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Skin Autofluorescence – A Non-invasive Measurement for Assessing Cardiovascular Risk and Risk of Diabetes

European Endocrinology, 2014;10(2):106–10 DOI: http://doi.org/10.17925/EE.2014.10.02.106

Abstract:

The results of the Diabetes Control and Complications Trial-Epidemiology of Diabetes Interventions and Complications (DCCT-EDIC) study have strengthened the ‘glycaemic memory’ concept, postulating that the quality of metabolic control over several years predicts the development of diabetic complications. To mirror long-term metabolic control, the degree of glycated haemoglobin (HbA1c) might not represent the optimal biomarker. Other substances with a longer persistence, like the so-called advanced glycation end-products (AGEs), which probably form the substrate of the glycaemic memory, might perform better. Newly developed methods such as the assessment of skin autofluorescence (SAF), enable fast, uncomplicated and non-invasive AGEs assessment. SAF was validated for diabetes screening and shows a good predictive value for the development of diabetic and cardiovascular complications. This article deals with the theoretical background and with available clinical data on this new variable.

Keywords: Advanced glycation end-products, skin autofluorescence, cardiovascular risk, diabetes, complications
Disclosure: Alin Stirban and Lutz Heinemann have received fees from DiagnOptics.
Received: March 17, 2014 Accepted: July 28, 2014
Correspondence: Alin Stirban, Director Endocrinology and Diabetes Complications, Institut für Stoffwechselforschung GmbH, Hellersbergstr. 9, 41460 Neuss, Germany. E: alin.stirban@profil.com
Support: The publication of this article was supported by DiagnOptics. The views and opinions expressed are those of the authors and not necessarily those of DiagnOptics.

Theoretical Background
Advanced glycation end-products (AGEs) and oxidative stress (OS) are two main contributors to the development of diabetic complications.1,2 AGEs represent a heterogeneous substance class, produced through nonenzymatic glycation of proteins, lipids or nucleic acids within the so-called Maillard reaction (MR). Intermediate products of the MR are Schiff’s bases and Amadori products (e.g. the glycated haemoglobin [ HbA1c]).3 The MR is important for nutrient preparation, explaining the browning of foods during heating causing specific colour and taste. Food AGEs are partially absorbed from the gut,4 but AGEs are also produced endogenously under physiological conditions. This process is exacerbated by hyperglycaemia, hyperlipidaemia or increased OS.3

Endogenous and exogenous AGEs are partially degraded in the body or eliminated via the kidneys. Modification of the aminoacid(s) in the active centre of the enzyme by the AGEs is responsible, for example, for the alterations of enzyme activity (non-receptor-dependent mechanisms). In addition, AGEs bind to specific receptors thus inducing intracellular processes such as OS or inflammation (receptor-dependent mechanisms). An increased endogenous and exogenous AGEs supply and accumulation contributes to the development of vascular complications in both patients with and without diabetes,3 thus playing a central role in the ‘glycaemic memory’ concept.

The Diabetes Control and Complications Trial (DCCT) demonstrated that improved metabolic control in patients with type 1 diabetes mellitus (T1DM) reduces microvascular and neuropathic complications.5 The fact that glycated proteins form stable AGEs, which accumulate in tissues affected by diabetes complications6 led to the establishment of the previously mentioned concept of glycaemic memory.7 The assumption is that AGEs represent the substrate of the glycaemic memory and cause diabetes complications.8 Measuring AGEs might therefore represent an integrated variable, reflecting tissue glucose exposure over several years and thus more accurately predicting the risk of diabetes complications than the HbA1c that mirrors glycaemic control over 8–12 weeks only.8,9

Circulating or tissue-bound AGEs can be measured using enzymelinked immunosorbent assay (ELISA), fluorescence spectroscopy, fluid chromatography and gas chromatography with mass spectrometry.10 While the measurement of circulating AGEs shows high physiological fluctuations (e.g. postprandial),4 the measurement of tissue-bound AGEs is more stable. In particular, tissues with a slow turnover (e.g. dermis, vascular walls and eye lenses) display a high AGEs accumulation and are therefore most suitable for AGEs assessment.11

The skin represents the most accessible tissue for AGEs measurements, with the biochemical analysis of skin biopsies constituting the golden standard.11,12 However, this method is invasive, expensive, requires analysis in specialised centres and results are available within days to weeks. A growing interest in the non-invasive assessment of AGEs existed lately and non-invasive methods were developed which measure the AGEs-related EUROPEAN ENDOCRINOLOGY 107 autofluorescence (AF) of the skin (AGE Reader, DiagnOptics, Groningen, the Netherlands, or SCOUT DS®, VeraLight, Albuquerque, New Mexico, USA), of the cornea or the lens (FluorotronTM, OcuMetrics, Mountain View, California, USA), allowing for a quick, reproducible and relatively low-cost measurement of AGEs accumulation.12–14 Interestingly, not all devices were developed from the very beginning with the purpose of measuring AGErelated fluorescence. The Fluorotron device primary purpose, for example, was to assess the retinal leakage by measuring fluorescein fluorescence (the excitation light it emits is of 440–480 nm and detector is capturing 531–634 nm, fluorescein ex/em of 490/520 nm) in the eye after intravenous injection. However, the instrument was demonstrated to be useful in the assessment of eye-related AGEs-like fluorescence.

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Keywords: Advanced glycation end-products, skin autofluorescence, cardiovascular risk, diabetes, complications