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.

Keywords: AGE; Advanced glycation end-products; Ankle-brachial index; Augmentation index; Glycemia; Prediabetes; Pulse wave velocity; Skin autofluorescence; Vascular stiffness.

Fig. 1

Associations between skin AF and glycemic status in the EPIC-DZD study. N = 3535. Glycemic status was defined as follows: normoglycemic (HbA1c < 5.7% and no antidiabetic treatment), prediabetes (6.5% > HbA1c ≥ 5.7% and no antidiabetic treatment), diabetes (antidiabetic treatment, HbA1c ≥ 6.5% or prevalent diabetes at EPIC-Potsdam baseline). Differences in medians of skin AF were compared with 1-way ANOVA with Tukey–Kramer’s correction for multiple testing. Linear trend in skin AF across glycemic strata was assessed with linear regression. AF autofluorescence, HbA_1c glycated hemoglobin 1C

Fig. 2

Adjusted associations between skin AF and vascular stiffness in the EPIC-DZD study. Adjusted associations between skin AF and parameters of vascular stiffness (a PWV, b AIx, c ABI) in the EPIC-DZD study, stratified by sex, median age, abdominal adiposity and glycemic status. Changes in vascular stiffness are per 1 unit increase in skin AF. Analyses were performed on fully adjusted model 2. p values for interaction terms: cfPWV: skin AF with sex, p = 0.002, with age, p = 0.07, with waist circumference, p = 0.02, with glycemic status, p = 0.77; aoPWV: skin AF with sex, p = 0.002, with age, p = 0.07, with waist circumference, p = 0.02, with glycemic status, p = 0.78; aoAIx: skin AF with sex, p = 0.0008, with age, p = 0.001, with waist circumference, p = 0.44, with glycemic status, p = 0.99; brAIx with sex, p = 0.006, with age, p = 0.004, with waist circumference, p = 0.67, with glycemic status, p = 0.37; ABI: skin AF with sex, p = 0.10, with age, p = 0.01, with waist circumference, p = 0.40, with glycemic status, p = 0.58. Analyses were adjusted for sex and age, BMI, waist circumference, smoking status (three categories: non-smoker, former smoker, current smoker), recreational physical activity (biking and sports, h/week), systolic and diastolic blood pressure, pulse, prevalent conditions (prevalent heart failure, prior myocardial infarction or stroke), antihypertensive and lipid-lowering treatment, CRP, LDL-, HDL- and total cholesterol, triglycerides and HbA1c. EPIC-DZD Sub-study of European Prospective Investigations into Cancer and Nutrition, AF autofluorescence, PWV pulse wave velocity, AIx augmentation index, ABI ankle-brachial index, ao aortic, br brachial, cf carotid-femoral

Fig. 3

Adjusted odds ratios for relationships between skin AF and vascular stiffness. Adjusted associations between skin AF and vascular stiffness defined as cfPWV ≥ 10 m/s (a) and cfPWV ≥ 12 m/s (b). Linearity was assessed with Wald test from restricted cubic splines, adjusted ORs are reported from logistic regression and per 1 unit increase in skin AF. Analyses were adjusted for sex and age, BMI, waist circumference, smoking status (three categories: non-smoker, former smoker, current smoker), recreational physical activity (biking and sports, h/week), systolic and diastolic blood pressure, pulse, prevalent conditions (prevalent heart failure, prior myocardial infarction or stroke), antihypertensive and lipid-lowering treatment, CRP, LDL-, HDL- and total cholesterol, triglycerides and HbA1c. AF autofluorescence, cfPWV carotid-femoral pulse wave velocity, OR odds ratio, CI confidence interval