Advertisement

Diabetologia

, Volume 37, Issue 9, pp 847–854 | Cite as

Vascular factors in diabetic neuropathy

  • S. Tesfaye
  • R. Malik
  • J. D. Ward
Review

Summary

Despite considerable research we still do not have a comprehensive explanation for the pathogenesis of diabetic neuropathy. Although chronic hyperglycaemia is almost certainly involved, it is not known whether the primary pathology is metabolic, microvascular, or an interaction between the two. Hyperglycaemia-induced polyol pathway hyperactivity associated with nerve sorbitol accumulation and myo-inositol depletion may play a part in the genesis of diabetic neuropathy. The case for microvascular disease in diabetic neuropathy is now strong. Fibre loss in human sural nerve is multifocal, suggesting ischaemia. The degree of vessel disease has been related to the severity of neuropathy. People with chronic obstructive pulmonary disease develop the so called “hypoxic neuropathy” in which similar microvascular changes occur as in diabetic neuropathy. In rats with experimental diabetic neuropathy nerve blood flow is reduced and oxygen supplementation or vasodilator treatment improved the deterioration in conduction velocity and nerve blood flow. Similarly, in human diabetic neuropathy, there is impaired nerve blood flow, epineurial arterio-venous shunting and a reduction in sural nerve oxygen tension. At what stage during the development of nerve damage these changes occur is yet to be determined.

