Acta Neuropathologica

, 113:431 | Cite as

Comparable myelinated nerve pathology in feline and human diabetes mellitus

  • Andrew P. Mizisin
  • Richard W. Nelson
  • B. K. Sturges
  • Karen M. Vernau
  • Richard A. LeCouteur
  • D. Colette Williams
  • Monica L. Burgers
  • G. Diane Shelton
Original Paper


The occurrence of diabetic neuropathy in cats provides an opportunity to study the development and treatment of neurological complications not present in diabetic rodent models, where few pathological alterations are evident. The present study further defines pathological alterations in nerve biopsies from 12 cats with spontaneously occurring diabetes mellitus. Peroneal nerve biopsies displayed concurrent injury to both Schwann cells and axons of myelinated fibers that was remarkably similar to that present in human diabetic neuropathy. In addition to demyelination, remyelination (constituting 20–84% of the total myelinated fiber population) was indicated by fibers with inappropriately thin myelin sheaths. Unlike our previous investigations, striking axonal injury was apparent, and consisted of dystrophic accumulations of membranous debris or neurofilaments, as well as degenerative fiber loss resulting in a 50% decrease in myelinated fiber density. In spite of extensive fiber loss, regenerative clusters were apparent, suggesting that axonal regeneration was not completely frustrated. These data highlight the potential utility of feline diabetic neuropathy as a model that faithfully replicates the nerve injury in human diabetes mellitus.


Axonal degeneration Axonal regeneration Axon-Schwann-cell networks Feline diabetic neuropathy Segmental demyelination Remyelination 


