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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.

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

Objective: HIV-1 infection is associated with an increased cardiovascular disease (CVD) risk. Advanced glycation end products are formed as stable markers of glycaemic and oxidative stress. Skin autofluorescence (SAF) as marker of accumulated advanced glycation end products is increased and predictive of CVD events in diabetes mellitus, chronic kidney disease (CKD), and preexisting CVD. We determined SAF levels in HIV-1 infected patients, testing the hypothesis that SAF predicts CVD events in HIV infection.Design: Single-centre prospective cohort study.Methods: In 2010-2011, SAF was measured in 91 patients. Development of CVD events was monitored during a median follow-up of 4.8 years. SAF values of the patients were expressed as a ratio (rSAF) to expected SAF levels in age-matched healthy volunteers.Results: Seventy-nine men and 12 women were included, mean age 47 years; 81 patients were on combination antiretroviral therapy. With a mean rSAF of 1.155, SAF levels in patients were 15.5% higher than predicted for their age (95% confidence interval, 10.0-20.0; PConclusion: SAF is increased in HIV-infected patients, and related with smoking, low nadir CD4(+) cell count, and MSM. Larger studies are needed to confirm whether SAF is an independent predictor of CVD events. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

Aims/hypothesis Earlier studies have shown that skin autofluorescence measured with an AGE reader estimates the accumulation of AGEs in the skin, which increases with ageing and is associated with the metabolic syndrome and type 2 diabetes. In the present study, we examined whether the measurement of skin autofluorescence can predict 4 year risk of incident type 2 diabetes, cardiovascular disease (CVD) and mortality in the general population. Methods For this prospective analysis, we included 72,880 participants of the Dutch Lifelines Cohort Study, who underwent baseline investigations between 2007 and 2013, had validated baseline skin autofluorescence values available and were not known to have diabetes or CVD. Individuals were diagnosed with incident type 2 diabetes by self-report or by a fasting blood glucose ≥7.0 mmol/l or HbA1c ≥48 mmol/mol (≥6.5%) at follow-up. Participants were diagnosed as having incident CVD (myocardial infarction, coronary interventions, cerebrovascular accident, transient ischaemic attack, intermittent claudication or vascular surgery) by self-report. Mortality was ascertained using the Municipal Personal Records Database. Results After a median follow-up of 4 years (range 0.5–10 years), 1056 participants (1.4%) had developed type 2 diabetes, 1258 individuals (1.7%) were diagnosed with CVD, while 928 (1.3%) had died. Baseline skin autofluorescence was elevated in participants with incident type 2 diabetes and/or CVD and in those who had died (all p

BACKGROUND: Skin autofluorescence (SAF) is a non-invasive marker of advanced glycation end products (AGEs). In diabetes, higher SAF levels has been positively associated with long-term complications, cardiovascular morbidity and mortality. Because little is known about the factors that influence SAF in non-diabetic individuals, we assessed the association of clinical and lifestyle parameters with SAF as well as their interactions in a large-scale, non-diabetic population and performed the same analyses in a type 2 diabetic subgroup.METHODS: In a cross-sectional study in participants from the LifeLines Cohort Study, extensive clinical and biochemical phenotyping, including SAF measurement, was assessed in 9009 subjects of whom 314 (3.5%) subjects with type 2 diabetes.RESULTS: Mean SAF was 2.04 ± 0.44 arbitrary units (AU) in non-diabetic individuals and 2.44 ± 0.55 AU in type 2 diabetic subjects (pCONCLUSIONS: In addition to the established literature on type 2 diabetes, we have demonstrated that SAF levels are associated with several clinical and lifestyle factors in the non-diabetic population. These parameters should be taken into consideration when using SAF as a screening or prediction tool for populations at risk for cardiovascular disease and diabetes. This article is protected by copyright. All rights reserved.

Skin autofluorescence (AF) has been associated with complications of diabetes. We evaluated the influence of skin color and ethnicity on the association between skin AF and the presence of diabetes-related complications. In a multiethnic type 2 diabetes cohort we investigated all patients with available skin AF measurements. The associations between skin AF and hemoglobin A1c (HbA1c) and the presence of complications of diabetes were estimated, stratified for ethnicity and quartiles of ultraviolet reflectance percentage (R%). In total, 810 patients (438 native Dutch, 372 non-Dutch) were included. Because of too low an R%, 32% of black Africans and 19% of Hindustanis were excluded. Non-Dutch patients had lower AF values compared with Dutch patients (median AF=2.69 [interquartile range (IQR), 2.26-3.09] vs. 3.06 [IQR, 2.65-3.50] arbitrary units; P

