Patients with complaints of numbness, tingling, and dysesthesias in
the toes and feet are frequently referred to neurologists. Often, the only
objective evidence for peripheral nerve dysfunction in these patients is limited
to small-caliber sensory nerve fibers. On examination these patients may have
reduced distal pinprick sensation, and distal leg skin biopsies show loss
of small-caliber nerve fibers. Studies focusing on small-caliber nerve fibers
have led to a growing impression that neuropathy can be associated with early
diabetes or impaired glucose tolerance (IGT). Often, neuropathy can be the
presenting symptom of either diabetes or IGT. Furthermore, the oral glucose
tolerance test appears to be a more sensitive measure of glucose dysmetabolism
in these patients than levels of fasting blood glucose or glycated hemoglobin.
Patients with IGT-associated neuropathy may represent an attractive target
population for future regenerative studies given that their neuropathy is
less severe and presumably more easily reversed than neuropathy occurring
in patients with diabetes.
Historically, small-caliber fibers have not been extensively evaluated
due to a lack of objective measures. Several measures to evaluate these fibers
are emerging, including skin biopsy with visualization of epidermal nerve
fibers. The accessibility of epidermal nerve fibers makes them an attractive
target for nerve injury models, which have potential for development as novel
outcome measures. Such approaches may address some of the challenges of past
diabetic polyneuropathy trials.