  1. 1.
    Akkina SK, Patterson CL, Wright DE (2001) GDNF rescues nonpeptidergic unmyelinated primary afferents in streptozotocin-treated diabetic mice. Exp Neurol 167:173–182PubMedCrossRefGoogle Scholar
  2. 2.
    Ballin RHM, Thomas PK (1968) Hypertrophic changes in diabetic neuropathy. Acta Neuropathol 11:93–102PubMedCrossRefGoogle Scholar
  3. 3.
    Benbow SJ, Chan AW, Bowsher A, McFarlane IA, Williams G (1994) A prospective study of painful symptoms, small fibre function and peripheral vascular disease in chronic painful diabetic neuropathy. Diabetic Med 11:17–21PubMedGoogle Scholar
  4. 4.
    Berthold CH (1978) Ultrastructure of the node-paranode region of mature feline ventral lumbar spinal-root fibres. Acta Soc Med Ups 73(suppl 9):37–70Google Scholar
  5. 5.
    Bianchi R, Buyukakilli B, Brines M, Savino C, Cavaletti G, Oggioni N, Laura G, Borgna M, Lombardi R, Cimen B, Comelekoglu U, Kamik A, Tataroglu C, Cerami A, Ghezzi P (2004) Erythropoietin both protects from and reverses experimental diabetic neuropathy. Proc Natl Acad Sci USA 101:823–828PubMedCrossRefGoogle Scholar
  6. 6.
    Bischoff A (1980) Morphology of diabetic neuropathy. Horm Metab Res Suppl 9:18–28PubMedGoogle Scholar
  7. 7.
    Blakemore WF (1972) Observations on oligodendrocyte degeneration, the resolution of status spongiosus and remyelination in cuprizone intoxication in mice. J Neurocytol 1:413–426PubMedCrossRefGoogle Scholar
  8. 8.
    Chopra JS, Hurwitz LJ, Montgomery DAD (1969) The pathogenesis of sural nerve changes in diabetes mellitus. Brain 92:391–418PubMedCrossRefGoogle Scholar
  9. 9.
    Christianson JA, Riekhof JT, Wright DE (2003) Restorative effects of neurotrophin treatment on diabetes-induced cutaneous axon loss in mice. Exp Neurol 179:188–199PubMedCrossRefGoogle Scholar
  10. 10.
    Collins GH, De F Webster H, Victor M (1964) The ultrastructure of myelin and axonal alterations in sciatic nerves of thiamine deficient and chronically starved rats. Acta Neuropathol 3:511–521PubMedCrossRefGoogle Scholar
  11. 11.
    Dahme E, Hafner A, Reusch C, Schmidt P (1989) Diabetic neuropathy in dogs and cats – a bioptic electron microscopic study. Tierarztl Prax 17:177–188PubMedGoogle Scholar
  12. 12.
    Diabetes Control, Complications Trial Group (1993) The effects of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986CrossRefGoogle Scholar
  13. 13.
    Engel AG, Banker BQ (1994) Ultrastructural changes in diseased muscle. In: Engel AG, Franzini-Armstrong C (eds) Myology, 2nd edn. McGraw-Hill, New York, pp 889–1017Google Scholar
  14. 14.
    Forcier NJ, Mizisin AP, Rimmer MA, Powell HC (1991) Cellular pathology of the nerve microenvironment in galactose intoxication. J Neuropathol Exp Neurol 50:235–255PubMedGoogle Scholar
  15. 15.
    Gatzinsky KP, Persson GH, Berthold CH (1996) Removal of retrogradely transported material from rat lumbosacral alpha-motor axons by paranodal axon-Schwann cell networks. Glia 20:115–126CrossRefGoogle Scholar
  16. 16.
    Gatzinsky KP, Holtmann B, Daraie B, Berthold CH, Sendtner M (2003) Early onset of degenerative changes at nodes of Ranvier in alpha-motor axons of Cntf null (/) mutant mice. Glia 42:340–349PubMedCrossRefGoogle Scholar
  17. 17.
    Gregersen G (1968) A study of peripheral nerves in diabetic subjects during ischaemia. J Neurol Neurosurg Psychiat 31:175–181PubMedCrossRefGoogle Scholar
  18. 18.
    Hirano A, Zimmerman HM (1971) Some new pathological findings in the central myelinated axon. J Neuropathol Exp Neurol 30:63–67PubMedGoogle Scholar
  19. 19.
    Jacobs JM, Cavanaugh JB (1972) Aggregations of filaments in Schwann cells of spinal roots of the normal rat. J Neurocytol 1:161–167PubMedCrossRefGoogle Scholar
  20. 20.
