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Diabetologia
Published in: Diabetologia 8/2005

01-08-2005 | Article

Increased accumulation of skin advanced glycation end-products precedes and correlates with clinical manifestation of diabetic neuropathy

Authors: R. Meerwaldt, T. P. Links, R. Graaff, K. Hoogenberg, J. D. Lefrandt, J. W. Baynes, R. O. B. Gans, A. J. Smit

Published in: Diabetologia | Issue 8/2005

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Abstract

Aims/hypothesis

The accumulation of AGE is related to the progression of the renal, retinal and vascular complications of diabetes. However, the relationship with diabetic neuropathy remains unclear. We recently showed that skin autofluorescence, measured non-invasively with an AutoFluorescence Reader (AFR), could be used to assess skin AGE accumulation. We evaluated the relationship between skin autofluorescence and the severity of diabetic neuropathy.

Materials and methods

Skin autofluorescence in arbitrary units (AU) was assessed in 24 diabetic patients with a history of neuropathic foot ulceration (NP+), 23 diabetic patients without clinical neuropathy (NP−) and 21 control subjects, using the AFR. Arterial occlusive disease was excluded in all. The severity of foot ulceration was assessed by the Wagner score. Peripheral nerve function was assessed by neurography, measuring motor and sensory nerve conduction velocity and amplitude of the median, peroneal and sural nerves. Heart rate variability (HRV) and baroreflex sensitivity (BRS) were measured by Finapres to assess autonomic nervous function.

Results

Autofluorescence was increased in NP− compared with control subjects. In NP+ patients, autofluorescence was further increased and correlated with the Wagner score. Autofluorescence correlated negatively with nerve conduction velocity and amplitude, HRV and BRS in both NP+ and NP− groups. Autofluorescence correlated with age, diabetes duration, mean HbA1c of the previous year, serum creatinine level, presence of microalbuminuria and severity of diabetic retinopathy.

