Skin AGEs and diabetic neuropathy

Abstract

Advanced glycation end-products (AGEs) are heterogeneous molecules produced by the non-enzymatic glycation of proteins, lipids, or nucleic acids during hyperglycaemia. Accumulation of AGEs in the peripheral nerves has recently been proposed as an additional risk factor for the development of diabetic neuropathy (DN). The gold standard for measurement of tissue-bound AGEs is tissue biopsy. However, their assessment with the newer, fast and simple method of skin autofluorescence (sAF) has recently gained special interest by virtue of its non-invasive, highly reproducible nature and its acceptable correlation with the reference method of skin biopsy. Accumulation of tissue AGEs evaluated by sAF has been shown to independently correlate with DN. Importantly, increasing evidence underscores their potential value as early biomarkers of the latter. Further important associations include diabetic nephropathy, diabetic retinopathy and cardiovascular autonomic neuropathy. However, the value of the implementation of screening with skin AGEs for DN remains unclear. The aim of the present review is to critically summarise current evidence on the association between skin AGEs and diabetic microvascular complications, with a particular emphasis on diabetic neuropathy, and to note the most important limitations of existing knowledge. Longer follow-up studies are also highly anticipated to clarify its role and provide data on patient selection and cost-effectiveness.

Keywords: Advanced glycation end-products; Autofluorescence; Complications; Diabetes mellitus; Microvascular; Neuropathy.

Fig. 1

The contribution of AGEs to the pathogenesis of diabetic neuropathy. A major mechanism includes activation of the polyol pathway, leading to NADPH depletion and increased production of reactive oxygen species (ROS). The latter contribute to AGEs accumulation. AGEs act via the receptor of advanced glycation end products (RAGE), promote neural inflammation, impair neuronal electrical activity and induce unfavourable gene changes. These perturbations, along with direct neuronal toxicity from intracellular sorbitol accumulation, culminate in diabetic neuropathy. AGEs: advanced glycation end products; NADPH: Nicotinamide adenine dinucleotide phosphate; RAGE: receptor of advanced glycation end products; ROS: reactive oxygen species

Fig. 2

Skin autofluorescence, as measured by the autofluorescence reader AGE reader mu connect (Diagnoptics, NL). Local creams should not have been applied for 12 h. The examinee places the forearm of his/her dominant upper limb on the silicone armrest of the device. In this armrest, there is a small examination window for selection of a skin area. The elbow should be aligned with the edge of the armrest and no movements should be made during measurement. The examiner switches on the device using the power button. Activation is performed through the menu on the touch screen. AGEs result is shown on the screen. Approximate measurement duration is 30 s. Interpretation of results may be facilitated by available age- and sex-adjusted normative data