    Kalichman MW, Powell HC, Mizisin AP (1998) Reactive, degenerative and proliferative Schwann cell responses in experimental galactose and human diabetic neuropathy. Acta Neuropathol 95:47–56PubMedCrossRefGoogle Scholar
  21. 21.
    King RH, Llewelyn JG, Thomas PK, Gilbey SG, Watkins PJ (1989) Diabetic neuropathy: abnormalities of Schwann cell and perineurial basal laminae. Implications for diabetic vasculopathy. Neuropathol Appl Neurobiol 15:339–355PubMedGoogle Scholar
  22. 22.
    Kramek BA, Moise NS, Cooper B, Raffe MR (1984) Neuropathy associated with diabetes mellitus in the cat. J Am Vet Med Assoc 184:42–45PubMedGoogle Scholar
  23. 23.
    Lauria G, Lombardi R, Borgna M, Penza P, Bianchi R, Savino C, Canta A, Nicolini G, Marmiroli P, Cavaletti G (2005) Intraepidermal nerve fiber density in rat foot pad: neuropathologic-neurophysiologic correlation. J Peripher Nerv Syst 10:202–208PubMedCrossRefGoogle Scholar
  24. 24.
    Llewelyn JG, Gilbey SG, Thomas PK, King RH, Muddle JR, Watkins PJ (1991) Sural nerve morphometry in diabetic autonomic and painful sensory neuropathy. A clinicopathological study. Brain 114:867–892PubMedCrossRefGoogle Scholar
  25. 25.
    Lutz TA, Rand JS (1995) Pathogenesis of feline diabetes mellitus. Vet Clin North Am Small Anim Pract 25:527–552PubMedGoogle Scholar
  26. 26.
    Maxwell DS, Kruger L, Pineda A (1969) The trigeminal nerve root with special reference to the central-peripheral transition zone: an electron microscopic study in the Macaque. Anat Rec 164:113–126PubMedCrossRefGoogle Scholar
  27. 27.
    Midroni G, Bilbao JM (1995) Biopsy diagnosis of peripheral neuropathy. Butterworth-Heinemann, BostonGoogle Scholar
  28. 28.
    Mizisin AP, Powell HC (1993) Schwann cell injury is attenuated by aldose reductase inhibition in galactose intoxication. J Neuropathol Exp Neurol 52:78–86PubMedGoogle Scholar
  29. 29.
    Mizisin AP, Bache M, DiStefano PS, Acheson A, Lindsey RM, Calcutt NA (1997) BDNF attenuates functional and structural disorders in nerves of galactose-fed rats. J Neuropathol Exp Neurol 56:1290–1301PubMedGoogle Scholar
  30. 30.
    Mizisin AP, Powell HC (1997) Schwann cell changes induced as early as one week after galactose intoxication. Acta Neuropathol 93:611–618PubMedCrossRefGoogle Scholar
  31. 31.
    Mizisin AP, Kalichman MW, Bache M, Dines KC, DiStefano PS (1998) NT-3 attenuates functional and structural disorders in sensory nerves of galactose-fed rats. J Neuropathol Exp Neurol 57:803–813PubMedGoogle Scholar
  32. 32.
    Mizisin AP, Shelton GD, Wagner S, Rusbridge C, Powell HC (1998) Myelin splitting, Schwann cell injury and demyelination in feline diabetic neuropathy. Acta Neuropathol 95:171–174PubMedCrossRefGoogle Scholar
  33. 33.
    Mizisin AP, Steinhardt C, O’Brien JS, Calcutt NA (2001) TX14(A), a prosaposin-derived peptide, reverses established nerve disorders in streptozotocin-diabetic rats and prevents them in galactose-fed rats. J Neuropathol Exp Neurol 60:953–960PubMedGoogle Scholar
  34. 34.
    Mizisin AP, Shelton GD, Burgers ML, Burgers ML, Powell HC, Cuddon PA (2002) Neurological complications associated with spontaneously occurring feline diabetes mellitus. J Neuropathol Exp Neurol 61:872–884PubMedGoogle Scholar
  35. 35.
    Mizisin AP, Powell HC (2003) Histopathology: diabetic peripheral neuropathy. In: FA Gries, Cameron NE, Low PA, Ziegler D (eds) Textbook of diabetic neuropathy. Thieme, Stuttgart, pp 83–87Google Scholar
  36. 36.
    Picavet PM, Lambillon DE (1993) Motor nerve conduction in the cat’s hind limb. Prog Vet Neurol 4:121–125Google Scholar
  37. 37.
    Rand J (1999) Current understanding of feline diabetes: part 1. pathogenesis. J Feline Med Surg 1:145–153CrossRefGoogle Scholar
  38. 38.
    Rand JS, Fleeman LM, Farrow HA, Appleton DJ, Lederer R (2004) Canine and feline diabetes mellitus: nature or nuture? J Nutr 134:2072S–2080SPubMedGoogle Scholar