Conclusions/interpretation

Skin autofluorescence correlates with the severity of peripheral and autonomic nerve abnormalities in diabetes, even before being clinically manifest. The AFR may be a convenient and rapid clinical tool for assessing risk of progression of long-term diabetic complications.
Literature
1.
Holzer SE, Camerota A, Martens L, Cuerdon T, Crystal-Peters J, Zagari M (1998) Costs and duration of care for lower extremity ulcers in patients with diabetes. Clin Ther 20:169–181CrossRefPubMed
2.
Young MJ, Boulton AJM, McLeod AF, Williams DRR, Sonksen PH (1993) A multicentre study of the prevalence of diabetic neuropathy in the UK hospital clinical population. Diabetologia 36:150–154CrossRefPubMed
3.
Boulton AJM (1996) The pathogenesis of diabetic foot problems: an overview. Diabet Med 13:12–16CrossRef
4.
Ewing DJ, Campbell IW, Clarke BF (1976) Mortality in diabetic autonomic neuropathy. Lancet 1:601–603CrossRefPubMed
5.
Cameron NE, Eaton SE, Cotter MA, Tesfaye S (2001) Vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy. Diabetologia 44:1973–1988CrossRefPubMed
6.
Baynes JW (2002) Glycation and advanced glycation reaction. In: Gries FA, Cameron NE, Low PA, Ziegler D (eds) Diabetic neuropathy. Thieme Medical, Stuttgart
7.
Obrosova IG (2003) Update on the pathogenesis of diabetic neuropathy. Curr Diab Rep 3:439–445PubMed
8.
King RH (2001) The role of glycation in the pathogenesis of diabetic polyneuropathy. Mol Pathol 54:400–408PubMed
9.
Schleicher E, Wagner E, Nerlich AG (1997) Increased accumulation of the glycoxidation product Ne-(carboxymethyl)lysine in human tissues in diabetes and aging. J Clin Invest 9:457–468
10.
Makita Z, Radoff S, Rayfield EJ et al (1991) Advanced glycosylation end products in patients with diabetic nephropathy. N Engl J Med 325:836–842PubMed
11.
Baynes JW, Thorpe SR (1999) Role of oxidative stress in diabetic complications. A new perspective on an old Paradigm. Diabetes 48:1–9PubMed
12.
Nishikawa T, Edelstein D, Du XL et al (2000) Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404:787–790CrossRefPubMed
13.
Monnier VM, Bautista O, DCCT Skin Collagen Ancillary Study Group (1999) Skin collagen glycation, glycoxidation, and crosslinking are lower in subjects with long-term intensive versus conventional therapy of type 1 diabetes. Diabetes 48:870–880PubMed
14.
15.
Stracke H, Lindemann A, Federlin K (1996) Benfotiamin–vitamin B combination in treatment of diabetic neuropathy. Exp Clin Endocrinol Diabetes 104:311–316PubMed
16.
Cameron NE, Cotter MA, Dines K, Love A (1992) Effects of aminoguanidine on peripheral nerve function and polyol pathway metabolites in streptozotocin-diabetic rats. Diabetologia 35:946–950CrossRefPubMed
17.
Dorrian CA, Cathcart S, Clausen J, Shapiro D, Dominiczak MH (1998) Factors in human serum interfere with the measurement of advanced glycation endproducts. Cell Mol Biol 44:1069–1079PubMed
18.
Meerwaldt R, Smit AJ, Navis GJ, van Roon AM, Graaff R, Gans ROB (2000) Increased skin autofluorescence in diabetes mellitus and renal failure. Diabetologia 44 [Suppl]:A1046
19.
Meerwaldt R, Graaff R, Oomen PHN et al (2004) Simple noninvasive assessment of advanced glycation endproduct accumulation. Diabetologia 47:1324–1330CrossRefPubMed
20.
Coremans JMC, Ince C, Bruining HA, Puppels GJ (1997) (Semi-) quantitative analysis of reduced nicotinamide adenine dinucleotide fluorescence image of blood perfused rat heart. Biophys J 72:1849–1860PubMed
21.
Na R, Stender IM, Henriksen M, Wulf HC (2001) Autofluorescence of human skin is age-related after correction for skin pigmentation and redness. J Invest Dermatol 116:536–540CrossRefPubMed
22.
Meijer JWG, van Sonderen E, Blaauwwiekel EE et al (2000) Diabetic neuropathy examination: a hierarchical scoring system to diagnose distal polyneuropathy in diabetes. Diabetes Care 23:750–753PubMed
23.
Dyck PJ (1998) Detection, characterization and staging of polyneuropathy: assessed in diabetics. Muscle Nerve 11:21–32CrossRef
24.
Kumar S, Fernando DJS, Veves A, Knowles EA, Young MJ, Boulton AJM (1991) Semmes Weinstein monofilaments: a simple, effective and inexpensive screening device for identifying diabetic patients at risk of foot ulceration. Diabetes Res Clin Pract 13:63–68CrossRefPubMed
25.
Young MJ, Breddy JL, Veves A, Boulton AJM (1994) The prediction of diabetic neuropathic foot ulceration using vibration perception thresholds. Diabetes Care 17:557–560PubMed
26.
