Summary
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 und 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.
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Pirart J (1978) Diabetes mellitus and its degenerative complications: 3 a prospective study of 4400 patients observed between 1947 and 1973. Diabetes Care 1: 168–188
Zimmerman BR (1987) Current status of aldose reductase inhibitors. Diabetes Care 10: 123–125
Gorio A (1986) Ganglioside enhancement of neuronal differentiation, plasticity and repair. CRC Cr Rev Clin Neurobiol 2: 241–296
Fagius J, Wahren LK (1981) Variability of sensory threshold determination in clinical use. J Neurol Sci 51: 11–27
Behse F, Buchthal F, Carlsen F, Knappeis GG (1975) Unmyelinated fibres and Schwann cells of sural nerve in neuropathy. Brain 98: 492–510
Bloom SR, Polak JM (1983) Regulatory peptides in the skin. Clin Exp Dermatol 8: 3–18
Gazelius B, Edwall B, Olgart L, Lundberg JM, Hökfelt T, Fischer JA (1988) Vasodilatory effects and coexistence of calcitonin generelated peptide (CGRP) and substance P in sensory nerves of cat dental pulp. Acta Physiol Scand 130: 33–40
Foreman JC (1987) Peptides and neurogenic inflammation. Br Med Bull 43: 386–400
Fuller RW, Conradson T-B, Dixon CMS, Crossman DC, Barnes PJ (1987) Sensory neuropeptide effects in human skin. Br J Pharmacol 92: 781–788
Gu J, Lazarides M, Pryor JP, Blank MA, Polak JM, Morgan R, Marangos PJ, Bloom SR (1984) Decrease of vasoactive intestinal polypeptide (VIP) in the penises from impotent men. Lancet II: 315–317
Crowe R, Lincoln J, Blacklong PF, Pryor JP, Lumley JSP, Burnstock G (1983) Vasoactive intestinal polypeptide-like immunoreactive nerves in diabetic penis: a comparison between streptozotocin-treated rats and man. Diabetes 32: 1075–1077
Lundberg JM, Hökfelt T, Schultzberg M, Uvnäs-Wallenstein K, Köhler C, Said SI (1979) Occurrence of vasoactive intestinal polypeptide (VIP)-like immunoreactivity in certain cholinergic neurons of the cat: evidence from combined immunohistochemistry and acetylcholinesterase staining. Neuroscience 4: 1539–1559
Low PA, Caskey PE, Tuck RR, Fealey RD, Dyck PJ (1983) Quantitative sudomotor axon reflex test in normal and neuropathic subjects. Ann Neurol 14: 573–580
Kennedy WR, Sakuta M, Sutherland D, Goetz FC (1984) Quantitation of the sweating deficiency in diabetes mellitus. Ann Neurol 15: 482–488
Landis SC, Fredieu JR (1986) Coexistence of calcitonin gene-related peptide and vasoactive intestinal peptide in cholinergic sympathetic innervation of rat sweat glands. Brain Res 377: 177–181
Pernow J, Saria A, Lundberg JM (1986) Mechanisms underlying pre- and post-functional effects of neuropeptide Y in sympathetic vascular control. Acta Physiol Scand 126: 239–249
Edvinsson L, Ekman R, Jansen I, Ottosson A, Uddman R (1987) Peptide-containing nerve fibers in human cerebral arteries: immunocytochemistry, radioimmunoassay, and in vitro pharmacology. Ann Neurol 21: 431–437
Zomzeley-Neurath C, Walker W (1980) In: Bradshaw RA, Schneider DM (eds) Proteins of the nervous system, 2nd ed. Raven Press, New York, pp 1–57
Hacker GW, Polak JM, Springall DR, Ballesta J, Cadieux A, Gu J, Trojanowski JQ, Dahl D, Marangos PJ (1985) Antibodies to neurofilament protein and other brain proteins reveal the innervation of peripheral organs. Histochemistry 82: 581–593
