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Erschienen in: Diabetologia 3/2005

01.03.2005 | Article

Sural nerve pathology in diabetic patients with minimal but progressive neuropathy

verfasst von: R. A. Malik, S. Tesfaye, P. G. Newrick, D. Walker, S. M. Rajbhandari, I. Siddique, A. K. Sharma, A. J. M. Boulton, R. H. M. King, P. K. Thomas, J. D. Ward

Erschienen in: Diabetologia | Ausgabe 3/2005

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Abstract

Aims/hypothesis

The early pathological features of human diabetic neuropathy are not clearly defined. Therefore we quantified nerve fibre and microvascular pathology in sural nerve biopsies from diabetic patients with minimal neuropathy.

Methods

Twelve diabetic patients underwent detailed assessment of neuropathy and fascicular sural nerve biopsy at baseline, with repeat assessment of neuropathy 8.7±0.6 years later.

Results

At baseline, neuropathic symptoms, neurological deficits, quantitative sensory testing, cardiac autonomic function and peripheral nerve electrophysiology showed minimal abnormality, which deteriorated at follow-up. Myelinated fibre density, fibre and axonal area, and g-ratio were normal but teased fibre studies showed paranodal abnormalities (p<0.001), segmental demyelination (p<0.01) and remyelination (p<0.01) without axonal degeneration. Unassociated Schwann cell profile density (p<0.04) and unmyelinated axon density (p<0.001) were increased and axon diameter was decreased (p<0.007). Endoneurial capillaries demonstrated basement membrane thickening (p<0.006), endothelial cell hyperplasia (p<0.004) and a reduction in luminal area (p<0.007).

