Differential hypertrophy and atrophy among all types of cutaneous innervation in the glabrous skin of the monkey hand during aging and naturally occurring type 2 diabetes

J Comp Neurol. 2007 Apr 1;501(4):543-67. doi: 10.1002/cne.21262.


Diabetic neuropathy (DN) is a common severe complication of type 2 diabetes. The symptoms of chronic pain, tingling, and numbness are generally attributed to small fiber dysfunction. However, little is known about the pathology among innervation to distal extremities, where symptoms start earliest and are most severe, and where the innervation density is the highest and includes a wide variety of large fiber sensory endings. Our study assessed the immunochemistry, morphology, and density of the nonvascular innervation in glabrous skin from the hands of aged nondiabetic rhesus monkeys and from age-matched monkeys that had different durations of spontaneously occurring type 2 diabetes. Age-related reductions occurred among all types of innervation, with epidermal C-fiber endings preferentially diminishing earlier than presumptive Adelta-fiber endings. In diabetic monkeys epidermal innervation density diminished faster, became more unevenly distributed, and lost immunodetectable expression of calcitonin gene-related peptide and capsaicin receptors, TrpV1. Pacinian corpuscles also deteriorated. However, during the first few years of hyperglycemia, a surprising hypertrophy occurred among terminal arbors of remaining epidermal endings. Hypertrophy also occurred among Meissner corpuscles and Merkel endings supplied by Abeta fibers. After longer-term hyperglycemia, Meissner corpuscle hypertrophy declined but the number of corpuscles remained higher than in age-matched nondiabetics. However, the diabetic Meissner corpuscles had an abnormal structure and immunochemistry. In contrast, the expanded Merkel innervation was reduced to age-matched nondiabetic levels. These results indicate that transient phases of substantial innervation remodeling occur during the progression of diabetes, with differential increases and decreases occurring among the varieties of innervation.

MeSH terms

  • Age Factors
  • Aging / metabolism
  • Aging / pathology*
  • Animals
  • Atrophy
  • Calcitonin Gene-Related Peptide / metabolism
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology*
  • Fluorescent Antibody Technique / methods
  • GAP-43 Protein / metabolism
  • Hand / pathology*
  • Hypertrophy
  • Macaca mulatta
  • Mechanoreceptors / cytology
  • Mechanoreceptors / metabolism
  • Models, Biological
  • Neurofilament Proteins / metabolism
  • Pacinian Corpuscles / pathology*
  • Proteins / metabolism
  • Skin / innervation*
  • Skin / pathology
  • TRPV Cation Channels / metabolism


  • GAP-43 Protein
  • Neurofilament Proteins
  • Proteins
  • TRPV Cation Channels
  • Calcitonin Gene-Related Peptide