Background: The metabolic syndrome (MetS) comprises several cardiometabolic risk factors associated with increased risk for both type 2 diabetes and cardiovascular disease. Skin autofluorescence (SAF), a non-invasive bio-marker of advanced glycation end products accumulation, is associated with cardiovascular complications in subjects with diabetes. The aim of the present study was to examine the association between SAF and the presence of MetS as well as its individual components in a general population.Methods: For this cross-sectional analysis, we included 78,671 non-diabetic subjects between 18 and 80 years of age who participated in the LifeLines Cohort Study and had SAF measurement obtained non-invasively using the AGE Reader. MetS was defined according to the revised NCEP ATP III criteria. Students unpaired t test was used to test differences between groups. Both logistic and linear regression analyses were performed in order to test associations between the individual MetS components and SAF.Results: Subjects with MetS had higher SAF (2.07 +/- 0.45 arbitrary units, AU) compared to individuals without MetS (1.89 +/- 0.42 AU) (p Conclusion: Skin autofluorescence was associated with the presence of MetS and some of its individual components. In addition, increasing SAF Z-scores were observed with a higher number of MetS components. Prospective studies are needed to establish whether SAF can be used as an (additional) screening tool to predict both cardiovascular disease and type 2 diabetes in high-risk populations.

Skin autofluorescence (AF) is related to the accumulation of advanced glycation end products (AGEs) and is one of the strongest prognostic markers of mortality in hemodialysis (HD) patients. The ai ...

Advanced glycation end-products (AGEs) are uremic toxins that accumulate progressively in hemodialysis (HD) patients. The aim of this study was to assess the 1-year increase in skin autofluorescence (ΔAF), a measure of AGEs accumulation and plasma markers, as predictors of mortality in HD patients. One hundred sixty-nine HD patients were enrolled in this study. Skin autofluorescence was measured twice, 1 year apart using an AGE Reader (DiagnOptics Technologies BV, Groningen, The Netherlands). Besides routine blood chemistry, additional plasma markers including superoxide dismutase, myeloperoxydase, intercellular adhesion molecule 1 (ICAM-1), C-reactive protein (hs-CRP), heart-type fatty acid binding protein (H-FABP), and von Willebrand factor were measured at baseline. The mortality of HD patients was followed for 36 months. Skin autofluorescence values of the HD patients at the two time points were significantly higher (P

Haemodialysis (HD) patients suffer from an increased risk of cardiovascular disease (CVD). Skin autofluorescence (SAF) is a strong marker for CVD. SAF indirectly measures tissue advanced glycation end products (AGE) being cumulative metabolites of oxidative stress and cytokine-driven inflammatory reactions. The dialysates often contain glucose. Autofluorescence of skin and plasma (PAF) were measured in patients on HD during standard treatment (ST) with a glucose-containing dialysate (n = 24). After that the patients were switched to a glucose-free dialysate (GFD) for a 2-week period. New measurements were performed on PAF and SAF after 1 week (M1) and 2 weeks (M2) using GFD. Nonparametric paired statistical analyses were performed between each two periods. SAF after HD increased non-significantly by 1.2% while when a GFD was used during HD at M1, a decrease of SAF by 5.2% (p = 0.002) was found. One week later (M2) the reduction of 1.6% after the HD was not significant (p = 0.33). PAF was significantly reduced during all HD sessions. Free and protein-bound PAF decreased similarly whether glucose containing or GFD was used. The HD resulted in a reduction of the total PAF of approximately 15%, the free compound of 20% and the protein bound of 10%. The protein bound part of PAF corresponded to approximately 56% of the total reduction. The protein bound concentrations after each HD showed the lowest value after 2 weeks using glucose-free dialysate (p

ObjectiveHigh 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.MethodsSkin 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).ResultsIn univariate analysis, skin AF correlated inversely with HDL anti-oxidative capacity (r=−0.305, P

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 Themean 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

Condensation. In women with a history of preeclampsia skin autofluorescence as marker of tissue AGEs accumulation is increased, supporting a common causal metabolic or vascular link between preeclampsia and cardiovascular diseases. Objective. To investigate whether skin autofluorescence (AF), as marker of tissue accumulation of advanced glycation end-products (AGEs), is elevated in women with a 4-year history of severe preeclampsia. Methods. About 17 formerly preeclamptic women and 16 controls were included. Skin AF and several traditional cardiovascular risk factors were recorded. Results. In comparison to controls, formerly preeclamptic women had higher skin AF of the legs, body mass index (BMI), blood pressure, and high-sensitivity C-reactive protein (hsCRP), HbA1C, and triglycerides in serum. Conclusion. Skin AF as well as cardiovascular risk factors is elevated in formerly preeclamptic women. These results suggest a common causal vascular link between preeclampsia and cardiovascular diseases.

