The role of endogenous nerve growth factor in human diabetic neuropathy

Nerve growth factor (NGF) is trophic to sensory and sympathetic fibers(1-3). In animal models, NGF is depleted in diabetic nerves(4) and NGF deprivation produces hypoalgesia(5). Exogenous NCF can reverse some of the pathological changes in diabetic nerves(1,6) and NGF excess leads to hyperalgesia(5). We have quantified sensory and autonomic function in early diabetic polyneuropathy and correlated changes with levels of NCF and neuropeptides in affected skin. We describe an early length-dependent dysfunction of sensory small-diameter fibers, prior to dysfunction of sympathetic fibers, with depletion of skin NCF and the sensory neuropeptide substance P. We describe a significant correlation between NCF depletion and decreased skin axon-reflex vasodilation, mediated by small sensory fibers partly via substance P release(3). Immunostaining shows depletion of NGF in keratinocytes in diabetic skin. We propose that a decrease in endogenous skin-derived NCF influences the presentation of diabetic polyneuropathy, although metabolic or vascular abnormalites may be the cause of the neuropathy(7,8). As loss of nociception and axon-reflex vasodilation contribute to diabetic foot ulceration(9), early and prolonged NGF treatment at an appropriate dose may provide rational prophylaxis for this condition.