Thompson RJ, Doran JF, Jackson P, Dhillon AP, Rode J (1983) PGP 9.5 — a new marker for vertebrate neurons and neuroendocrine cells. Brain Res 278: 224–228
Gulbenkian S, Wharton JM, Polak JM (1987) The visualisation of cardiovascular innervation in the guinea pig using an antiserum to protein gene product 9.5 (PGP 9.5). J Autonom Nerv Syst 18: 235–247
Karanth SS, Springall DR, Lucas S, Levy D, Ashby P, Levene MM, Polak JM (1989) Changes in nerves and neuropeptides in skin from 100 leprosy patients investigated by immunocytochemistry. J Pathol 156: 15–26
Abraham RR, Abraham RM, Wynn V (1986) Autonomie and electrophysiological studies in patients with signs or symptoms of diabetic neuropathy. Electroencephalogr Clin Neurophysiol 63: 223–230
Levy DM, Abraham RR, Abraham RM (1987) Small- and largefiber involvement in early diabetic neuropathy: a study with the medial plantar response and sensory thresholds. Diabetes Care 10: 441–447
Ewing DJ, Clarke BF (1982) Diagnosis and management of diabetic autonomie neuropathy. Br Med J 285: 916–918
Faerman I, Faccio E, Calb I, Razumny J, Franco N, Dominguez A, Podestá HA (1982) Autonomie neuropathy in the skin: a histological study of the sympathetic nerve fibres in diabetic anhidrosis. Diabetologia 22: 96–99
Johnson PC, Doll SC (1984) Dermal nerves in human diabetic subjects. Diabetes 33: 244–250
Waxman SG, Brill MH, Geschwind N, Sabin TD, Lettvin JY (1976) Probability of conduction deficit as related to fiber length in random-distribution models of peripheral neuropathies. J Neurol Sci 29: 39–53
Morley GK, Mooradian AD, Levine AS, Morley JE (1984) Mechanism of pain in diabetic peripheral neuropathy: effect of glucose on pain perception in humans. Am J Med 77: 79–82
Aronin N, Leeman SE, Clements RS Jr (1987) Diminished flare response in neuropathic diabetic patients: comparison of effects of substance P, histamine, and capsaicin. Diabetes 36: 1139–1143
Parkhouse N, Le Quesne PM (1988) Quantitative objective assessment of peripheral nociceptive C fibre function. J Neurol Neurosurg Psychiatry 51: 28–34
Jakobsen J, Sidenius P, Braendgaard H (1986) A proposal for a classification of neuropathies according to their axonal transport abnormalities. J Neurol Neurosurg Psychiatry 49: 986–990
Marini P, Vitadello M, Bianchi R, Triban C, Gorio A (1986) Impaired axonal transport of acetylcholinesterase in the sciatic nerve of alloxan-diabetic rats: effects of ganglioside treatment. Diabetologia 29: 254–258
Newrick PG, Wilson AJ, Jakubowski J, Boulton ATM, Ward JD (1986) Sural nerve oxygen tension in diabetes. Br Med J 293: 1053–1054
Sima AAF, Bril V, Nathaniel V, McEwen TAJ, Brown MB, Lattimer SA, Greene DA (1988) Regeneration and repair of myelinated fibers in sural-nerve biopsy specimens from patients with diabetic neuropathy treated with sorbinil. N Engl J Med 319: 542–548
Consensus statement: report and recommendations of the San Antonio conference on diabetic neuropathy (1988) Diabetes Care 11: 592–597
Lawrence RD (1965) The diabetic life: a concise practical manual, 17th edn. Churchill, London, p 157
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Levy, D.M., Karanth, S.S., Springall, D.R. et al. Depletion of cutaneous nerves and neuropeptides in diabetes mellitus: an immunocytochemical study. Diabetologia 32, 427–433 (1989). https://doi.org/10.1007/BF00271262
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DOI: https://doi.org/10.1007/BF00271262