Key words

Diabetic neuropathy microangiopathy nerve hypoxia blood flow 

Abbreviations

RICF

resistance to ischaemic conduction failure

References

  1. 1.
    Ward JD, Goto Y (1990) Diabetic neuropathy. John Wiley and Sons, ChichesterGoogle Scholar
  2. 2.
    Ward JD (1982) The diabetic leg. Diabetologia 22: 141–147CrossRefPubMedGoogle Scholar
  3. 3.
    Watkins PJ (1984) Pain and diabetic neuropathy. BMJ 288: 168–169PubMedGoogle Scholar
  4. 4.
    Archer AG, Watkins PJ, Thomas PK, Sharma AK, Payan J (1983) The natural history of acute painful neuropathy in diabetes mellitus. J Neurol Neurosurg Psychiatry 26: 491–499Google Scholar
  5. 5.
    Tesfaye S, Malik R, Harris N, Jakubowski J, Mody C, Ward JD (1993) Painful and severe autonomic neuropathy following insulin: further evidence for microvascular disease in neuropathy. Diabetes 42: 196A (Abstract)Google Scholar
  6. 6.
    Tomlinson DR (1992) The pharmacology of diabetic neuropathy. Diabetes Metab Rev 8: 67–84PubMedGoogle Scholar
  7. 7.
    Harati Y (1987) Diabetic peripheral neuropathies. Annals Inter Med 107: 546–559Google Scholar
  8. 8.
    Young RJ (1993) Structural functional interactions in the natural history of diabetic polyneuropathy: a key to the understanding of neuropathic pain? Diabetic Med 10 [Suppl 2]: 89S-90SPubMedGoogle Scholar
  9. 9.
    Vinik AI, Holland MT, Le Beau JM, Liuzzi FJ, Stansberry KB, Colen LB (1992) Diabetic neuropathies. Diabetes Care 15: 1926–1975PubMedGoogle Scholar
  10. 10.
    The Diabetes Control and Complications Trial Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin dependent diabetes mellitus. N Engl J Med 329: 977–986Google Scholar
  11. 11.
    Tesfaye S, Stevens L, Stephenson J, Ward JD on behalf of the EURODIAB IDDM Study Group (1993) The prevalence of diabetic neuropathy and its relation to glycaemic control in insulin dependent subjects in Europe. Diabetologia 36 [Suppl 1]: A176 (Abstract)Google Scholar
  12. 12.
    Pirart J (1978) Diabetes mellitus and its degenerative complications: a prospective study of 4400 patients observed between 1947 and 1973. Diabetes Care 1: 168–188 and 252–263Google Scholar
  13. 13.
    Ward JD, Barnes CG, Fisher DJ, Jessop JD, Baker RWR (1971) Improvement in nerve conduction following treatment in newly diagnosed diabetics. Lancet I: 428–430CrossRefGoogle Scholar
  14. 14.
    Boulton AJM, Drury J, Clarke B, Ward JD (1982) Continuous subcutaneous insulin infusion in the management of painful diabetic neuropathy. Diabetes Care 5: 386–390PubMedGoogle Scholar
  15. 15.
    Fedele D, Bellavere F, Cardone C, Ferri M, Crepaldi G (1985) Improvement of cardiovascular autonomic reflexes after amelioration of metabolic control in insulin-dependent diabetic subjects with severe autonomic neuropathy. Horm Metabol Res 17: 410–413Google Scholar
  16. 16.
    Ziegler D, Mayer P, Muhlen H, Gries FA (1991) The natural history of somatosensory and autonomic nerve dysfunction in relation to glycaemic control during the first 5 years after diagnosis of type 1 (insulin-dependent) diabetes mellitus. Diabetologia 34: 822–829PubMedGoogle Scholar
  17. 17.
    Pryce TD (1893) On diabetic neuritis with a clinical and pathological description of three cases of diabetic pseudo-tabes. Brain 16: 416–424Google Scholar
  18. 18.
    Woltman HW, Wilder RM (1929) Diabetes mellitus pathological changes in the spinal cord and peripheral nerves. Arch Intern Med 44: 576–603Google Scholar
  19. 19.
