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 sexmatched 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 ε -(carboxymethyl)-lysine (CML) and N ε -(carboxyethyl)lysine (CEL).Results. Autofluorescence correlated with CLF, pentosidine, CML, and CEL (r=0.47-0.62, p≤0.002). 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.

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 < 0.001). AF correlated with collagen-linked fluorescence (r ‫؍‬ 0.71, P < 0.001), pentosidine (r ‫؍‬ 0.75, P < 0.001), and carboxy(m)ethyllysine (both r ‫؍‬ 0.45, P < 0.01). Skin AF is a strong and independent predictor of mortality in ESRD. This supports a role for AGE as a contributor to mortality and CVD and warrants interventions specifically aimed at AGE accumulation.

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.

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.

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.

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 diabetesassociated 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.

Accumulation of advanced glycation end products (AGEs) is thought to play a role in the pathogenesis of chronic complications of diabetes mellitus and renal failure. Several studies indicate that AGE accumulation in tissue may reflect the cumulative effect of hyperglycemia and oxidative stress over many years. Simple quantitation of AGE accumulation in tissue could provide a tool for assessing the risk of long-term complications. Because several AGEs exhibit autofluorescence, we developed a noninvasive autofluorescence reader (AFR). Skin autofluorescence measured with the AFR correlates with collagen-linked fluorescence and specific skin AGE levels from skin biopsy samples. Furthermore, skin autofluorescence correlates with long-term glycemic control and renal function, and preliminary results show correlations with the presence of long-term complications in diabetes. The AFR may be useful as a clinical tool for rapid assessment of risk for AGE-related long-term complications in diabetes and in other conditions associated with AGE accumulation.

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.