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Structure-function relationships within peripheral nerves in diabetic neuropathy: the hydration hypothesis

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Summary

To define the quantitative relationship between peripheral nerve structure and function imposed by endoneurial oedema in the diabetic state, we determined values for sural nerve hydration structure as measured by magnetic resonance spectroscopy, and for neurological function with scores for nerve conduction properties (NCV-score), neuropathic symptoms (NS-score), and examination signs (NE-score). The coefficient of sural nerve hydration was elevated to 30±6% (p<0.05) in 79 symptomatic neuropathic diabetic subjects with an average of 15 years of diabetes mellitus, compared to a value of 25±3% in 72 non-diabetic control subjects. In contrast, in 75 asymptomatic diabetic subjects with an average of 6 additional years of diabetes, the mean hydration coefficient was only 28±5% (p<0.05). A nerve hyperhydration state was identified with a prevalence of 25% within the asymptomatic group characterized by nerve hydration greater than the 95th percentile, early changes in nerve electrophysiology and neurological examination, but with no symptomatology of neuropathy. Stratification of the symptomatic neuropathic group by worsening nerve electrophysiology, demonstrates a coincident deterioration in neurological examination (RR=5.39 at maximum NCV-score), and neuropathy symptomatology (RR=4.80 at maximum NE-score). The present data are consistent with the hypothesis that endoneurial oedema initiates deterioration sequentially in nerve electrophysiology, followed by abnormal findings on neurological examination, preceding the patient's final perception of symptomatic stocking-glove peripheral diabetic neuropathy.

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Abbreviations

MRS:

Magnetic resonance spectroscopy

NCV:

nerve conduction velocity

NE:

neurological examination

NS:

neurological symptoms

IDDM:

insulin-dependent diabetes mellitus

NIDDM:

non-insulin-dependent diabetes mellitus

References

  1. Clements RA (1979) Diabetic neuropathy — new concepts of its etiology. Diabetes 28: 604–611

    PubMed  Google Scholar 

  2. Powell HC (1983) Pathology of diabetic neuropathy: new observations, new hypotheses. Lab Invest 49: 515–518

    PubMed  Google Scholar 

  3. Gabbay KH (1973) The sorbitol pathway and the complications of diabetes. N Engl J Med 288: 831–836

    PubMed  Google Scholar 

  4. Sima AAF, Bril V, Nathaniel V et al. (1988) Regeneration and repair of myelinated fibers in sural-nerve biopsy specimens from patients with diabetic neuropathy treated with sorbinil. N Engl J Med 319: 548–555

    PubMed  Google Scholar 

  5. Sima AAF, Greene DA, Brown MB et al. (1993) Effect of hyperglycemia and the aldose reductase inhibitor tolrestat on sural nerve biochemistry and morphometry in advanced diabetic peripheral polyneuropathy. J Diab Comp 7: 157–169

    Article  Google Scholar 

  6. Tesfaye S, Harris N, Jakubowski JJ et al. (1993) Impaired blood flow and arterio-venous shunting in human diabetic neuropathy: a novel technique of nerve photography and fluorescein angiography. Diabetologia 36: 1266–1274

    PubMed  Google Scholar 

  7. Newrick PG, Wilson AF, Jakubowski J, Boulton AJM, Ward JD (1986) Sural nerve oxygen tension in diabetes. BMJ 293: 1053–1954

    PubMed  Google Scholar 

  8. Britland ST, Young RJ, Sharma AK, Clarke BF (1990) Relationship of endoneurial capillary abnormalities to type and severity of diabetic polyneuropathy. Diabetes 39: 909–913

    PubMed  Google Scholar 

  9. Malik RA, Newrick PG, Sharma AK et al. (1989) Micro angiopathy in human diabetic neuropathy: relationship between capillary abnormalities and the severity of neuropathy. Diabetologia 32: 92–102

    PubMed  Google Scholar 

  10. Malik RA, Veves A, Masson EA, Sharma AK et al. (1992) Endoneurial capillary abnormalities in mild human diabetic neuropathy. J Neurol Neurosurg Psychiatry 55: 557–561