    Fagerberg SE (1959) Diabetic neuropathy: a clinical and histological study on the significance of vascular affections. Acta Med Scand 164 [Suppl 345]: 5–81Google Scholar
  20. 20.
    Bischoff A (1980) Morphology of diabetic neuropathy. Horm Metab Res 9 [Suppl]: 18–28Google Scholar
  21. 21.
    Brownlee M, Cerami A, Vlassara H (1988) Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med 318: 1315–1321PubMedGoogle Scholar
  22. 22.
    Malik RA, Veves A, Masson EA et al. (1992) Endoneurial capillary abnormalities in mild human diabetic neuropathy. J Neurol Neurosurg Psychiatry 55: 557–561PubMedGoogle Scholar
  23. 23.
    Powell HC, Rosoff J, Myers RR (1985) Microangiopathy in human diabetic neuropathy. Acta Neuropathol (Berl) 68: 295–305Google Scholar
  24. 24.
    Yasuda H, Dyck PJ (1987) Abnormalities of endoneurial micro vessels and sural nerve pathology in diabetic neuropathy. Neurology 37: 20–28PubMedGoogle Scholar
  25. 25.
    Malik RA, Newrick PG, Sharma AK et al. (1989) Microangiography in human diabetic neuropathy: relationship between capillary abnormalities and the severity of neuropathy. Diabetologia 32: 92–102PubMedGoogle Scholar
  26. 26.
    Britland ST, Young RJ, Sharma AK, Clarke BF (1990) Relationship of endoneurial capillary abnormalities to type and severity of diabetic polyneuropathy. Diabetes 39: 909–913PubMedGoogle Scholar
  27. 27.
    Malik RA, Tesfaye S, Thompson SD et al. (1993) Endoneurial localisation of microvascular damage in human diabetic neuropathy. Diabetologia 36: 454–459PubMedGoogle Scholar
  28. 28.
    Timperly WR, Ward JD, Preston FE, Duckworth T, O'Malley BC (1976) Clinical and histological studies in diabetic neuropathy. Diabetologia 12: 237–243PubMedGoogle Scholar
  29. 29.
    Williams E, Timperly WR, Ward JD, Duckworth T (1980) Electronmicroscopical studies of vessels in diabetic peripheral neuropathy. J Clin Pathol 33: 462–470PubMedGoogle Scholar
  30. 30.
    Timperly WR, Boulton AJM, Davies Jones GAB, Jarrat JA, Ward JD (1985) Small vessel disease in progressive diabetic neuropathy associated with good metabolic control. J Clin Pathol 38: 1030–1038PubMedGoogle Scholar
  31. 31.
    Dyck PJ, Hansen S, Karnes J et al. (1985) Capillary number and percentage closed in human diabetic sural nerve. Proc Nat Acad Sci (USA) 82: 2513–2517Google Scholar
  32. 32.
    Malik RA, Tesfaye S, Thompson SD et al. (1994) Transperineurial capillary abnormalities in the sural nerve of patients with diabetic neuropathy. Microvascular Res [In Press]Google Scholar
  33. 33.
    Ford I, Malik RA, Newrick PG, Preston FE, Ward JD, Greaves M (1992) Relationship between haemostatic factors and capillary morphology in human diabetic neuropathy. Thromb Haemost 68: 628–633PubMedGoogle Scholar
  34. 34.
    Newrick PG, Wilson AJ, Jakubowski J, Boulton AJM, Ward JD (1986) Sural nerve oxygen tension in diabetes. BMJ 293: 1053–1054PubMedGoogle Scholar
  35. 35.
    Johnson PC, Doll SC, Cromey DW (1986) Pathogenesis of diabetic neuropathy. Ann Neurol 19: 450–457PubMedGoogle Scholar
  36. 36.
    Beggs J, Johnson PC, Olafsen A, Watkins CL, Cleary C (1991) Transperineurial arterioles in human sural nerve. J Neuropathol Exp Neurol 6: 704–718Google Scholar
  37. 37.
    Dyck PJ, Karnes JL, O'Brien P, Okazaki H, Lias A, Engelstad J (1986) The spatial distribution of fibre loss in diabetic polyneuropathy suggests ischaemia. Ann Neurol 19: 440–449PubMedGoogle Scholar
  38. 38.