Objective. To investigate whether advanced glycation endproducts (AGEs) in the skin are increased in patients with systemic sclerosis (SSc) and are related to the presence of disease-related and traditional cardiovascular risk factors.Methods. Skin autofluorescence, as a measure for the accumulation of AGEs, was assessed by measuring UV-A light excitation-emission matrices (AF-EEMS) in 41 SSc patients and 41 age- and sex-matched controls. Traditional cardiovascular risk factors and disease-related risk factors were recorded.Results. Skin AF-EEMS did not differ between SSc patients and controls (1.68±0.58 a.u. versus1.63±0.41 a.u.,P=0.684). Skin AF-EEMS in SSc patients was associated with levels of CRP (r=0.44,P=0.004), Medsger's severity scale (r=0.45,P=0.006), and use of agents intervening in the renin-angiotensin system (r=0.33,P=0.027). When analysing SSc patients and controls together, in multivariate analysis, only age and use of agents intervening in the renin-angiotensin system were independently associated with AF-EEMS.Conclusion. These data demonstrate that skin AGEs are not increased in SSc patients.

Background: Accumulation of advanced glycation end products (AGEs) is accelerated during glycemic and oxidative stress and is an important predictor of complications in diabetes mellitus (DM).Study Design: Here we both review and present original data on the relationship between skin autofluorescence (SAF), a noninvasive measure of AGEs, and short-and intermediate-term glycemic variations.Results: Acute changes in glucose levels during an oral glucose tolerance test in 56 persons with varying degrees of glucose tolerance did not influence SAF. AGE-rich meals result in a transient postprandial rise in SAF of 10% 2-4 h later. This could not be attributed to meal-induced glycemic changes and is probably caused by the AGE content of the meal. In type 1DM major intermediate-term improvements of glycemic control as depicted by multiple hemoglobin A1c (HbA1c) measurements were associated with lower skin AGE levels. In a well-controlled, stable type 2DM cohort, only a weak correlation was found between SAF and HbA1c. In both studies skin AGE/SAF levels predicted complications of diabetes with an accuracy superior to that of HbA1c. SAF has also been proposed as a new tool in diagnosing impaired glucose tolerance (IGT) and DM. It proved to be more sensitive than either fasting glucose or HbA1c.Conclusions: SAF is not influenced by short-term glycemic variations. AGE-rich meals may, however, cause a transient rise postprandially. There is a weak correlation between SAF or skin AGEs and current or time-integrated HbA1c levels. SAF has strong added value in risk prediction of complications of diabetes and is a promising tool for early detection of diabetes and IGT.

P>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 center dot 265, P = 0 center dot 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 center dot 549, P

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.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.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 (P0.01), 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.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.

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.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%. Skin autofluorescence was measured non-invasively with an autofluorescence reader. Skin autofluorescence was classified by the median (i.e. low risk median).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%).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.

Background. ST-elevation myocardial infarction Back, (STEMI) is associated with increased inflammation and oxidative stress, enhancing the formation of advanced glycation endproducts (AGEs). Thew , encompass characteristic fluorescence: pattern, which can be non-invasively measured as skin autofluorescence (AF). In this study we investigate whether skin AF is elevated in STEMI, its association with inflammatory and glycaemic stress,and its predictive value for future events.Methods. Skin AF was measured in 88 STEMI patients (mean age 64 +/- 13 years) within 72 hours and around six months after discharge, in 81 stable coronary artery disease (sCAD) patients (64 +/- 10 years), and in 32 healthy controls (63 +/- 11 years). The cumulative one-year incidence Of all-cause mortality and hospitalisation for myocardial infarction Or heart failure was documented.Results. Skin AF was significantly higher in STEMI compared with sCAD and controls, irrespective of: confounders, and was associated with HbA1c and C-reactive protein. Skin AF decreased significantly in STEMI patients, when measured >200 days after discharge. In STEMI patients, skin AF above g the median was predictive of future events (hazard ratio 11.6, 95% CI 1.5 to 90.8, p=0.019). Conclusion . Skin AF is elevated in STEMI, is associated with inflammation and glycaemic stress, and predicts future major adverse cardiac events. (Neth Heart J 2009;17:162-8.)

