Skin denervation in type 2 diabetes: correlations with diabetic duration and functional impairments

Abstract

Sensory neuropathy is a prominent component of diabetic neuropathy. It is not entirely clear how diabetes influences skin innervation, and whether these changes are correlated with clinical signs and laboratory findings. To investigate these issues, we performed skin biopsies on the distal leg of 38 consecutive type 2 diabetic patients with sensory symptoms in lower limbs (25 males and 13 females, aged 56.2 +/- 9.4 years) and analysed the correlations of intraepidermal nerve fibre (IENF) densities in skin with glycaemic status (duration of diabetes, HbA1C, and fasting and post-prandial glucose levels), and functional parameters of small fibres (warm and cold thresholds) and large fibres (vibratory threshold and parameters of nerve conduction studies). Clinically, 23 patients (60.5%) had signs of small-fibre impairment, and 19 patients (50.0%) had signs of large-fibre impairment. IENF densities were much lower in diabetic patients than in age- and gender-matched controls (1.794 +/- 2.120 versus 9.359 +/- 3.466 fibres/mm, P < 0.0001), and 81.6% (31/38) of diabetic patients had reduced IENF densities. IENF densities were negatively associated with the duration of diabetes (standardized coefficient: -0.422, P = 0.015) by analysis with a multivariate linear regression model. Abnormal results of functional examinations were present in 81.6% (warm threshold), 57.9% (cold threshold), 63.2% (vibratory threshold) and 49% (amplitude of sural sensory action potential) of diabetic patients. Among the three sensory thresholds, the warm threshold temperature had the highest correlation with IENF densities (standardized coefficient: -0.773, P < 0.0001). On nerve conduction studies in lower-limb nerves, there were abnormal responses in 54.1% of sural nerves, and 50.0% of peroneal nerves. Of neurophysiological parameters, the amplitude of the sural sensory action potential had the highest correlation with IENF density (standardized coefficient: 0.739, P < 0.0001). On clinical examination, 15 patients showed no sign of small-fibre impairment, but seven of these patients had reduced IENF densities. In conclusion, small-fibre sensory neuropathy presenting with reduced IENF densities and correlated elevation of warm thresholds is a major manifestation of type 2 diabetes. In addition, the extent of skin denervation increases with diabetic duration.

Remote neurotrophic support of epidermal nerve fibres in experimental diabetes

“…Both diabetes and impaired glucose tolerance are associated with a decreased ENFD in humans [16,40]. In particular, the duration of clinical diabetes has an inverse correlation with ENFD [16,41]. Clearly, there are similarities between our experimental findings and the human condition, and future studies may lead to potential clinical interventions for patients with diabetic small fibre neuropathy.…”

Diabetic Painful and Insensate Neuropathy: Pathogenesis and Potential Treatments

“…Emerging new techniques such as corneal confocal microscopy, a reiterative, rapid, noninvasive in vivo imaging technique for quantitative assessment of degeneration and regeneration of corneal nerve fibers, 65,66 and skin biopsy with visualization and quantitation of epidermal nerve fibers [67][68][69] have generated enormous potential for a better understanding the mechanisms underlying small nerve fiber degeneration, a phenomenon that may ultimately lead to a complete loss of sensory function and that is a major cause of foot amputation.…”

Reduced Vascular Endothelial Growth Factor Expression and Intra-Epidermal Nerve Fiber Loss in Human Diabetic Neuropathy

“…IENF density (IENFD) is significantly reduced in diabetic patients with minimal neuropathy (7), is related to painful symptoms and neuropathic deficits (8), and may improve after lifestyle intervention (9). In the present study we used skin biopsy samples to quantify IENF loss in relation to the expression of HIF-1␣ and its principle target gene, VEGF and its receptor (vascular endothelial growth factor receptor 2 [VEGFR-2]), in diabetic patients with increasing severity of neuropathy.…”