    Dyck PJ, Lais A, Karnes JL, O'Brien P, Rizza R (1986) Fibre loss is primary and multifocal in sural nerves in diabetic polyneuropathy. Ann Neurol 19: 425–439PubMedGoogle Scholar
  39. 39.
    Asbury AK, Aldredge H, Hershberg R, Fisher CM (1970) Oculomotor palsy in diabetes mellitus: a clinico-pathological study. Brain 93: 555–566PubMedGoogle Scholar
  40. 40.
    Raff MC, Sangalang V, Asbury AK (1968) Ischaemic mononeuropathy multiplex associated with diabetes mellitus. Arch Neurol 18: 487–499PubMedGoogle Scholar
  41. 41.
    Korthals JK, Gieron MA, Dyck PJ (1988) Intima of epineurial arterioles is increased in diabetic polyneuropathy. Neurology 38: 1582–1586PubMedGoogle Scholar
  42. 42.
    Roberts JT (1948) The effect of occlusive arterial disease of the extremities of the blood supply of nerves: experimental and clinical studies on the vasa nervorum. Am Heart J 35: 369–392CrossRefGoogle Scholar
  43. 43.
    Korthals JK, Wisniewski HM (1975) Peripheral ischaemia. I. Experimental model. J Neurol Sci 24: 65–76CrossRefPubMedGoogle Scholar
  44. 44.
    Nukada H, Dyck PJ (1984) Microsphere embolization of nerve capillaries and fibre degeneration. Am J Pathol 115: 275–287PubMedGoogle Scholar
  45. 45.
    Benstead TJ, Sangalang VE, Dyck PJ (1990) Acute endothelial swelling is induced in endoneurial microvessels by ischaemia. J Neurol Sci 99: 37–49CrossRefPubMedGoogle Scholar
  46. 46.
    Tuck RR, Schmelzer JD, Low PA (1984) Endoneurial blood flow and oxygen tension in the sciatic nerves of rats with experimental diabetic neuropathy. Brain 107: 935–950PubMedGoogle Scholar
  47. 47.
    Cameron NE, Cotter MA, Low PA (1991) Nerve blood flow in early experimental diabetes in rats: relation to conduction deficits. Am J Physiol 261: E1-E8PubMedGoogle Scholar
  48. 48.
    Cameron NE, Cotter MA, Ferguson K, Robertson S, Radcliffe MA (1991) Effects of chronic alpha-adrenergic receptor blockade on peripheral nerve conduction, hypoxic resistance, polyols, Na+-K+-ATPase activity and vascular supply in STZ-D rats. Diabetes 40: 1652–1658PubMedGoogle Scholar
  49. 49.
    Cameron NE, Cotter MA, Robertson S (1992) Angiotensin converting enzyme inhibition prevents the developments of muscle and nerve dysfunction and stimulates angiogenesis in streptozotocin-diabetic rats. Diabetologia 35: 12–18PubMedGoogle Scholar
  50. 50.
    Low PA, Tuck RR, Dyck PJ, Schmelzer JD, Yao JK (1984) Prevention of some electrophysiologic and biochemical abnormalities with oxygen supplementation in experimental diabetic neuropathy. Proc Natl Acad Sci USA 81: 6894–6898PubMedGoogle Scholar
  51. 51.
    Low PA, Schmelzer JD, Ward KK, Curran GL, Poduslo JF (1988) Effect of hyperbaric oxygenation on normal and chronic streptozotocin diabetic peripheral nerves. Exp Neurol 99: 201–212CrossRefPubMedGoogle Scholar
  52. 52.
    Low PA, Schmelzer JD, Ward KK, Yao JK (1986) Experimental chronic hypoxic neuropathy: relevance to diabetic neuropathy. Am J Physiol 250: E94-E99PubMedGoogle Scholar
  53. 53.
    Benstead TJ, Dyck PJ, Low P (1988) Chronic hypoxia induces selective maldevelopment of peripheral myelin in rat. J Neuropathol Exp Neurol 47: 599–608PubMedGoogle Scholar
  54. 54.
    Smith WJ, Diemel LT, Leach RM, Tomlinson DR (1991) Central hypoxaemia in rats provokes neurological defects similar to those seen in experimental diabetes mellitus: evidence for a partial role of endoneurial hypoxia in diabetic neuropathy. Neuroscience 45: 255–259CrossRefPubMedGoogle Scholar
  55. 55.