Objectives. To examine whether skin advanced glycation endproducts (AGEs) accumulation, plasma levels of AGEs-N-epsilon-carboxymethyllysine (CML) and N-epsilon-carboxyethyllysine (CEL)-and serum levels of soluble receptor for AGEs (sRAGE) are elevated in SLE patients compared with controls, and whether these parameters are related to disease activity and endothelial cell (EC) activation.Methods. Ten SLE patients (9 women, age 34 +/- 13 yrs, mean +/- S.D.) and 10 age- and sex-matched controls were included. Patients were analysed during inactive as well as active disease. Skin AGE accumulation was estimated using ultraviolet-A (UV-A) light for measurement of autofluorescence obtained by ExcitationEmission matrix Scanner (AF-EEMS). Levels of CML and CEL were determined by tandem mass spectrometry. Levels of sRAGE and of soluble vascular cell adhesion molecule-1 (sVCAM-1) were determined by ELISAs.Results. Skin AF-EEMS was increased in SLE patients compared with controls (P Conclusions. Skin AGEs and levels of sRAGE and sVCAM-1 were elevated in SLE patients, whereas levels of CML and CEL were comparable with controls. As sRAGE even further increased during endothelial activation, it might be hypothesized that sRAGE acts as a decoy receptor. Why this proposed mechanism is insufficient to prevent increased AGE accumulation in the skin of SLE patients has to be established.

OBJECTIVE—Skin autofluorescence is a noninvasive measure of the level of tissue accumulation of advanced glycation end products, representing cumulative glycemic and oxidative stress. Recent studies have already shown a relationship between skin autofluorescence and diabetes complications, as well as the predictive value of skin autofluorescence for total and cardiovascular mortality in type 2 diabetes. Our aim was to investigate the predictive value of skin autofluorescence for the development of microvascular complications in type 2 diabetes. RESEARCH DESIGN AND METHODS—At baseline, skin autofluorescence of 973 type 2 diabetic patients with well-controlled diabetes was noninvasively measured with an autofluorescence reader. The aggregate clinical outcome was defined as the development of any diabetes-associated microvascular complication of 881 surviving patients, which was assessed at baseline and at the end of follow-up. Single end points were the development of diabetes-associated retinopathy, neuropathy, and (micro)albuminuria. RESULTS—After a mean follow-up period of 3.1 years, baseline skin autofluorescence was significantly higher in patients who developed any microvascular complication, neuropathy, or (micro)albuminuria but not in those who developed retinopathy. Multivariate analyses showed skin autofluorescence as a predictor for development of any microvascular complication along with A1C, for development of neuropathy along with smoking, and for development of (micro)albuminuria together with sex, A1C, and diabetes duration. Skin autofluorescence did not have predictive value for the development of retinopathy, albeit diabetes duration did. CONCLUSIONS—Our study is the first observation of skin autofluorescence measurement as an independent predictor of development of microvascular complications in type 2 diabetes.

Introducton: Despite their unfavourable cardiovascular risk profile, patients with glycogen storage disease type Ia (GSD Ia) do not develop premature atherosclerosis. We hypothesized that this paradox might be related to a decreased formation of advanced glycation end products (AGEs) resulting from lifetime low plasma glucose levels and decreased oxidative stress. Methods: In 8 GSD Ia patients (age 20-34 years) and 30 matched controls we measured carotid intima-media thickness (IMT), skin autofluorescence (AF; a non-invasive index for AGEs), and specific AGEs (pentosidine, N-(carboxymethyl)lysine (CML), N-(carboxyethyl)lysine (CEL)) and collagen linked fluorescence (CLF, measured at excitation/emission wavelength combinations of 328/378 and 370/440 nm) in skin samples. Results: Carotid IMT was significantly lower in GSD Ia patients. Skin AF did not differ between patients and controls. The skin samples showed higher CEL levels in the patient group (p=0.008), but similar levels of pentosidine, CML, and CLF. In the total group, skin AF correlated with CML (r=0.39, p=0.031), CLF 328/378 nm (r=0.53; p=0.002) and CLF 370/440 nm (r=0.60; p=0.001). In the control group, AF also correlated with the maximum carotid IMT (r=0.6; p=0.004). Conclusion: Although our data confirm that GSD Ia patients present with a reduced burden of atherosclerosis, this phenomenon cannot be explained by differences in AGE accumulation as measured in the skin.

