Depletion of cutaneous nerves and neuropeptides in diabetes mellitus: an immunocytochemical study

Abstract

Immunocytochemistry for the general neuronal marker protein gene product 9.5 and four neuropeptides (calcitonin gene-related peptide, substance P, vasoactive intestinal polypeptide and neuropeptide Y) was performed on 20 skin biopsy specimens from 19 diabetic patients, age range 20-75 years, 17 Type 2 (non-insulin-dependent) and 3 Type 1 (insulin-dependent). Fifteen specimens were from the lower limb, 3 from the upper limb and 2 from the abdominal wall. Seven subjects had lower limb neurophysiological tests. All but one specimen showed reduced protein gene product 9.5 and neuropeptide immunoreactivity. Reduced protein gene product 9.5 and neuropeptide immunoreactivity was found in specimens taken from the abdominal wall and hand as well as those from the leg, and also in specimens from patients undergoing amputation for peripheral vascular disease. In general, the greater the number of abnormal neurophysiological tests, the greater the extent of neuronal abnormalities. Three patients with normal tests had abnormalities of dermal innervation. While these changes are also found in other axonal neuropathies, in the absence of other causes of peripheral nerve disease and of macrovascular disease, immunocytochemistry of skin biopsies may have a role in the assessment of diabetic neuropathy and its response to treatment.

SOD2 protects neurons from injury in cell culture and animal models of diabetic neuropathy

“…a lower IENFD than the SOD2 +/+ db/db mice (p < 0.05). The anticipated differences between epidermal nerve fiber densities in diabetic and control animals (regardless of SOD2 expression) were also in accordance with published reports in human patients (Yasuda et al, 1985;Levy et al, 1989;Kennedy et al, 1996;Arezzo, 1999) and experimental models of DN (Christianson et al, 2003).…”

“…The foot pad innervation study in the male C57BL/6J SOD2 +/+ and SOD2 +/− mice confirmed that there was no hind paw neuropathy. This anatomical assessment of neuropathy is part of the standard neuropathy phenotyping recommended by the AMDCC (www.amdcc.org) and is sensitive and reproducible (Levy et al, 1989;Kennedy et al, 1996;Arezzo, 1999). The TRAP values suggest that these mice did not develop significant oxidative stress in the DRG, so we may conclude that loss of one copy of SOD2 was not sufficient to increase oxidative stress in vivo, despite our observations in vitro.…”

Aldose Reductase Pathway Inhibition Improved Vascular and C-Fiber Functions, Allowing for Pressure-Induced Vasodilation Restoration During Severe Diabetic Neuropathy

“…Uehara et al (35) revealed that the pain sensation in diabetic mice was initially hyperalgesic, followed by late hypoesthesia in the presence of severe neuropathy. In diabetic patients, thermal hypoalgesia is associated with degenerative neuropathy, which includes the loss of epidermal C-fiber terminals (33,36). Accordingly, with increasing duration of diabetes (7-9 weeks), there is a loss of C-fibers in diabetic mice (16,37).…”

Prevention of sensory disorders in diabetic Sprague-Dawley rats by aldose reductase inhibition or treatment with ciliary neurotrophic factor

“…Abnormal perception of heat and heat-induced pain occurs in diabetic patients and can range from thermal hyperalgesia in early stages of neuropathy to the progressive thermal hypoalgesia associated with degenerative neuropathy, which includes the loss of the epidermal C fibre terminals involved in thermal nociception [23,24,25]. The thermal response latency represents a similar test in diabetic rodents, but it is not yet clear whether loss of epidermal C fibres occurs in diabetic rats with thermal hypoalgesia.…”