Conclusions/interpretation

The early pathological features of human diabetic neuropathy include an abnormality of the myelinated fibre Schwann cell and unmyelinated fibre degeneration with regeneration. These changes are accompanied by a significant endoneurial microangiopathy.
Literatur
1.
Zurück zum Zitat Abbott CA, Carrington AL, Ashe H et al (2002) The North-West Diabetes Foot Care Study: incidence of, and risk factors for, new diabetic foot ulceration in a community-based patient cohort. Diabet Med 19:377–384CrossRef Abbott CA, Carrington AL, Ashe H et al (2002) The North-West Diabetes Foot Care Study: incidence of, and risk factors for, new diabetic foot ulceration in a community-based patient cohort. Diabet Med 19:377–384CrossRef
2.
Zurück zum Zitat Forsblom CM, Sane T, Groop P-H et al (1998) Risk factors for mortality in Type II (non-insulin-dependent) diabetes: evidence of a role for neuropathy and a protective effect of HLA-DR4. Diabetologia 41:1253–1262CrossRefPubMed Forsblom CM, Sane T, Groop P-H et al (1998) Risk factors for mortality in Type II (non-insulin-dependent) diabetes: evidence of a role for neuropathy and a protective effect of HLA-DR4. Diabetologia 41:1253–1262CrossRefPubMed
3.
Zurück zum Zitat Nishikawa T, Edelstein D, Du XL et al (2000) Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404:787–790CrossRefPubMed Nishikawa T, Edelstein D, Du XL et al (2000) Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404:787–790CrossRefPubMed
4.
Zurück zum Zitat Boulton AJ, Malik RA, Arezzo JC, Sosenko JM (2004) Diabetic somatic neuropathies. Diabetes Care 27:1458–1486 Boulton AJ, Malik RA, Arezzo JC, Sosenko JM (2004) Diabetic somatic neuropathies. Diabetes Care 27:1458–1486
5.
Zurück zum Zitat Dyck PJ, Davies JL, Wilson DM, Service FJ, Melton LJ 3rd, O’Brien PC (1999) Risk factors for severity of diabetic polyneuropathy: intensive longitudinal assessment of the Rochester Diabetic Neuropathy Study cohort. Diabetes Care 22:1479–1486 Dyck PJ, Davies JL, Wilson DM, Service FJ, Melton LJ 3rd, O’Brien PC (1999) Risk factors for severity of diabetic polyneuropathy: intensive longitudinal assessment of the Rochester Diabetic Neuropathy Study cohort. Diabetes Care 22:1479–1486
6.
Zurück zum Zitat Tesfaye S, Malik RA, Ward JD (1994) Vascular factors in diabetic neuropathy. Diabetologia 37:847–854 Tesfaye S, Malik RA, Ward JD (1994) Vascular factors in diabetic neuropathy. Diabetologia 37:847–854
7.
Zurück zum Zitat Newrick PG, Wilson AJ, Jakubowski J, Boulton AJM, Ward JD (1986) Sural nerve oxygen tension in diabetes. Br Med J 193:1053–1054 Newrick PG, Wilson AJ, Jakubowski J, Boulton AJM, Ward JD (1986) Sural nerve oxygen tension in diabetes. Br Med J 193:1053–1054
8.
Zurück zum Zitat Valls-Canals J, Povedano M, Montero J, Pradas J (2002) Diabetic polyneuropathy: axonal or demyelinating? Electromyogr Clin Neurophysiol 42:3–6 Valls-Canals J, Povedano M, Montero J, Pradas J (2002) Diabetic polyneuropathy: axonal or demyelinating? Electromyogr Clin Neurophysiol 42:3–6
9.
Zurück zum Zitat Dyck PJ, Zimmerman BR, Vilen TH et al (1988) Nerve glucose, fructose, sorbitol, myo-inositol, and fibre degeneration and regeneration in diabetic neuropathy. N Engl J Med. 319:542–548 Dyck PJ, Zimmerman BR, Vilen TH et al (1988) Nerve glucose, fructose, sorbitol, myo-inositol, and fibre degeneration and regeneration in diabetic neuropathy. N Engl J Med. 319:542–548
10.
Zurück zum Zitat 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 114:867–892 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 114:867–892
11.
Zurück zum Zitat Malik RA, Veves A, Walker D et al (2001) Nerve fibre pathology in diabetic patients with mild neuropathy: relationship to symptoms, peripheral nerve electrophysiology, and quantitative sensory testing. Acta Neuropathol 101:367–374 Malik RA, Veves A, Walker D et al (2001) Nerve fibre pathology in diabetic patients with mild neuropathy: relationship to symptoms, peripheral nerve electrophysiology, and quantitative sensory testing. Acta Neuropathol 101:367–374
