patients (15 of those with diabetes mellitus, DM). Each time the median of three measures were used. Skin-AF was measured before and after each one HD at the end of February and May in 31 patients (22 men/9 women); the end of May and August in 28 (20 m/8 w); the end of August and March in 25 (19 m/6 w). Paired statistical analyses were performed during all four periods (n = 23, 17 m/6 w); as was HbA1c of those with DM. There was at a median 5.6% increase in skin-AF during the winter period (February-May, P = 0.004) and a 10.6% decrease in the skin-AF during the summer (May-August, P

The study aims to evaluate the relationship between skin autofluorescence, a marker of advanced glycated end-products accumulation in tissue, and high-sensitive cardiac troponin T, a cardiovascular biomarker, in Japanese subjects with diabetes. A total of 145 subjects with diabetes and 32 nondiabetic subjects as control attending the outpatient clinic were examined. Skin autofluorescence was measured using the AGE Reader™. Univariate and multivariate regression analyses were used to identify the factors associated with the high-sensitive cardiac troponin T and N-terminal pro-B-type natriuretic peptide values. Skin autofluorescence, high-sensitive cardiac troponin T, and maximum intima-media thickness values were significantly higher in subjects with diabetes than in nondiabetic subjects. Diabetic subjects with skin autofluorescence level⩾2.47 AU (median value) had higher levels of N-terminal pro-B-type natriuretic peptide ( p = 0.006), high-sensitive cardiac troponin T ( p

Background Advanced glycation end-products play a role in diabetic vascular complications. Their optical properties allow to estimate their accumulation in tissues by measuring the skin autofluorescence (SAF). We searched for an association between SAF and major adverse cardiovascular events (MACE) incidence in subjects with Type 1 Diabetes (T1D) during a 7 year follow-up. Methods During year 2009, 232 subjects with T1D were included. SAF measurement, clinical [age, sex, body mass index (BMI), comorbidities] and biological data (HbA1C, blood lipids, renal parameters) were recorded. MACE (myocardial infarction, stroke, lower extremity amputation or a revascularization procedure) were registered at visits in the center or by phone call to general practitioners until 2016. Results The participants were mainly men (59.5%), 51.5 ± 16.7 years old, with BMI 25.0 ± 4.1 kg/m2, diabetes duration 21.5 ± 13.6 years, HbA1C 7.6 ± 1.1%. LDL cholesterol was 1.04 ± 0.29 g/L, estimated Glomerular Filtration Rates (CKD-EPI): 86.3 ± 26.6 ml/min/1.73 m2. Among these subjects, 25.1% were smokers, 45.3% had arterial hypertension, 15.9% had elevated AER (≥ 30 mg/24 h), and 9.9% subjects had a history of previous MACE. From 2009 to 2016, 22 patients had at least one new MACE: 6 myocardial infarctions, 1 lower limb amputation, 15 revascularization procedures. Their SAF was 2.63 ± 0.73 arbitrary units (AU) vs 2.08 ± 0.54 for other patients (p = 0.002). Using Cox-model, after adjustment for age (as the scale time), sex, diabetes duration, BMI, hypertension, smoking status, albumin excretion rates, statin treatment and a previous history of MACE, higher baseline levels of SAF were significantly associated with an increased risk of MACE during follow-up (HR = 4.13 [1.30–13.07]; p = 0.02 for 1 AU of SAF) and Kaplan–Meier curve follow-up showed significantly more frequent MACE in group with SAF upper the median (p = 0.001). Conclusion A high SAF predicts MACE in patients with T1D. Electronic supplementary material The online version of this article (10.1186/s12933-018-0718-8) contains supplementary material, which is available to authorized users.

Background: The cardio-ankle vascular index (CAVI) is a novel physiological marker of atherosclerosis that reflects systemic arterial stiffness. The aim of this study was to clarify the clinical significance of CAVI as a risk factor for cardiovascular diseases (CVDs) in elderly patients with type 2 diabetes mellitus. Methods: This cross-sectional study enrolled 216 elderly (≥ 65 years) outpatients with type 2 diabetes mellitus who were undergoing antidiabetic treatment (96 males and 120 females; mean age, 75 ± 7 years (mean ± standard deviation)). Associations between CAVI and various clinical parameters were examined. Results: CAVI was significantly higher in patients with a history of CVD than in those without a history of CVD (10.4 ± 1.4 vs. 9.5 ± 1.0, respectively, P < 0.001). There were significantly positive correlations between CAVI and various clinical parameters, such as skin autofluorescence (r = 0.47, P < 0.001), high-sensitivity cardiac troponin T levels (r = 0.39, P < 0.001), and reactive oxygen metabolite levels (r = 0.28, P < 0.001). Furthermore, multiple regression analyses revealed that these clinical parameters ((skin autofluorescence (β = 0.30, P < 0.001), high-sensitivity cardiac troponin T levels (β = 0.18, P < 0.001), reactive oxygen metabolite levels (β = 0.15, P < 0.01), and a history of CVD (β = 0.19, P < 0.001)) were independent variables when CAVI was used as a subordinate factor. Conclusion: Findings of this study indicate that CAVI may be an important CVD risk factor in elderly patients with type 2 diabetes mellitus. Further investigations in a large number of prospective studies, including intervention therapies, are required to validate our results. J Clin Med Res. 2018;10(4):330-336 doi: https://doi.org/10.14740/jocmr3364w

Post stroke infection occurs in 15–20% of acute stroke patients and is associated with a poor longterm outcome. In a prospective study on 113 acute ischemic stroke patients with diabetes mellitus 15.9% suffered nosocomial infection. We found chronic hyperglycemia measured by skin autofluorescence in arbitrary units to be an independent predictor of a nosocomial infection post stroke (OR = 3.24 [CI 95%: 1.13; 9.26], p = 0.029). Skin autofluorescence represents the glycemic memory beyond HbA1c. Potential mechanisms leading from increased skin autofluorescence to vulnerability for infectious complications include more severe strokes due to preexisting vasculopathy and exacerbated post stroke immunosuppression.