Tissue advanced glycation end products (AGE) are a measure of cumulative metabolic stress and trigger cytokines driven inflammatory reactions. AGE are thought to contribute to the chronic complications of diabetes and ESRD. Tissue autofluorescence is related to the accumulation of AGE. Therefore, skin autofluorescence (AF) may provide prognostic information on mortality in hemodialysis (HD) patients. Skin AF was measured noninvasively with an AF reader at baseline in 109 HD patients. Overall and cardiovascular mortality was monitored prospectively during a period of 3 yr. The AF reader was validated against AGE contents in skin biopsies from 29 dialysis patients. Forty-two of the 109 (38.5%) HD patients died. Cox regression analysis showed that AF was an independent predictor of overall and cardiovascular mortality (for overall mortality odds ratio [OR] 3.9), as were pre-existing cardiovascular disease (CVD; OR 3.1), C-reactive protein (OR 1.1), and serum albumin (OR 0.3). Multivariate analysis revealed that 65% of the variance in AF could be attributed to the independent effects of age, dialysis and renal failure duration, presence of diabetes, triglycerides levels, and C-reactive protein. AF was also independently linked to the presence of CVD at baseline (OR 8.8; P

Aims/hypothesis: The accumulation of AGE is related to the progression of the renal, retinal and vascular complications of diabetes. However, the relationship with diabetic neuropathy remains unclear. We recently showed that skin autofluorescence, measured non-invasively with an AutoFluorescence Reader ( AFR), could be used to assess skin AGE accumulation. We evaluated the relationship between skin autofluorescence and the severity of diabetic neuropathy. Materials and methods: Skin autofluorescence in arbitrary units (AU) was assessed in 24 diabetic patients with a history of neuropathic foot ulceration (NP+), 23 diabetic patients without clinical neuropathy (NP-) and 21 control subjects, using the AFR. Arterial occlusive disease was excluded in all. The severity of foot ulceration was assessed by the Wagner score. Peripheral nerve function was assessed by neurography, measuring motor and sensory nerve conduction velocity and amplitude of the median, peroneal and sural nerves. Heart rate variability (HRV) and baroreflex sensitivity BRS) were measured by Finapres to assess autonomic nervous function. Results: Autofluorescence was increased in NP- compared with control subjects. In NP+ patients, autofluorescence was further increased and correlated with the Wagner score. Autofluorescence correlated negatively with nerve conduction velocity and amplitude, HRV and BRS in both NP+ and NP- groups. Autofluorescence correlated with age, diabetes duration, mean HbA(1)c of the previous year, serum creatinine level, presence of microalbuminuria and severity of diabetic retinopathy. Conclusions/interpretation: Skin autofluorescence correlates with the severity of peripheral and autonomic nerve abnormalities in diabetes, even before being clinically manifest. The AFR may be a convenient and rapid clinical tool for assessing risk of progression of long- term diabetic complications.

Aims/hypothesis. The accumulation of AGE is thought to play a role in the pathogenesis of chronic complications of diabetes mellitus and renal failure. All current measurements of AGE accumulation require invasive sampling. We exploited the fact that several AGE exhibit autofluorescence to develop a non-invasive tool for measuring skin AGE accumulation, the Autofluorescence Reader (AFR). We validated its use by comparing the values obtained using the AFR with the AGE content measured in extracts from skin biopsies of diabetic and control subjects.Methods. Using the AFR with an excitation light source of 300-420 nm, fluorescence of the skin was measured at the arm and lower leg in 46 patients with diabetes (Type 1 and 2) and in 46 age- and sex-matched control subjects, the majority of whom were Caucasian. Autofluorescence was defined as the average fluorescence per nm over the entire emission spectrum (420-600 nm) as ratio of the average fluorescence per nm over the 300-420-nm range. Skin biopsies were obtained from the same site of the arm, and analysed for collagen-linked fluorescence (CLF) and specific AGE: pentosidine, N-epsilon-(carboxymethyl)lysine (CML) and N-epsilon-(carboxyethyl)lysine (CEL).Results. Autofluorescence correlated with CLF, pentosidine, CML, and CEL (r=0.47-0.62, pless than or equal to0.002). In 32 of 46 diabetic patients (70%), autofluorescence values were above the 95% CI of the mean value in control subjects, and correlated with age, diabetes duration, mean HbA(1)c of the previous year and creatinine levels.Conclusions/interpretation. The AFR offers a simple alternative to invasive measurement of AGE accumulation and, to date, has been validated in non-pigmented skin. The AFR may prove to be a useful clinical tool for rapid risk assessment of AGE-related long-term complications in diabetes mellitus and in other conditions associated with AGE accumulation.

