Skin Autofluorescence is a Noninvasive Surrogate Marker for Diabetic Microvascular Complications and Carotid Intima–Media Thickness in Japanese Patients with Type 2 Diabetes: A Cross-sectional Study

Abstract

IntroductionAdvanced glycation end-products (AGEs) are known to play an important role in the pathogenesis of diabetic complications. Skin autofluorescence (AF), a marker of AGE accumulation in tissue, can be measured noninvasively using a skin AF reader. The present study aimed to evaluate the relationships of skin AF with diabetic microvascular complications and carotid intima–media thickness (IMT), a surrogate marker for atherosclerosis, in Japanese subjects with type 2 diabetes (T2D).MethodsOne hundred sixty-two subjects with T2D and 42 nondiabetic control subjects attending the outpatient clinic were examined. Skin AF and carotid max-IMT were measured using an AGE Reader™ and ultrasonography, respectively. Nephropathy was classified into five stages based on the urinary albumin-to-creatinine ratio (UACR) as follows: (1) pre-nephropathy (stage 1) (UACR < 30 mg/g Cr); (2) incipient nephropathy (stage 2) (30 ≤ UACR < 300 mg/g Cr); (3) overt nephropathy (stage 3) (UACR ≥ 300 mg/g Cr); (4) kidney failure (stage 4) (estimated glomerular filtration rate (eGFR) < 30 ml/min/1.732); and (5) dialysis therapy (stage 5). Patients with kidney failure and those receiving dialysis therapy were excluded because the sample size was too small. Retinopathy was diagnosed as nondiabetic retinopathy (NDR), nonproliferative retinopathy (NPDR), or proliferative retinopathy (PDR). Diabetic peripheral neuropathy (DPN) was diagnosed if two or more of the following were present: neuropathic symptoms (decreased sensation, positive neuropathic sensory symptoms), symmetric decreased distal sensation, and unequivocally decreased or absent ankle reflexes.ResultsSkin AF values were significantly higher in subjects with T2D (2.53 ± 0.45 AU) than in nondiabetic subjects (2.19 ± 0.34 AU, p < 0.001). Skin AF significantly increased with the severity of DPN (2.39 ± 0.37 with DPN vs 2.80 ± 0.48 without DPN, p < 0.001), retinopathy (NDR 2.42 ± 0.45, mild and moderate NPDR 2.64 ± 0.42, p = 0.042, severe NPDR and PDR 2.85 ± 0.35, p < 0.001), and nephropathy (pre-nephropathy 2.42 ± 0.44, incipient nephropathy 2.62 ± 0.45, p = 0.049, overt nephropathy 2.59 ± 0.46, p = 0.80). Skin AF was an independent determinant of the presence of DPN (OR 8.49, 95% CI 2.04–44.32, p = 0.006) and retinopathy (OR 3.73, 95% CI 1.20–12.90, p = 0.028) but not of diabetic nephropathy after correcting for confounding factors. In addition, skin AF (β = 0.170, p = 0.029) was an independent determinant of max-IMT, as was age (β = 0.436, p < 0.0001), after adjusting for other risk factors.ConclusionSkin AF as measured using an AGE Reader is a noninvasive surrogate marker for diabetic microvascular complications and early-stage atherosclerosis.

Association between Subclinical Atherosclerosis Markers and the Level of Accumulated Advanced Glycation End-Products in the Skin of Patients with Diabetes

“…The present study also confirmed that skin AF was associated with arterial thickening assessed by max-IMT and arterial stiffness assessed by baPWV, which was consistent with previous studies 7 – 9 , 21 ) . Considering the crucial roles of AGEs in the pathogenesis of atherosclerosis, it is reasonable that the index of AGEs accumulation in skin is associated with arterial thickening and/or stiffness.…”

“…Recently, the level of accumulated fluorescent AGEs in the skin has become measurable non-invasively as skin autofluorescence (skin AF) using an autofluorescence reader. Skin AF intensity is correlated with accumulation of skin AGEs assessed by skin biopsy 5 ) and has been shown to be associated with coronary artery calcification score used for the predictor of CVD 6 ) , diabetic complications and above mentioned indices of early-stage atherosclerosis such as carotid IMT and PWV 7 – 9 ) . With regard to endothelial dysfunction, however, such an association has not yet been validated in patients with DM, while Wang et al found a strong association between skin AF and FMD in uremic patients on hemodialysis 10 ) .…”

Are Advanced Glycation End Products in Skin Associated with Vascular Dysfunction Markers? A Meta-Analysis

“…The flowchart of this systematic review and meta-analysis is presented in Figure 1 . The search retrieved a total of 90 articles, of which 25 studies [ 12 , 13 , 15 , 16 , 17 , 18 , 20 , 21 , 22 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ] were selected for inclusion in the systematic review according to the inclusion criteria. Finally, 12 studies evaluating the association between PWv and SAF and 17 studies evaluating the association between C-IMT and SAF were identified and considered in the meta-analysis.…”

The Clinical Application of Skin Autofluorescence: An Indicator of Glycemic Control and Diabetic Nephropathy Progression

“…The study emphasized the role of skin AF as a predictor in the progression of DN. In view of type 2 diabetic patients, a recent study also confirmed that skin AF also significantly increased with the severity of DN [18].…”