    Stevens EJ, Lockett MJ, Carrington AL, Tomlinson DR (1993) Essential fatty acid treatment prevents nerve ischaemia and associated conduction anomalies in rats with experimental diabetes mellitus. Diabetologia 36: 397–401PubMedGoogle Scholar
  56. 56.
    Yasuda H, Sonobe M, Yamashita M et al. (1989) Effect of prostaglandin E1 analogue TFC 612 on diabetic neuropathy in streptozotocin-induced diabetic rats: comparison with aldose reductase inhibitor ONO 2235. Diabetes 38: 832–838PubMedGoogle Scholar
  57. 57.
    Stevens EJ, Carrington AL, Tomlinson DR (1994) Nerve ischaemia in diabetic rats: time-course of development, effect of insulin treatment plus comparison of streptozotocin and BB models. Diabetologia 37: 43–48CrossRefPubMedGoogle Scholar
  58. 58.
    Pugliese G, Tilton RG, Williamson JR (1991) Glucose-induced metabolic imbalances in the pathogenesis of diabetic vascular disease. Diabetes Metab Rev 7: 35–59PubMedGoogle Scholar
  59. 59.
    Williamson JR, Chang K, Allison W, Kilo C (1993) Endoneurial blood flow changes in diabetic rats. Diabetic Med 10 [Suppl 2]: 49S-51SPubMedGoogle Scholar
  60. 60.
    Monafo WW, Eliasson SV, Shimazaki S, Sugimoto H (1988) Regional blood flow in resting and stimulated sciatic nerve of diabetic rats. Exp Neurol 99: 607–614CrossRefPubMedGoogle Scholar
  61. 61.
    Boulton AJM, Scarpello JHB, Ward JD (1982) Venous oxygenation in the diabetic neuropathic foot: evidence of arterio-venous shunting? Diabetologia 22: 6–8CrossRefPubMedGoogle Scholar
  62. 62.
    Tesfaye S, Harris N, Jakubowski J et al. (1993) Impaired blood flow and arterio-venous shunting in human diabeic neuropathy: a novel technique of nerve photography and fluorescein angiography. Diabetologia 36: 1266–1274PubMedGoogle Scholar
  63. 63.
    Llewelyn JG, Thomas PK, Fonseca V, King RHM, Dandona P (1986) Acute painful diabetic neuropathy precipitated by strict glycaemic control. Acta Neuropathol (Berl) 72: 157–163Google Scholar
  64. 64.
    Ward JD, Simms JM, Knight G, Boulton AJM, Sandler DA (1983) Venous distension in the diabetic neuropathic foot (physical sign of arterio-venous shunting). J Roy Soc Med 76: 1011–1014Google Scholar
  65. 65.
    Edmonds ME, Roberts VC, Watkins PJ (1982) Blood flow in the diabetic neuropathic foot. Diabetologia 22: 9–15CrossRefPubMedGoogle Scholar
  66. 66.
    Van-den-Hoogen F, Brawn LA, Sherriff S, Watson N, Ward JD (1986) Arteriovenous shunting in quadriplegia. Paraplegia 25: 282–286Google Scholar
  67. 67.
    Tesfaye S, Harris N, Wilson RM, Ward JD (1992) Exercise induced conduction velocity increment: a marker of impaired nerve blood flow in diabetic neuropathy. Diabetologia 35: 155–159PubMedGoogle Scholar
  68. 68.
    Greaves M, Preston FE (1984) Haemostatic abnormalities in diabetes. In: Jarrett RJ (ed) Metabolic aspects of cardiovascular disease 2. Diabetes and heart disease. Oxford: Elsevier, pp 47–80Google Scholar
  69. 69.
    O'Mally BC, Timperly WR, Ward JD, Porter NR, Preston FE (1975) Platelet abnormalities in diabetic neuropathy. Lancet II: 1274–1276CrossRefGoogle Scholar
  70. 70.
    McMillan DE, Utterback NG, La Puma J (1978) Reduced erythrocyte deformability in diabetes. Diabetes 27: 895–901PubMedGoogle Scholar
  71. 71.
    Wautier J-L, Paton RC, Wautier MP et al. (1981) Increased adhesion of erythrocytes to endothelial cells in diabetes mellitus and its relation to vascular complications. N Eng J Med 305: 237–242Google Scholar
  72. 72.