Aims/hypothesis Skin fluorescence (SF) is a non-invasive marker of AGEs and is associated with the long-term complications of diabetes. SF increases with age and is also greater among individuals with diabetes. A familial correlation of SF suggests that genetics may play a role. We therefore performed parallel genome-wide association studies of SF in two cohorts. Methods Cohort 1 included 1,082 participants, 35–67 years of age with type 1 diabetes. Cohort 2 included 8,721 participants without diabetes, aged 18–90 years. Results rs1495741 was significantly associated with SF in Cohort 1 (p

Introduction: The objectives of this study were to determine small arterial elasticity (SAE) in systemic lupus erythematosus (SLE) and to investigate its relationship with intima media thickness (IMT), accumulation of advanced glycation end products (AGEs), endothelial activation and inflammation.Methods: Thirty SLE patients with inactive disease and 30 age- and sex-matched healthy controls were included. Twenty patients with essential hypertension (EH) served as positive control. SAE was assessed by pulse-wave analysis using tonometric recordings of the radial artery. IMT of the carotid arteries was measured by ultrasound. AGE accumulation was assessed with an AGE-reader. Endothelial activation markers and C-reactive protein (CRP) were determined by enzyme-linked immunosorbent assay (ELISA).Results: SAE was decreased in SLE (P = 0.01) and further decreased in EH (P Conclusions: SAE is decreased in SLE patients without increased IMT, independently of traditional cardiovascular risk factors. Longitudinal studies are needed to investigate whether SAE, endothelial activation and AGE accumulation are early markers for cardiovascular disease in SLE.

BACKGROUND: Hepatitis C may cause increased levels of oxidative stress that contribute to accumulation of advanced glycation end products (AGEs), which increase the risk of cardiovascular disease (CVD). The aim of this study was to determine the influence of hepatitis C on AGE accumulation in haemodialysis patients. METHODS: AGE accumulation was measured by means of skin autofluorescence (AF) in 92 haemodialysis (HD) patients and 93 age-matched healthy controls. In the HD patients, CVD-related biochemical variables were also measured. The HD patients were tested for hepatitis C virus (HCV) antibodies and allocated to a HCV+ or HCV- group. RESULTS: Skin AF of the healthy subjects was lower than skin AF in the HD patients (3.13 +/- 0.95 vs 2.2 +/- 0.47; P < 0.001). We calculated the average increase of skin AF in the healthy subjects to be 0.017 arbitrary units per year, being 14 times lower than in HD patients with CVD only and 20 times lower than in HD patients suffering from combined CVD and diabetes mellitus (DM). Multivariate regression analysis showed that AGE accumulation in HD patients can be described by the independent effects of age, DM, CVD and HD vintage. Although inter-cellular adhesion molecule 1 and liver enzymes were elevated in HCV+ HD patients, levels of oxidative stress markers and skin AF were not significantly different between HCV+ and HCV- HD patients. CONCLUSIONS: AGE accumulation was higher in the HD patients than in the healthy controls. AGE accumulation did not differ in HCV+ and HCV- HD patients. This might be due to the fact that hepatitis C did not cause oxidative stress in our HD population. Independent markers of AGE accumulation were age, HD vintage, DM and CVD, but not hepatitis C.

Objective. To investigate whether advanced glycation endproducts (AGEs) are increased in patients with systemic lupus erythematosus (SLE), and are related to atherosclerosis, which is accelerated in SLE, and its traditional and non-traditional disease-related risk factors.Methods. Fifty-five SLE patients with inactive disease and 55 age- and sex-matched controls were included. The amount of skin autofluorescence (AF), as a measure for the accumulation of AGEs, was assessed by measuring UV-A light excitation-emission matrices (AF-EEMS). Traditional risk factors and disease-related factors were recorded. Plasma levels of C-reactive protein (CRP), as a marker for systemic inflammation, were assessed. Intima-media thickness (IMT) of the common carotid artery was determined by ultrasound.Results. Skin AF-EEMS was increased in SLE patients as compared with controls (1.50 +/- 0.5 a.u. vs 1.28 +/- 0.4a.u., P=0.006). Regarding all included risk factors, univariate analyses in patients revealed that AF-EEMS was associated with age (r= 0.48, PConclusion. AGES are increased in SLE compared with controls. Our findings indicate that AGE accumulation is associated with disease duration and might contribute to the development of accelerated atherosclerosis in SLE and, therefore, could be used for assessment of risk for long-term vascular complications.

