title: Increased axonal regeneration and swellings in intraepidermal nerve fibers characterize painful phenotypes of diabetic neuropathy.
abstract: We examined changes in intraepidermal nerve fibers (IENFs) to differentiate patients with diabetic neuropathy (DN) and diabetic neuropathic pain (DN-P) from those with DN without pain (DN-NOP). Punch skin biopsies were collected from the proximal thigh (PT) and distal leg (DL) of normal subjects, patients with type 2 diabetes without evidence of DN (DM), or DN-P and DN-NOP patients. Protein gene product 9.5-positive (PGP+) immunohistochemistry was used to quantify total IENF, and growth-associated protein 43 (GAP43) for regenerating IENF. Compared to normal subjects and patients with type 2 diabetes without evidence of DN, both DN-P and DN-NOP have reduced PGP+ IENF densities in DL and PT. Although GAP43+ IENF densities were also reduced in DL for both DN-P and DN-NOP, the GAP43+ IENF densities in PT of DN-P remained at the control levels. Higher GAP43/PGP ratios were detected in DN-P compared to DN-NOP in the DL and PT. In parallel, increased numbers of axonal swellings per PGP+ fiber (axonal swelling/PGP) were detected in DN-P compared to normal subjects, patients with type 2 diabetes without evidence of DN, and DN-NOP in the DL. These axonal swellings were positive for tropomyosin-receptor-kinase A and substance P, suggesting that they are associated with nociception.
  
  
  CONCLUSIONS
  Among patients with DN, the ratios of GAP43/PGP and axonal swelling/PGP are likely to differentiate painful from painless phenotypes.
authors.affiliation: Department of Neurology, University of Michigan Medical Center, Ann Arbor, Michigan 48109-2200, USA. chengt@umich.edu
authors.forename: Hsinlin T
authors.initials: HT
authors.lastname: Cheng
authors.forename: Jacqueline R
authors.initials: JR
authors.lastname: Dauch
authors.forename: Michael T
authors.initials: MT
authors.lastname: Porzio
authors.forename: Brandon M
authors.initials: BM
authors.lastname: Yanik
authors.forename: Wilson
authors.initials: W
authors.lastname: Hsieh
authors.forename: A Gordon
authors.initials: AG
authors.lastname: Smith
authors.forename: J Robinson
authors.initials: JR
authors.lastname: Singleton
authors.forename: Eva L
authors.initials: EL
authors.lastname: Feldman
mesh_terms: D000368:Aged; D001369:Axons / Q000473:pathology*; D003929:Diabetic Neuropathies / Q000150:complications*; D004817:Epidermis / Q000294:innervation*; D005260:Female; D019922:GAP-43 Protein / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009410:Nerve Degeneration; D009412:Nerve Fibers / Q000378:metabolism / Q000473:pathology; D009437:Neuralgia / Q000209:etiology*; D010147:Pain Measurement; D020917:Receptor, trkA / Q000378:metabolism; D013373:Substance P / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism
chemical_list: D019922:GAP-43 Protein; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D013373:Substance P; D020917:Receptor, trkA
keywords: Diabetic pain; intraepidermal nerve fiber; peripheral neuropathy