  39. 39.
    Sasaki H, Schmelzer JD, Low PA (2003) Oxidative injury and apoptosis of dorsal root ganglion neurons in chronic experimental diabetic neuropathy. Diabetes 52:165–171CrossRefGoogle Scholar
  40. 40.
    Schroder JM, Sommer C (1991) Mitochondrial abnormalities in human sural nerves: fine structural evaluation of cases with mitochondrial myopathy, hereditary and non-hereditary neuropathies, and review of the literature. Acta Neuropathol 82:471–482PubMedCrossRefGoogle Scholar
  41. 41.
    Spencer PS, Thomas PK (1974) Ultrastructural studies of the dying-back process II. The sequestration and removal by Schwann cells and oligodendrocytes of organelles from normal and diseased axons. J Neurocytol 3:763–783PubMedCrossRefGoogle Scholar
  42. 42.
    Spencer PS, Schaumberg HH (1978) Pathobiology of neurotoxic axonal degeneration. In: Waxman SG (ed) Physiology and pathobiology of axons. Raven, New York, pp 265–282Google Scholar
  43. 43.
    Tamura E, Parry GJ (1994) Severe radicular pathology in rats with long-standing diabetes. J Neurol Sci 127:29–35PubMedCrossRefGoogle Scholar
  44. 44.
    Thomas PK Lascelles RG (1965) Schwann-cell abnormalities in diabetic neuropathy. Lancet 62:1355–1357CrossRefGoogle Scholar
  45. 45.
    Thomas PK, Lascelles RG (1966) The pathology of diabetic neuropathy. Q J Med 140:489–509Google Scholar
  46. 46.
    Thomas PK, King RH, Sharma AK (1980) Changes with age in the peripheral nerves of the rat. An ultrastructural study. Acta Neuropathol 52:1–6PubMedCrossRefGoogle Scholar
  47. 47.
    Thomas PK, Tomlinson DR (1993) Diabetic and hypoglycemic neuropathy. In: Dyck PJ, Thomas PK, Griffin JW, Low PA, Poduslo JF (eds) Peripheral neuropathy, 3rd edn. WB Saunders, Philadelphia, pp 1219–1250Google Scholar
  48. 48.
    Tuler SM, Bowen JM (1990) Measurement of conduction velocity of the peroneal nerves based on recordings from the extensor digitorum brevis muscle. J Am Anim Hosp Assoc 26:164–168Google Scholar
  49. 49.
    UK Prospective Diabetes Study Group (1998) Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type II diabetes (UK PDS 33). Lancet 352:837–853CrossRefGoogle Scholar
  50. 50.
    Veves A, Malik RA, Lye RH, Masson EA, Sharma AK, Schady W, Boulton AJ (1991) The relationship between sural nerve morphometric findings and measures of peripheral nerve function in mild diabetic neuropathy. Diabet Med 8:917–921PubMedCrossRefGoogle Scholar
  51. 51.
    Vital C, Bouillot S, Canron M-H, Vital A (2002) Schwannian crystalline-like inclusions bodies (Fardeau–Engel bodies) revisited in peripheral neuropathy. Ultrastruct Pathol 26:9–13PubMedCrossRefGoogle Scholar
  52. 52.
    Ward JD, Barnes CG, Fisher DJ, Jessop JD, Baker RWR (1971) Improvement in nerve conduction following treatment in newly diagnosed diabetics. Lancet 1:428–431PubMedCrossRefGoogle Scholar
  53. 53.
    Weibel ER (1979) Stereological methods. Academic, New YorkGoogle Scholar
  54. 54.
    Wolff A (1984) Neuropathy associated with transient diabetes mellitus in 2 cats. Mod Vet Pract 65:726–728PubMedGoogle Scholar
  55. 55.
    Yagihashi S, Matsunaga M (1979) Ultrastructural pathology of peripheral nerves in patients with diabetic neuropathy. Tohoku J Exp Med 129:357–366PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Andrew P. Mizisin
    • 1
  • Richard W. Nelson
    • 2
  • B. K. Sturges
    • 2
  • Karen M. Vernau
    • 2
  • Richard A. LeCouteur
    • 2
  • D. Colette Williams
    • 2
  • Monica L. Burgers
    • 1
  • G. Diane Shelton
    • 1
  1. 1.Department of Pathology, School of MedicineUniversity of CaliforniaSan DiegoUSA
  2. 2.School of Veterinary MedicineUniversity of CaliforniaDavisUSA

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