    Baba Y, Kai M, Kamanda T, Setoyama S, Otsugi S (1979) Higher levels of erythrocyte membrane microviscosity in diabetes. Diabetes 28: 1138–1140PubMedGoogle Scholar
  73. 73.
    McMillan DE (1982) Further observations in serum viscosity change in diabetes mellitus. Metabolism 31: 274–278CrossRefPubMedGoogle Scholar
  74. 74.
    Steiness IB (1961) Influence of diabetic status on VP during ischaemia. Acta Med Scad 170: 319Google Scholar
  75. 75.
    Newrick PG, Boulton AJM, Ward JD (1987) Nerve ischaemia resistance: an early abnormality in diabetes. Diabetic Med 4: 517–520PubMedGoogle Scholar
  76. 76.
    Low PA, Ward KK, Schmelzer JD et al. (1985) Relationship of resistance to ischaemic conduction failure to energy metabolism in experimental diabetic neuropathy. Am J Physiol 248: E457-E462PubMedGoogle Scholar
  77. 77.
    Masson EA, Church SE, Woodcock AA, Hanley SP, Boulton AJM (1988) Is resistance to ischaemic conduction failure induced by hypoxia? Diabetologia 31: 762–765CrossRefPubMedGoogle Scholar
  78. 78.
    Appenzeller O, Dhital KK, Cowen T, Burnstock G (1984) The nerve to blood vessels supplying blood to nerves: the innervation of the vasa nervorum. Brain Research 304: 383–386CrossRefPubMedGoogle Scholar
  79. 79.
    Malik RA, Masson EA, Sharma AK et al. (1990) Hypoxic neuropathy: relevance to human diabetic neuropathy. Diabetologia 33: 311–318PubMedGoogle Scholar
  80. 80.
    Stoebner P, Mezin P, Vila A, Grosse R, Kopp N, Paramelle B (1989) Microangiopathy of endoneurial vessels in hypoxemic chronic obstructive pulmonary disease. Acta Neuropathol 78: 388–395PubMedGoogle Scholar
  81. 81.
    Robertson S, Cameron NE, Cotter NA (1992) The effect of calcium antagonist nifedipine on peripheral nerve function in streptozotocin-diabetic rats. Diabetologia 35: 1113–1117PubMedGoogle Scholar
  82. 82.
    Hotta N, Kakuta H, Fakasawa H et al. (1992) Effect of niceritrol on streptozotocin-induced diabetic neuropathy in rats. Diabetes 41: 587–591PubMedGoogle Scholar
  83. 83.
    Maxfield EK, Cameron NE, Cotter MA, Dines KC (1993) Angiotensin II receptor blockade improves nerve function, modulates nerve blood flow and stimulates endoneurial angiogenesis in streptotocin-diabetic rats. Diabetologia 36: 1230–1237PubMedGoogle Scholar
  84. 84.
    Low PA, Kihara M, Cameron N, Cotter J, Poduslo J (1993) Cause and effect of ischaemia in chronic experimental diabetic neuropathy. Diabetic Med 10 [Suppl 2]: 52S-55SPubMedGoogle Scholar
  85. 85.
    Bravenboer B, Kappelle AC, Hamers FPT, van Buren T, Erkelens DW, Gispen WH (1992) Potential use of glutathione for the prevention and treatment of diabetic neuropathy in the streptozotocin-induced diabetic rat. Diabetologia 35: 813–817PubMedGoogle Scholar
  86. 86.
    Low PA, Nickander KK (1991) Oxygen free radical effects in sciatic nerve in experimental diabetes. Diabetes 40: 873–877PubMedGoogle Scholar
  87. 87.
    Cameron NE, Cotter MA, Archibald V, Dines KC, Maxfield EK (1994) Anti-oxidant and pro-oxidant effects on nerve conduction velocity, endoneurial blood flow and oxygen tension in non-diabetic and streptozotocin-diabetic rats. Diabetologia 37: 449–459CrossRefPubMedGoogle Scholar
  88. 88.
    Jamal GA, Carmichael H (1990) The effect of gammalinolenic acid on human diabetic peripheral neuropathy: a double-blind placebo-controlled trial. Diabetic Med 7: 319–323PubMedGoogle Scholar
  89. 89.
    Cameron NE, Cotter MA, Robertson S (1991) Essential fatty acid diet supplementation: effects on peripheral nerve and skeletal muscle function and capillarization in streptozotocin-induced diabetic rats. Diabetes 40: 532–539PubMedGoogle Scholar
