Association between small fiber neuropathy and higher skin accumulation of advanced glycation end products in patients with type 1 diabetes

INTRODUCTION Advanced glycation end products (AGEs) play a crucial role in the pathogenesis of diabetic peripheral neuropathy (DPN).
OBJECTIVES The aim of the study was to assess the skin accumulation of AGEs in patients with long‑lasting type 1 diabetes in relation to the presence of DPN.
PATIENTS AND METHODS We evaluated 178 patients with type 1 diabetes (99 men; age, 43 years [interquartile range [IQR], 34–54 years]; disease duration, 25 years [IQR, 18–31 years]). DPN was diagnosed if 2 or more of the following 5 abnormalities were present: symptoms of neuropathy, lack of ankle reflexes, and impaired sensation of touch, temperature, and/or vibration. PGP 9.5‑immunoreactive nerve fibers were counted to assess intraepidermal nerve fiber density (IENFD) in skin biopsy. The accumulation of AGEs in the skin was assessed on the basis of skin autofluorescence (AF). 
RESULTS Patients with DPN (45%), compared with those without neuropathy, had higher skin AF (2.6 AU [IQR, 2.3–3.1 AU] vs 2.1 AU [IQR, 1.8–2.5 AU]; P <0.001) and lower IENFD (10 fibers/mm [IQR, 7–14 fibers/mm] vs 12 fibers/mm [IQR, 8–16 fibers/mm]; P = 0.005). We found a positive correlation between skin AF and patients’ age (Rs = 0.44; P <0.001), diabetes duration (Rs = 0.32; P <0.001), and a negative correlation between skin AF and the estimated glomerular filtration rate (Rs = –0.26, P <0.001) and IENFD (Rs = –0.22; P = 0.004). In a multiple linear regression analysis, skin AF was independently associated with age (β = 0.45; P <0.001), glycated hemoglobin level (β = 0.19; P = 0.007), and IENFD (β = - 0.14; P = 0.04) (R2 = 0.27; P <0.001). In multivariate logistic regression, the presence of DPN was independently associated with skin AF (odds ratio, 4.16; 95% confidence interval, 1.88–9.20; P <0.001).
CONCLUSIONS The presence of DPN, and particularly small fiber neuropathy, is associated with a higher accumulation of AGEs in the skin of patients with type 1 diabetes.