Advanced glycation end-products, measured as skin autofluorescence, associate with vascular stiffness in diabetic, pre-diabetic and normoglycemic individuals: a cross-sectional study

Abstract

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.

Advanced Glycations End Products in the Skin as Biomarkers of Cardiovascular Risk in Type 2 Diabetes

“…SAF is strongly correlated with pulse wave velocity, brachial and aortic augmentation indices, and ankle-brachial index, all of them markers of arterial stiffness [ 72 ]. Birukov et al [ 84 ] recently investigated the relationships between SAF and vascular stiffness in a large study performed in diabetic and non-diabetic populations. These authors concluded that SAF might be involved in vascular stiffening independently of cardiometabolic risk factors, and it could be a rapid and non-invasive method for the assessment of macrovascular disease progression across all glycemic strata [ 84 ].…”

“…Birukov et al [ 84 ] recently investigated the relationships between SAF and vascular stiffness in a large study performed in diabetic and non-diabetic populations. These authors concluded that SAF might be involved in vascular stiffening independently of cardiometabolic risk factors, and it could be a rapid and non-invasive method for the assessment of macrovascular disease progression across all glycemic strata [ 84 ]. However, Osawa et al [ 82 ], in a smaller study including only subjects with type 2 diabetes, showed that SAF was significantly associated with C-IMT and pulse wave velocity (PWv), but it was not an independent determinant of C-IMT and PWv after adjustment for confounders [ 82 ].…”

Dicarbonyl Stress in Diabetic Vascular Disease

“…In a subset of patients of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort (EPIC-DZD), AGEs were measured independent of diabetes status and vascular stiffness. Skin autofluorescence was positively associated with markers of vascular stiffness, such as pulse wave velocity and augmentation index in diabetic patients, and the ankle-brachial index was inversely associated with skin autofluorescence across all sex, age, and glycaemia strata [ 92 ].…”

Circulating levels of AGEs and soluble RAGE isoforms are associated with all-cause mortality and development of cardiovascular complications in type 2 diabetes: a retrospective cohort study

“…A significantly increased burden of AGEs was described in aging and age-related diseases (ARDs), primarily in diabetes mellitus [ 2 , 4 ], and their levels, measured using skin autofluorescence, were associated with a significant increase in the incidence of major adverse cardiovascular events (MACE) in a multitude of chronic conditions, including heart failure [ 5 ], type 2 diabetes [ 6 ], and end-stage renal disease [ 7 ]. The contribution of AGEs in fostering endothelial dysfunction and exacerbating atherosclerosis has been confirmed by their robust association with non-invasive measures of arterial stiffness, which is more pronounced in men and younger individuals [ 8 ]. The membrane-bound RAGE (FL-RAGE) is a pattern recognition receptor that recognizes AGEs and several other ligands, some of which act as damage-associated molecular patterns (DAMPS) and pathogen-associated molecular patterns (PAMPs) [ 9 – 11 ].…”