OBJECTIVE—Advanced glycation end products (AGEs) are biomarkers of metabolic stress and are thought to contribute to the increase of coronary heart disease (CHD) in diabetes. Tissue autofluorescence is related to the accumulation of AGEs. The aim of the present study was to evaluate the relationship between skin autofluorescence and metabolic burden (hyperglycemia and hyperlipidemia) and its relationship with CHD and mortality. RESEARCH DESIGN AND METHODS—Skin autofluorescence was measured noninvasively with an autofluorescence reader in 48 type 1 and 69 type 2 diabetic patients and 43 control subjects. The presence of CHD was observed at baseline and mortality during a follow-up period of 5 years. RESULTS—Autofluorescence correlated with mean A1C, triglycerides, and LDL. Autofluorescence values further increased with age, microalbuminuria, dialysis treatment, and diabetes duration. Autofluorescence was strongly related to the presence of CHD (odds ratio 7.9) and predicted mortality (3.0). Multivariate analysis showed that autofluorescence was more strongly associated with CHD and mortality compared with A1C, triglycerides, and LDL. CONCLUSIONS—Skin autofluorescence is strongly related to cumulative metabolic burden. Skin autofluorescence seems strongly associated with cardiac mortality and may provide important clinical information for risk assessment.

Aims: To investigate whether skin autofluorescence (AF), a non-invasive marker for advanced glycation end products (AGEs), is elevated in stable coronary artery disease (sCAD) and to investigate its relationship with serum levels of the soluble receptor for AGEs (sRAGE), neopterin and C-reactive protein (CRP).Methods and results: Skin AF and serum levels of sRAGE, neopterin and CRP were assessed in 63 sCAD patients (mean age: 64.7 +/- 10.5 years), comprising 78% males, 19% subjects with diabetes, and 22% current smokers and in 33 (mean age: 63.4 +/- 10.0 years) healthy non-diabetic and non-smoking age and gender matched controls. Skin AF was significantly increased in sCAD compared with controls, irrespective of diabetes, current smoking and renal function. Levels of sRAGE (standardized beta: 0.43 (explaining 17% of variance in skin AF); P Conclusion: These data demonstrate that skin AF is elevated in sCAD and is related to sRAGE and neopterin, making it an easily applicable tool to improve our understanding of inflammatory and oxidative stress in cardiovascular disease. (C) 2007 Elsevier Ireland Ltd. All rights reserved.

OBJECTIVE—Advanced glycation end products (AGEs) are thought to have a role in the pathogenesis of diabetes complications. We recently reported the association between skin autofluorescence, as a measure of tissue AGE accumulation, and diabetic neuropathy in a selected diabetic population. In this study, we investigated the relation between skin autofluorescence and clinical variables including micro- and macrovascular complications in a type 2 diabetes primary care population. RESEARCH DESIGN AND METHODS—Clinical data and skin autofluorescence were obtained in the type 2 diabetes group (n = 973) and in a control group (n = 231). Skin autofluorescence was assessed by illumination of the lower arm with a fluorescent tube (peak intensity ∼370 nm). RESULTS—Skin autofluorescence was significantly higher in type 2 diabetic patients compared with control subjects in each age category. Multiple regression analysis showed significant correlation of skin autofluorescence with age, sex, diabetes duration, BMI, smoking, HbA1c, plasma creatinine, HDL cholesterol, and albumin-to-creatinine ratio in the type 2 diabetes group (R2 = 25%) and with age and smoking in the control group (R2 = 46%). Skin autofluorescence was significantly higher in the type 2 diabetes group, with both micro- and macrovascular disease, compared with the group without complications and the group with only microvascular complications. CONCLUSIONS—This study confirms in a large group of type 2 diabetic patients that skin autofluorescence is higher compared with age-matched control subjects and is associated with the severity of diabetes-related complications. Skin autofluorescence reflecting vascular damage might be a rapid and helpful tool in the diabetes outpatient clinic for identifying diabetic patients who are at risk for developing complications.

Objective: Advanced glycation end-products are considered to be markers of oxidative stress and to be involved in the atherosclerotic process. We investigated skin autofluorescence, which reflected advanced glycation end-product accumulation, in recently preeclamptic women and its relationship with intima-media thickness, which is a marker of atherosclerosis.Study design: Skin autofluorescence of the arm and leg was measured in 26 preeclamptic women and 17 control subjects at 3 to 13 months after delivery. Lipid profiles, smoking habits, and intima-media thickness of 5 carotid and femoral artery segments were recorded.Results: The preeclampsia group was younger and had higher values for blood pressure, insulin resistance, common femoral artery intima-media thickness, and skin autofluorescence of the leg. With the use of linear regression analysis, the difference in leg auto fluorescence was explained only by preeclampsia. In the preeclampsia group, skin autofluorescence of the leg correlated with smoking and common femoral artery intima-media thickness.Conclusion: These results support the hypothesis of accelerated atherosclerosis in recently preeclamptic women and the possible involvement of advanced glycation end-product accumulation. (c) 2006 Mosby, Inc. All rights reserved.