12.
Zurück zum Zitat Malik RA, Newrick PG, Sharma AK et al (1989) Microangiopathy in human diabetic neuropathy: relationship between capillary abnormalities and the severity of neuropathy. Diabetologia 32:92–102PubMed Malik RA, Newrick PG, Sharma AK et al (1989) Microangiopathy in human diabetic neuropathy: relationship between capillary abnormalities and the severity of neuropathy. Diabetologia 32:92–102PubMed
13.
Zurück zum Zitat Malik RA, Veves A, Masson EA et al (1992) Endoneurial capillary abnormalities in mild human diabetic neuropathy. J Neurol Neurosurg Psychiatry 55:557–561 Malik RA, Veves A, Masson EA et al (1992) Endoneurial capillary abnormalities in mild human diabetic neuropathy. J Neurol Neurosurg Psychiatry 55:557–561
14.
Zurück zum Zitat Bradley J, Thomas PK, King RHM, Llewelyn JG, Muddle JR, Watkins PJ (1990) Morphometry of endoneurial capillaries in diabetic sensory and autonomic neuropathy. Diabetologia 33:611–618CrossRef Bradley J, Thomas PK, King RHM, Llewelyn JG, Muddle JR, Watkins PJ (1990) Morphometry of endoneurial capillaries in diabetic sensory and autonomic neuropathy. Diabetologia 33:611–618CrossRef
15.
Zurück zum Zitat Britland ST, Young RJ, Sharma AK, Clarke BF (1990) Relationship of endoneurial capillary abnormalities to type and severity of diabetic polyneuropathy. Diabetes 39:909–913PubMed Britland ST, Young RJ, Sharma AK, Clarke BF (1990) Relationship of endoneurial capillary abnormalities to type and severity of diabetic polyneuropathy. Diabetes 39:909–913PubMed
16.
Zurück zum Zitat Cotter MA, Jack AM, Cameron NE (2002) Effects of the protein kinase Cβ inhibitor LY333531 on neural and vascular function in diabetic rats. Clin Sci 103:311–321 Cotter MA, Jack AM, Cameron NE (2002) Effects of the protein kinase Cβ inhibitor LY333531 on neural and vascular function in diabetic rats. Clin Sci 103:311–321
17.
Zurück zum Zitat Walker D, Carrington A, Cannan SA et al (1999) Peripheral nerve structural abnormalities do not explain the reduction in nerve conduction velocity or nerve blood flow in the streptozotocin diabetic rat. J Anat 195:419–427CrossRef Walker D, Carrington A, Cannan SA et al (1999) Peripheral nerve structural abnormalities do not explain the reduction in nerve conduction velocity or nerve blood flow in the streptozotocin diabetic rat. J Anat 195:419–427CrossRef
18.
Zurück zum Zitat Wright A, Nukada H (1994) Sciatic nerve morphology and morphometry in mature rats with streptozocin-induced diabetes. Acta Neuropathol (Berl) 88:571–578 Wright A, Nukada H (1994) Sciatic nerve morphology and morphometry in mature rats with streptozocin-induced diabetes. Acta Neuropathol (Berl) 88:571–578
19.
Zurück zum Zitat Sima AA, Zhang W, Li ZG, Murakawa Y, Pierson CR (2004) Molecular alterations underlie nodal and paranodal degeneration in type 1 diabetic neuropathy and are prevented by C-peptide. Diabetes 53:1556–1563 Sima AA, Zhang W, Li ZG, Murakawa Y, Pierson CR (2004) Molecular alterations underlie nodal and paranodal degeneration in type 1 diabetic neuropathy and are prevented by C-peptide. Diabetes 53:1556–1563
20.
Zurück zum Zitat Thomas PK, Beamish NG, Small JR et al (1996) Paranodal structure in diabetic sensory polyneuropathy. Acta Neuropathol (Berl) 92:614–620CrossRef Thomas PK, Beamish NG, Small JR et al (1996) Paranodal structure in diabetic sensory polyneuropathy. Acta Neuropathol (Berl) 92:614–620CrossRef
21.
Zurück zum Zitat Engelstad JK, Davies JL, Giannini C, O’Brien PC, Dyck PJ (1997) No evidence for axonal atrophy in human diabetic polyneuropathy. J Neuropathol Exp Neurol 56:255–262 Engelstad JK, Davies JL, Giannini C, O’Brien PC, Dyck PJ (1997) No evidence for axonal atrophy in human diabetic polyneuropathy. J Neuropathol Exp Neurol 56:255–262