    PubMed  Google Scholar 

  11. Malik RA, Tesfaye S, Thompson SD et al. (1993) Endoneurial localization of microvascular damage in human diabetic neuropathy. Diabetologia 36: 454–459

    PubMed  Google Scholar 

  12. Griffey RH, Eaton RP, Sibbitt RR, Sibbitt WL Jr, Bicknell JM (1988) Diabetic neuropathy: structural analysis of nerve hydration by magnetic resonance spectroscopy. JAMA 260: 2872–2878

    PubMed  Google Scholar 

  13. Eaton RP, Sibbitt WL Jr, Bicknell JM, King MK, Griffey RH, Sibbitt RR (1993) Sural nerve water in-vivo in normal humans measured by magnetic resonance spectroscopy: relation to age, height, gender, and neurological profile. Muscle Nerve 16: 307–311

    PubMed  Google Scholar 

  14. Bicknell JM, King MK, Eaton RP, Sibbitt WL Jr (1994) Neuropathic symptoms neurologic examination deficits and nerve conduction abnormalities are present in a healthy volunteer population and increase with age. Int J Diabetes 2: 77–85

    Google Scholar 

  15. Koechner D, Petropoulos H, Eaton RP, Hart BL, Brooks WM (1995) Segmentation of small structures in magnetic resonance images: semi-automated tissue hydration measurement. J Magn Reson Imaging 5: 347–351

    PubMed  Google Scholar 

  16. Lancaster HO (1949) The derivation and partition of chisquare in certain discrete distributions. Biometrika 36: 117–129

    Google Scholar 

  17. Irwin JO (1949) A note on the subdivision of chi-square into components. Biometrika 36: 130–134

    Google Scholar 

  18. Pirart J (1978) Diabetes mellitus and its degenerative complications: a prospective study of 4,400 patients observed between 1947 and 1973. Diabetes Care 1: 168–252

    Google Scholar 

  19. Eaton RP (1986) The collagen hydration hypothesis: a new paradigm for the secondary complications of diabetes mellitus. J Chron Dis 39: 763–766

    Article  PubMed  Google Scholar 

  20. Ratliff DM, Vanderjagt DJ, Eaton RP, Vanderjagt DL (1995) Increased levels of aldose reductase and glyoxalase-I in mononuclear cells from IDDM patients. J Invest Med 43: 187A (Abstract)

    Google Scholar 

  21. Hamada Y, Kitoh R, Raskin P (1991) Increased erythrocyte aldose reductase activity in type I diabetic patients. Diabet Med 8: 226–231

    PubMed  Google Scholar 

  22. Hamada Y, Kitoh R, Raskin P (1993) Association of erythrocyte aldose reductase activity with diabetic complications in type 1 diabetes mellitus. Diabet Med 10: 33–38

    PubMed  Google Scholar 

  23. Nishimura C, Saito T, Ito T, Omori Y, Tanimoto T (1994) High levels of erythrocyte aldose reductase and diabetic retinopathy in NIDDM patients. Diabetologia 37: 328–330

    Article  PubMed  Google Scholar 

  24. Dent MT, Tebbs SE, Gonzales AM, Ward JD, Wilson RM (1991) L Neutrophil aldose reductase activity and its associations with established diabetic microvascular complications. Diabet Med 8: 439–442

    PubMed  Google Scholar 

  25. Graham A, Brown L, Hedge PJ, Gammack AJ, Markham AF (1991) Structure of the human aldose reductase gene. J Biol Chem 266: 6872–6877

    PubMed  Google Scholar 

  26. Wang K, Bohren KM, Gabbay KH (1993) Characterization of the human aldose reductase gene promoter. J Biol Chem 268: 16052–16058

    PubMed  Google Scholar 

  27. Yamaoka T, Nishimura C, Yamashita K et al. (1995) Acute onset of diabetic pathological changes in transgenic mice with human aldose reductase cDNA. Diabetologia 38: 255–261

    Article  PubMed  Google Scholar 

  28. Dorin RI, Shah VO, Kaplan DL, Vela BS, Zager PG (1995) Regulation of aldose reductase gene expression in renal cortex and medulla of rats. Diabetologia 38: 46–54