Background. Accumulation of advanced glycation end-products (AGEs) has been implicated in the pathogenesis of chronic transplant dysfunction and cardiovascular disease in renal transplant recipients. We aimed to investigate which factors are associated with tissue AGE accumulation in renal transplant recipients.Methods. The AGE accumulation was assessed using a validated skin-autofluorescence reader (AFR) in 285 consecutive renal transplant recipients (57% male, aged 50 +/- 12 years) visiting the outpatient clinic at a median (interquartile range) time of 73 (32-143) months after transplantation. Furthermore, various transplant- and recipient-related factors of interest were collected.Results. Average skin-autofluorescence of lower arm and leg was 2.7 +/- 0.8 a.u. Skin-autofluorescence was positively determined by recipient age, systolic blood pressure, smoking, high-sensitivity C-reactive protein, duration of pre-transplant dialysis, and negatively by plasma vitamin C levels, creatinine clearance at baseline, and change in creatinine clearance since one year after transplantation in linear multivariate regression analysis. Together, these factors explained 41% of the variance of skin-autofluorescence.Conclusions. Skin-autofluorescence was associated with several risk factors for cardiovascular disease and chronic renal transplant dysfunction. These results are in line with the hypothesis that AGEs play a role in the pathogenesis of these conditions in renal transplant recipients. Prospective studies are required to investigate whether the AFR can be used as a simple, non-invasive tool to identify and monitor patients at risk for chronic renal transplant dysfunction and cardiovascular disease.

OBJECTIVE: To assess endothelial function at die level of skin microvasculature, using iontophoretic administration of acetylcholine (endothelium-dependent vasodilator) and sodium nitroprusside (endothelium-independent vasodilator), in women who recently had a preeclamptic pregnancy.METHODS: Microvascular skin reactivity was assessed by laser Doppler perfusion monitoring and iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP) in 25 women with a history of early onset preeclampsia and 23 women with previous uncomplicated pregnancies, all of whom were between 3 and 11 months postpartum.RESULTS: Mean (+/- standard error of the mean) ACh-mediated vasodilatation, expressed as a percentage increase in flux, was higher in women who decently had a preeclampsia than in controls (535 +/- 46% versus 314 +/- 29%, P CONCLUSION: The increased ACh-mediated vasodilatation in the microcirculation of recently preeclamptic women indicates abnormal endothelial function. Furthermore, it may represent a compensatory response to an impaired vasodilatory response of the macrocirculation, thereby supporting the hypothesis of an underlying (micro)angiopathy.

The standardisation of manoeuvres to perform clinically discriminative microvascular flow reserve tests is still poorly developed, as well as the response analysis. The aim of this study was to establish a reproducible analysis method for the post-occlusive reactive hyperaemia (PORE) test measured using laser Doppler perfusion monitoring (LDPM). LDPM data were measured from the PORH response of 24 Fontaine class II-III peripheral atherosclerotic/arterial obstructive disease (PAOD) patients and 30 healthy subjects. The PORH response was recorded from the dorsum of the foot after 3 min of arterial occlusion at the thigh. The resulting tracings were analysed by describing their morphology through five defined parameters: resting flux (RF), time to RF level (t(RF)), maximum flux (MF) during reactive hyperaermia, time to maximum flux (t(MF)) and time to half recovery (t(HR)). While the time parameters were discriminative between patients and controls, flux parameters were not. The time to resting flux (t(RF)) led to the most discriminative model that correctly predicted 88.5% of the cases. Hence, we concluded that obtaining tRF with the presented procedures provides an optimal model to quantify the patient's microvascular condition from the PORH response. (c) 2005 Elsevier Inc. All rights reserved.

To the Editor: With much interest we read the article published by Khan et al1 in the November 2005 issue of Hypertension on microvascular reactivity during normal and preeclamptic pregnancies. They showed that microvascular responses to iontophoretically applied acetylcholine and sodium nitroprusside are enhanced in women who will develop preeclampsia before the clinical symptoms of the syndrome appear. The authors found, however, no differences in the microvascular responses 6 weeks postpartum and stated that there was no study that had compared these responses shortly after pregnancy. We recently published our study in which we measured microvascular reactivity using iontophoresis and laser Doppler flowmetry between 3 to 11 months postpartum in 25 women who had a serious early onset (