22.
Zurück zum Zitat Eckersley L (2002) Role of the Schwann cell in diabetic neuropathy. Int Rev Neurobiol 50:293–321 Eckersley L (2002) Role of the Schwann cell in diabetic neuropathy. Int Rev Neurobiol 50:293–321
23.
Zurück zum Zitat Mizisin AP, Shelton GD, Burgers ML, Powell HC, Cuddon PA (2002) Neurological complications associated with spontaneously occurring feline diabetes mellitus. J Neuropathol Exp Neurol 61:872–884 Mizisin AP, Shelton GD, Burgers ML, Powell HC, Cuddon PA (2002) Neurological complications associated with spontaneously occurring feline diabetes mellitus. J Neuropathol Exp Neurol 61:872–884
24.
Zurück zum Zitat Vincent AM, Brownlee M, Russell JW (2002) Oxidative stress and programmed cell death in diabetic neuropathy. Ann NY Acad Sci 959:368–383 Vincent AM, Brownlee M, Russell JW (2002) Oxidative stress and programmed cell death in diabetic neuropathy. Ann NY Acad Sci 959:368–383
25.
Zurück zum Zitat Sekido H, Suzuki T, Jomori T, Takeuchi M, Yabe-Nishimura C, Yagihashi S (2004) Reduced cell replication and induction of apoptosis by advanced glycation end products in rat Schwann cells. Biochem Biophys Res Commun 320:241–248CrossRef Sekido H, Suzuki T, Jomori T, Takeuchi M, Yabe-Nishimura C, Yagihashi S (2004) Reduced cell replication and induction of apoptosis by advanced glycation end products in rat Schwann cells. Biochem Biophys Res Commun 320:241–248CrossRef
26.
Zurück zum Zitat Young RJ, Zhou YQ, Rodriguez E, Prescott RJ, Ewing DJ, Clarke BF (1986) Variable relationship between peripheral somatic and autonomic neuropathy in patients with different syndromes of diabetic polyneuropathy. Diabetes 35:192–197 Young RJ, Zhou YQ, Rodriguez E, Prescott RJ, Ewing DJ, Clarke BF (1986) Variable relationship between peripheral somatic and autonomic neuropathy in patients with different syndromes of diabetic polyneuropathy. Diabetes 35:192–197
27.
Zurück zum Zitat Ochoa J (1978) Recognition of unmyelinated fibre disease: morphologic criteria. Muscle Nerve 1:375–387CrossRef Ochoa J (1978) Recognition of unmyelinated fibre disease: morphologic criteria. Muscle Nerve 1:375–387CrossRef
28.
Zurück zum Zitat DCCT Research Group (1995) The effect of intensive diabetes therapy on the development and progression of neuropathy. Ann Int Med 122:561–568 DCCT Research Group (1995) The effect of intensive diabetes therapy on the development and progression of neuropathy. Ann Int Med 122:561–568
29.
Zurück zum Zitat Partanen J, Niskanen L, Lehtinen J, Mervaala E, Siitonen O, Uusitupa M (1995) Natural history of peripheral neuropathy in patients with non-insulin dependent diabetes. N Engl J Med 333:39–84CrossRef Partanen J, Niskanen L, Lehtinen J, Mervaala E, Siitonen O, Uusitupa M (1995) Natural history of peripheral neuropathy in patients with non-insulin dependent diabetes. N Engl J Med 333:39–84CrossRef
30.
Zurück zum Zitat Arezzo JC, Zotova E (2002) Electrophysiologic measures of diabetic neuropathy: mechanism and meaning. Int Rev Neurobiol 50:229–255 Arezzo JC, Zotova E (2002) Electrophysiologic measures of diabetic neuropathy: mechanism and meaning. Int Rev Neurobiol 50:229–255
31.
Zurück zum Zitat Britland ST, Young RJ, Sharma AK, Clarke BF (1990) Association of painful and painless diabetic polyneuropathy with different patterns of nerve fibre degeneration and regeneration. Diabetes 39:898–908 Britland ST, Young RJ, Sharma AK, Clarke BF (1990) Association of painful and painless diabetic polyneuropathy with different patterns of nerve fibre degeneration and regeneration. Diabetes 39:898–908
32.
