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Early increase precedes a depletion of VIP and PGP‐9.5 in the skin of insulin‐dependent diabetics—correlation between quantitative immunohistochemistry and clinical assessment of peripheral neuropathy

Diabetic neuropathy affects both sensory and autonomic peripheral nerve fibres. Vasoactive intestinal polypeptide (VIP) is present in autonomic fibres which modulate sweat secretion, while calcitonin gene‐related peptide (CGRP) is localized to cutaneous sensory fibres. In this study, immunohistochemistry and image analysis were used to assess changes of VIP and CGRP, and of the pan‐neuronal marker protein gene‐product (PGP)‐9.5, in skin biopsies of 18 patients affected by type 1 diabetes (age range 18–46 years) and from seven aged‐matched controls. Patients were divided into three groups: group 1 (n=6), with diabetes for 6 months to 3 years; group 2 (n=5), with the disease for 5–10 years; and group 3 (n=7), with diabetes for more than 10 years. VIP immunoreactivity (IR) and PGP‐9.5‐IR were significantly reduced around sweat glands (P <0.005) in groups 2 and 3. Epidermal CGRP‐IR and PGP‐9.5‐IR were significantly reduced in group 3 (P <0.05). Twenty‐eight per cent (5/18) of all patients showed high VIP‐IR around sweat glands (>95 per cent confidence limits of controls) and all of these patients had diabetes for less than 3 years. Conversely, 55 per cent (10/18) of patients had low VIP‐IR (<5 per cent confidence limit of controls). The latter, compared with the former, showed a significantly longer duration of diabetes (Fisher exact test P=0·002), presence of clinical autonomic neuropathy (Fisher exact test P=0.04), and a reduced sural nerve conduction velocity (Fisher exact test P=0.04). These results suggest that quantitative immunohistochemical analysis of peptide‐containing cutaneous nerves allows an objective evaluation of nerve fibre alterations at early stages of diabetes than is currently possible with neurophysiological functional tests.