  90. 90.
    Reja A, Tesfaye S, Harris N, Ward JD (1993) Improvement in nerve conduction and quantitative sensory tests after treatment with lisinopril. Diabetic Med 10 [Suppl 3]: S18 (Abstract)Google Scholar
  91. 91.
    Young MJ, Veves A, Walker MG, Boulton AIM (1992) Correlations between nerve function and tissue oxygenation in diabetic patients: further clues to the aetiology of diabetic neuropathy? Diabetologia 35: 1146–1150PubMedGoogle Scholar
  92. 92.
    Baynes JW (1991) Role of oxidative stress in the development of complications in diabetes. Diabetes 40: 405–412PubMedGoogle Scholar
  93. 93.
    Corbett JA, Tilton RG, Chang K et al. (1992) Aminoguanidine, a novel inhibitor of nitric oxide formation, prevents diabetic vascular dysfunction. Diabetes 41: 552–556PubMedGoogle Scholar
  94. 94.
    McVeigh GE, Brennan GM, Johnston GD et al. (1992) Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 35: 771–776PubMedGoogle Scholar
  95. 95.
    Tooke JE (1986) Microvascular haemodynamics in diabetes mellitus. Clin Sci 70: 119–125PubMedGoogle Scholar
  96. 96.
    Gabbay KH, Merola LO, Field RA (1966) Sorbitol pathway: presence in nerve and cord with substrate accumulation in diabetes. Science 151: 209–210PubMedGoogle Scholar
  97. 97.
    Ward JD, Baker RWR, Davis B (1972) Effect of blood sugar control on the accumulation of sorbitol and fructose in nervous tissue. Diabetes 21: 1173–1178PubMedGoogle Scholar
  98. 98.
    Dyck PJ, Zimmerman BR, Todd HV et al. (1988) Nerve glucose, fructose, sorbitol, myo-inositol and fibre degeneration and regeneration in diabetic neuropathy. N Engl J Med 319: 542–548PubMedGoogle Scholar
  99. 99.
    Greene D, Lattimer SA, Sima AAF (1987) Sorbitol, phosphoinositides, and sodium-potassium-ATPase in the pathogenesis of diabetic complications. N Engl J Med 316: 599–606PubMedGoogle Scholar
  100. 100.
    Greene D, Lattimer SA (1983) Impaired rat sciatic nerve sodium-potassium-ATPase in acute streptozotocin diabetes and its correction by dietary myo-inositol supplementation. J Clin Invest 72: 1058–1063PubMedGoogle Scholar
  101. 101.
    Das PK, Bray GM, Aguayo AJ, Rasminisky M (1976) Diminished ouabain-sensitive, sodium-potassium-ATPase activity in sciatic nerves of rats with streptozotocin-induced diabetes. Exp Neurol 53: 285–288CrossRefPubMedGoogle Scholar
  102. 102.
    Spritz N, Marinan B, Singh H (1974) Effects of insulin on the incorporation of 14-C leucine into the protein components of sciatic nerve myelin. Diabetes 23: 358Google Scholar
  103. 103.
    Sidenius P, Jakobson J (1987) Axonal transport in human and experimental diabetes. In: Dyck PJ, Thomas PK, Asbury AK, Winegrad AI, Porte D (eds). Diabetic neuropathy. Philadelphia: WB Saunders 260–265Google Scholar
  104. 104.
    Ishii DN (1993) Insulin and related neurotrophic factors in diabetic neuropathy. Diabetic Med 10 [Suppl 2]: 14S-15SPubMedGoogle Scholar
  105. 105.
    Schmidt RE (1993) The role of nerve growth factor in the pathogenesis and therapy of diabetic neuropathy. Diabetic Med 10 [Suppl 2]: 10S-13SPubMedGoogle Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • S. Tesfaye
    • 1
  • R. Malik
    • 2
  • J. D. Ward
    • 3
  1. 1.Diabetes UnitWalton HospitalWaltonUK
  2. 2.Department of MedicineManchester Royal InfirmaryManchesterUK
  3. 3.Diabetes Research UnitRoyal Hallamshire HospitalSheffieldUK

Personalised recommendations