Zurück zum Zitat Sima AAF, Nathaniel V, Bril V, McEwen TAJ, Greene DA (1988) Histopathological heterogeneity of neuropathy in insulin-dependent and non-insulin dependent diabetes, and demonstration of axo–glial dysjunction in human diabetic neuropathy. J Clin Invest 81:349–364 Sima AAF, Nathaniel V, Bril V, McEwen TAJ, Greene DA (1988) Histopathological heterogeneity of neuropathy in insulin-dependent and non-insulin dependent diabetes, and demonstration of axo–glial dysjunction in human diabetic neuropathy. J Clin Invest 81:349–364
33.
Zurück zum Zitat Sugimura K, Dyck PJ (1981) Sural nerve myelin thickness and axis cylinder calibre in human diabetes. Neurology 31:1087–1091 Sugimura K, Dyck PJ (1981) Sural nerve myelin thickness and axis cylinder calibre in human diabetes. Neurology 31:1087–1091
34.
Zurück zum Zitat Said G, Goulon-Goeau C, Slama G, Tchobroutsky G (1992) Severe early-onset polyneuropathy in insulin-dependent diabetes mellitus. A clinical and pathological study. N Engl J Med 326:1257–1263 Said G, Goulon-Goeau C, Slama G, Tchobroutsky G (1992) Severe early-onset polyneuropathy in insulin-dependent diabetes mellitus. A clinical and pathological study. N Engl J Med 326:1257–1263
35.
Zurück zum Zitat Ziegler D, Mayer P, Gries F (1988) Evaluation of thermal, pain, and vibration sensation thresholds in newly diagnosed Type 1 diabetic patients. J Neurol Neurosurg Psychiatry 51:1420–1424 Ziegler D, Mayer P, Gries F (1988) Evaluation of thermal, pain, and vibration sensation thresholds in newly diagnosed Type 1 diabetic patients. J Neurol Neurosurg Psychiatry 51:1420–1424
36.
Zurück zum Zitat Sumner CJ, Sheth S, Griffin JW, Cornblath DR, Polydefkis M (2003) The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology 60:108–111 Sumner CJ, Sheth S, Griffin JW, Cornblath DR, Polydefkis M (2003) The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology 60:108–111
37.
Zurück zum Zitat Malik RA, Kallinikos P, Abbott CA et al (2003) Corneal confocal microscopy: a non-invasive surrogate of nerve fibre damage and repair in diabetic patients. Diabetologia 46:683–688 Malik RA, Kallinikos P, Abbott CA et al (2003) Corneal confocal microscopy: a non-invasive surrogate of nerve fibre damage and repair in diabetic patients. Diabetologia 46:683–688
38.
Zurück zum Zitat Giannini C, Dyck PJ (1994) Ultrastructural morphometric abnormalities of sural nerve endoneurial microvessels in diabetes mellitus. Ann Neurol 36:408–415PubMed Giannini C, Dyck PJ (1994) Ultrastructural morphometric abnormalities of sural nerve endoneurial microvessels in diabetes mellitus. Ann Neurol 36:408–415PubMed
39.
Zurück zum Zitat Giannini C, Dyck PJ (1995) Basement membrane reduplication and pericyte degeneration precede development of diabetic polyneuropathy and are associated with its severity. Ann Neurol 37:498–504CrossRef Giannini C, Dyck PJ (1995) Basement membrane reduplication and pericyte degeneration precede development of diabetic polyneuropathy and are associated with its severity. Ann Neurol 37:498–504CrossRef
40.
Zurück zum Zitat Thrainsdottir S, Malik RA, Dahlin LB et al (2003) Endoneurial capillary abnormalities presage deterioration of glucose tolerance and accompany peripheral neuropathy in man. Diabetes 52:2615–2622PubMed Thrainsdottir S, Malik RA, Dahlin LB et al (2003) Endoneurial capillary abnormalities presage deterioration of glucose tolerance and accompany peripheral neuropathy in man. Diabetes 52:2615–2622PubMed
Metadaten
Titel
Sural nerve pathology in diabetic patients with minimal but progressive neuropathy
verfasst von
R. A. Malik
S. Tesfaye
P. G. Newrick
D. Walker
S. M. Rajbhandari
I. Siddique
A. K. Sharma
A. J. M. Boulton
R. H. M. King
P. K. Thomas
J. D. Ward
Publikationsdatum
01.03.2005
Erschienen in
Diabetologia / Ausgabe 3/2005
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-004-1663-5

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