Task Force of the European Society of Cardiology and the Northern American Society of Pacing and Electrophysiology (1996) Heart rate variability. Standards of measurement, physiological interpretation and clinical use. Circulation 93:1043–1065
27.
Lefrandt JD, Hoogenberg K, van Roon AM, Dullaart RPF, Gans ROB, Smit AJ (1999) Baroreflex sensitivity is depressed in microalbuminuric type 1 diabetic patients at rest and during sympathetic manoeuvres. Diabetologia 42:1345–1349CrossRefPubMed
28.
Robbe HW, Mulder LJ, Ruddel H, Langewitz WA, Veldman JB, Mulder G (1987) Assessment of baroreceptor reflex sensitivity by means of spectral analysis. Hypertension 10:538–543PubMed
29.
Cerami C, Hounds H, Nicholl L et al (1997) Tobacco smoke is a source of toxic reactive glycation products. Proc Natl Acad Sci U S A 94:13915–13920CrossRefPubMed
30.
Nicoll ID, Stitt AW, Moore JE (1998) Increased levels of advanced glycation endproducts in the lenses and blood vessels of cigarette smokers. Mol Med 4:594–601PubMed
31.
Koschinsky T, He CJ, Mitsuhashi T et al (1997) Orally absorbed reactive glycation products (glycotoxins): an environmental risk factor in diabetic nephropathy. Proc Natl Acad Sci U S A 94:6474–6479PubMed
32.
Thornalley PJ (2002) Glycation in diabetic neuropathy: characteristics, consequences, causes, and therapeutic options. Int Rev Neurobiol 50:37–57PubMed
33.
Cellek S, Qu W, Schmidt AM, Moncade S (2004) Synergistic action of advanced glycation end products and endogenous nitric oxide leads to neural apoptosis in vitro: a new insight into selective nitregic neuropathy in diabetes. Diabetologia 47:331–339CrossRefPubMed
34.
Tanaka Y, Uchino H, Shimizu T et al (1999) Effect of metformin on advanced glycation endproduct formation and peripheral nerve function in streptozotocin-induced diabetic rats. Eur J Pharmacol 376:17–22CrossRefPubMed
35.
Baba M, Ozaki I (2001) Electrophysiological changes in diabetic neuropathy: from subclinical alterations to disabling abnormalities. Arch Physiol Biochem 109:234–240CrossRefPubMed
36.
Veves A, Akbari CM, Primavera J et al (1998) Endothelial dysfunction and the expression of endothelial nitric oxide synthetase in diabetic neuropathy, vascular disease, and foot ulceration. Diabetes 47:457–463PubMed
37.
Jude EB, Abbott CA, Young MJ, Anderson SG, Douglas JT, Boulton AJ (1999) The potential role of cell adhesion molecules in the pathogenesis of diabetic neuropathy. Diabetologia 41:330–336CrossRef
38.
Goova MT, Kislinger T, Qu W et al (2001) Blockade of receptor for advanced glycation end-products restores effective wound healing in diabetic mice. Am J Pathol 159:513–525PubMed
39.
Pierce GF (2001) Inflammation in nonhealing diabetic wounds. Am J Pathol 159:399–403PubMed
40.
Toyre JP, Partanen JV, Niskanen LK, Lansimies EA, Uusitupa MI (1997) Divergent development of autonomic and peripheral somatic neuropathies in NIDDM. Diabetologia 40:953–958CrossRefPubMed
41.
Burger AJ, Weinrauch LA, D’Elia JA, Aronson D (1999) Effect of glycemic control on heart rate variability in type 1 diabetic patients with cardiac autonomic neuropathy. Am J Cardiol 84:687–691CrossRefPubMed
42.
Lefrandt JD, Mulder MC, Bosma E, Smit AJ, Hoogenberg K (2001) Relation between autonomic function and blood glucose in the nondiabetic range. Diabetes Care 24:2017
43.
Lefrandt JD, Mulder MC, Bosma E, Smit AJ, Hoogenberg K (2003) Inverse relationship between blood glucose and autonomic function in healthy subjects. Diabetes Care 23:1862–1864
44.
Lefrandt JD, Diercks GF, van Boven AJ, Crijns HJ, van Gilst WH, Gans RO (2000) High fasting glucose and QTc duration in a large healthy cohort. Diabetologia 43:1332–1333
45.
Beisswenger PJ, Makita Z, Curphey TJ et al (1995) Formation of immunochemical advanced glycosylation end products precede and correlate with early manifestations of renal and retinal disease in diabetes. Diabetes 44:824–829PubMed
46.
Baynes JW, Thorpe SR (2000) Glycoxidation and lipoxidation in atherogenesis. Free Radic Biol Med 28:1708–1716CrossRefPubMed
Metadata
Title
Increased accumulation of skin advanced glycation end-products precedes and correlates with clinical manifestation of diabetic neuropathy
Authors
R. Meerwaldt
T. P. Links
R. Graaff
K. Hoogenberg
J. D. Lefrandt
J. W. Baynes
R. O. B. Gans
A. J. Smit
Publication date
01-08-2005
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 8/2005
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-005-1828-x

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