Original Report| Volume 14, ISSUE 9, P941-947, September 2013

Download started.


Increased Axonal Regeneration and Swellings in Intraepidermal Nerve Fibers Characterize Painful Phenotypes of Diabetic Neuropathy


      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.


      Among patients with DN, the ratios of GAP43/PGP and axonal swelling/PGP are likely to differentiate painful from painless phenotypes.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The Journal of Pain
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Britland S.T.
        • Young R.J.
        • Sharma A.K.
        • Clarke B.F.
        Association of painful and painless diabetic polyneuropathy with different patterns of nerve fiber degeneration and regeneration.
        Diabetes. 1990; 39: 898-908
        • Cheng H.T.
        • Callaghan B.
        • Dauch J.R.
        • Feldman E.L.
        Cytoskeleton, axonal transport, and mechanisms of axonal neuropathy.
        in: Nixon R.A. Yuan A. Cytoskeleton of the Nervous System. Springer, New York2011: 657-678
        • Cheng H.T.
        • Dauch J.R.
        • Hayes J.M.
        • Hong Y.
        • Feldman E.L.
        Nerve growth factor mediates mechanical allodynia in a mouse model of type 2 diabetes.
        J Neuropathol Exp Neurol. 2009; 68: 1229-1243
        • Cheng H.T.
        • Dauch J.R.
        • Hayes J.M.
        • Yanik B.M.
        • Feldman E.L.
        Nerve growth factor/p38 signaling increases intraepidermal nerve fiber densities in painful neuropathy of type 2 diabetes.
        Neurobiol Dis. 2012; 45: 280-287
        • Christianson J.A.
        • Riekhof J.T.
        • Wright D.E.
        Restorative effects of neurotrophin treatment on diabetes-induced cutaneous axon loss in mice.
        Exp Neurol. 2003; 179: 188-199
        • Ebenezer G.J.
        • McArthur J.C.
        • Thomas D.
        • Murinson B.
        • Hauer P.
        • Polydefkis M.
        • Griffin J.W.
        Denervation of skin in neuropathies: The sequence of axonal and Schwann cell changes in skin biopsies.
        Brain. 2007; 130: 2703-2714
        • Fantini F.
        • Johansson O.
        Expression of growth-associated protein 43 and nerve growth factor receptor in human skin: A comparative immunohistochemical investigation.
        J Invest Dermatol. 1992; 99: 734-742
        • Gibbons C.H.
        • Griffin J.W.
        • Polydefkis M.
        • Bonyhay I.
        • Brown A.
        • Hauer P.E.
        • McArthur J.C.
        The utility of skin biopsy for prediction of progression in suspected small fiber neuropathy.
        Neurology. 2006; 66: 256-258
        • Herrmann D.N.
        • McDermott M.P.
        • Henderson D.
        • Chen L.
        • Akowuah K.
        • Schifitto G.
        Epidermal nerve fiber density, axonal swellings and QST as predictors of HIV distal sensory neuropathy.
        Muscle Nerve. 2004; 29: 420-427
        • Holland N.R.
        • Stocks A.
        • Hauer P.
        • Cornblath D.R.
        • Griffin J.W.
        • McArthur J.C.
        Intraepidermal nerve fiber density in patients with painful sensory neuropathy.
        Neurology. 1997; 48: 708-711
        • Kennedy W.R.
        • Nolano M.
        • Wendelschafer-Crabb G.
        • Johnson T.L.
        • Tamura E.
        A skin blister method to study epidermal nerves in peripheral nerve disease.
        Muscle Nerve. 1999; 22: 360-371
        • Lauria G.
        • Lombardi R.
        • Camozzi F.
        • Devigili G.
        Skin biopsy for the diagnosis of peripheral neuropathy.
        Histopathology. 2009; 54: 273-285
        • Lauria G.
        • Morbin M.
        • Lombardi R.
        • Borgna M.
        • Mazzoleni G.
        • Sghirlanzoni A.
        • Pareyson D.
        Axonal swellings predict the degeneration of epidermal nerve fibers in painful neuropathies.
        Neurology. 2003; 61: 631-636
        • McArthur J.C.
        • Stocks E.A.
        • Hauer P.
        • Cornblath D.R.
        • Griffin J.W.
        Epidermal nerve fiber density: Normative reference range and diagnostic efficiency.
        Arch Neurol. 1998; 55: 1513-1520
        • Polydefkis M.
        • Hauer P.
        • Griffin J.W.
        • McArthur J.C.
        Skin biopsy as a tool to assess distal small fiber innervation in diabetic neuropathy.
        Diabetes Technol Ther. 2001; 3: 23-28
        • Said G.
        • Slama G.
        • Selva J.
        Progressive centripetal degeneration of axons in small fibre diabetic polyneuropathy.
        Brain. 1983; 106: 791-807
        • Shun C.T.
        • Chang Y.C.
        • Wu H.P.
        • Hsieh S.C.
        • Lin W.M.
        • Lin Y.H.
        • Tai T.Y.
        • Hsieh S.T.
        Skin denervation in type 2 diabetes: Correlations with diabetic duration and functional impairments.
        Brain. 2004; 127: 1593-1605
        • Singleton J.R.
        • Bixby B.
        • Russell J.W.
        • Feldman E.L.
        • Peltier A.
        • Goldstein J.
        • Howard J.
        • Smith A.G.
        The Utah Early Neuropathy Scale: A sensitive clinical scale for early sensory predominant neuropathy.
        J Peripher Nerv Syst. 2008; 13: 218-227
        • Sorensen L.
        • Molyneaux L.
        • Yue D.K.
        The level of small nerve fiber dysfunction does not predict pain in diabetic Neuropathy: A study using quantitative sensory testing.
        Clin J Pain. 2006; 22: 261-265
        • Sorensen L.
        • Molyneaux L.
        • Yue D.K.
        The relationship among pain, sensory loss, and small nerve fibers in diabetes.
        Diabetes Care. 2006; 29: 883-887
        • Veves A.
        • Backonja M.
        • Malik R.A.
        Painful diabetic neuropathy: Epidemiology, natural history, early diagnosis, and treatment options.
        Pain Med. 2008; 9: 660-674
        • Yasuda H.
        • Terada M.
        • Maeda K.
        • Kogawa S.
        • Sanada M.
        • Haneda M.
        • Kashiwagi A.
        • Kikkawa R.
        Diabetic neuropathy and nerve regeneration.
        Prog Neurobiol. 2003; 69: 229-285