    Article  PubMed  Google Scholar 

  29. Bondy C, Cowley BD Jr, Lightman SL, Kador PF (1990) Feedback inhibition of aldose reductase gene expression in rat renal medulla. Galactitol accumulation reduces enzyme mRNA levels and depletes cellular inositol content. J Clin Invest 86: 1103–1108

    PubMed  Google Scholar 

  30. Wu RR, Lyons PA, Want A, Sainsbury AJ, Chung S, Palmer TN (1993) Effects of galactose feeding on aldose reductase gene expression. J Clin Invest 92: 155–159

    PubMed  Google Scholar 

  31. Ghahary A, Luo JM, Gong YW, Chakrabarti S, Sima AA, Murphy LJ (1989) Increased renal aldose reductase activity, immunoreactivity, and mRNA in streptozocin-induced diabetic rats. Diabetes 38: 1067–1071

    PubMed  Google Scholar 

  32. Ko BC, Lam KS, Wat NM, Chung SS (1995) An (A-C) dinucleotide repeat polymorphic marker at the 5′ end of the aldose reductase gene is associated with early-onset diabetic retinopathy in NIDDM patients. Diabetes 44: 727–732

    PubMed  Google Scholar 

  33. Jedziniak JA, Chylack LT Jr, Cheng HM et al. (1981) The sorbitol pathway in the human lens: aldose reductase and polyol dehydrogenase. Invest Ophthal Vis Res 20: 314–326

    Google Scholar 

  34. Dyck PJ, Karnes JL, O'Brien P et al. (1986) The spatial distribution of fiber loss in diabetic polyneuropathy suggests ischemia. Ann Neurol 19: 440–449

    PubMed  Google Scholar 

  35. Johnson PC, Doll SC, Cromey DW (1986) Pathogenesis of diabetic neuropathy. Ann Neurol 19: 450–457

    PubMed  Google Scholar 

  36. Nukada H, Dyck PJ (1984) Microsphere embolization of nerve capillaries and fiber degeneration. Am J Pathol 115: 275–287

    PubMed  Google Scholar 

  37. Dyck PJ, Hansen S, Karnes J et al. (1985) Capillary number and percentage closed in human diabetic sural nerve. Proc Natl Acad Sci USA 82: 2513–2517

    PubMed  Google Scholar 

  38. Yasuda H, Dyck PJ (1987) Abnormalities of endoneurial micro vessels and sural nerve pathology in diabetic neuropathy. Neurology 37: 20–28

    PubMed  Google Scholar 

  39. Fagerberg SE (1959) Diabetic neuropathy: a clinical and histological study on the significance of vascular affections. Acta Med Scand 164 [Suppl 345]: 1–70

    Google Scholar 

  40. Brown MJ, Asbury AK (1984) Diabetic neuropathy. Ann Neurol 15: 2–12

    PubMed  Google Scholar 

  41. Sima AAF, Nathaniel V, Bril V (1988) Histopathological heterogeneity of neuropathy in IDDM and non-IDDM, and demonstration of axo-glial dysjunction in human diabetic neuropathy. J Clin Invest 81: 349–364

    PubMed  Google Scholar 

  42. Sima AAF, Prashar A, Nathaniel V, Bril V, Werb MR, Greene DA (1993) Overt diabetic neuropathy: repair of axo-glial dysjunction and axonal atrophy by aldose reductase inhibition and its correlation to improvement in nerve conduction velocity. Diabet Med 10: 115–121

    PubMed  Google Scholar 

  43. Veves A, Malik RA, Lye RH et al. (1991) The relationship between sural nerve morphometric findings and measures of peripheral nerve function in mild diabetic neuropathy. Diabet Med 8: 917–921

    PubMed  Google Scholar 

  44. Hendricksen PH, Oley PL, Wieneke GH, Bravenboer B, Banga JD (1992) Subclinical diabetic neuropathy: similarities between electro-physiological results of patients with type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 35: 690–695

    PubMed  Google Scholar 

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Eaton, R.P., Qualls, C., Bicknell, J. et al. Structure-function relationships within peripheral nerves in diabetic neuropathy: the hydration hypothesis. Diabetologia 39, 439–446 (1996). https://doi.org/10.1007/BF00400675

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  • DOI: https://doi.org/10.1007/BF00400675

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