Higher skin autofluorescence, but not plasma AGEs, is associated with lower ankle-brachial index

Marcelle GA van Eupen, Miranda T Schram, Pieter C Dagnelie, Nicolaas Schaper, Carla J.H. van der Kallen, Ronald MA Henry, Andries J Smit, Casper G Schalkwijk

Individuals with type 2 diabetes mellitus (T2DM) are at an increased cardiovascular disease (CVD) risk and advanced glycation endproducts (AGEs) are thought to play an important role in this increased atherogenesis. Therefore, we investigated the associations between skin autofluorescence (SAF) and plasma AGEs with the ankle-brachial index (ABI) and carotid intima-media thickness (cIMT), as proxy measures of CVD, in individuals with normal glucose metabolism (NGM), impaired glucose metabolism (IGM) and type 2 diabetes (T2DM).
We studied a cohort of 773 individuals from The Maastricht Study (425 NGM, 128 IGM and 220 T2DM) with mean age of 60±8y, 45% women. SAF was measured by use of the AGE Reader. Plasma levels of protein-bound pentosidine were measured with HPLC and fluorescence detection. Plasma protein-bound Nε-(carboxymethyl)lysine (CML) and Nε-(carboxyethyl)lysine (CEL) were measured with UPLC and tandem mass spectrometry. Associations were analysed with linear regression analyses and adjusted for age, sex, glucose metabolism status, waist circumference, smoking, systolic and diastolic blood pressure, antihypertensive, lipid lowering or oral glucose lowering medication use, insulin use, eGFR, total-to-HDL-cholesterol ratio, triglycerides, and prior CVD.

Higher SAF was associated with a lower ABI (sβ -0.13, 95%-CI -0.21;-0.05) but not with cIMT (sβ -0.02 95%-CI -0.10;0.06). In contrast, higher plasma CML was associated with a higher ABI (sβ 0.13, 95%-CI 0.06;0.21) and higher plasma CEL was associated with lower cIMT (sβ -0.07, 95%-CI -0.14;0.00).

Our observation that SAF was associated with a lower ABI supports the hypothesis that AGE accumulation is involved in the development of peripheral arteriosclerosis. However, we did not observe any association with cIMT, a proxy of  atherosclerosis. In addition, our results indicate that SAF, reflecting AGE accumulating over time in tissues with slow turnover, may be a better reflection of AGE accumulation in tissues than plasma AGEs.