Aktuelle Neurologie 2006; 33(10): 543-552
DOI: 10.1055/s-2006-940077
Übersicht
© Georg Thieme Verlag KG Stuttgart · New York

Peripher-neurogene Läsionen bei Diabetes mellitus

Peripheral Neurogenic Lesions in Diabetes MellitusS.  Haußleiter1 , M.  Tegenthoff1
  • 1Neurologische Universitätsklinik Ruhr-Universität Bochum BG-Kliniken Bergmannsheil
Further Information

Publication History

Publication Date:
25 September 2006 (online)

Zusammenfassung

Polyneuropathien sind generalisierte Erkrankungen des peripheren Nervensystems. Der Diabetes mellitus ist die Hauptursache solcher Neuropathien, und die Neuropathie wiederum ist die häufigste diabetische Komplikation. Alle Diabetesformen sind gekennzeichnet durch eine chronische Hyperglykämie und die Entwicklung diabetesspezifischer mikrovaskulärer Veränderungen. Die Blutgefäße benötigen zur Funktionserhaltung eine angemessene neurale Regulation und die Nervenzellen entsprechend eine ausreichende kapilläre Ernährung. Die diabetische Neuropathie entsteht vermutlich sowohl direkt durch die schädlichen Auswirkungen der Hyperglykämie auf das Nervenparenchym, als auch indirekt durch die Veränderungen des neurovaskulären Blutflusses mit konsekutiver neuronaler Ischämie. Primäre Ursache und größter Risikofaktor für pathologische Veränderungen und klinische Komplikationen bei einem therapeutisch unzureichend eingestellten Diabetes mellitus ist die permanent existierende Hyperglykämie im Organismus. Die meisten Zellen reduzieren bei einem Überangebot an Glukose entsprechende Transportvorgänge nach intrazellulär. Renale, retinale und neuronale Zellen verfügen jedoch nicht über diesen Mechanismus und können daher nicht adäquat auf persistierende Hyperglykämien reagieren. Die Abhängigkeit pathologischer Auswirkungen vom intrazellulären Glukosespiegel legt nahe, dass sich ursächliche Mechanismen ebenfalls innerhalb der Zelle abspielen. Der Polyol- und Hexosaminpfad, eine vermehrte Glykosylierung, die Aktivierung der Proteinkinase C und oxidativer Stress scheinen hierbei wesentlich zu sein. Sie beschreiben einerseits direkte toxische Auswirkungen der Hyperglykämie und resultierender pathophysiologischer Konsequenzen (Oxidanzien, Hyperosmolarität, Glykosylierungsprodukte) auf das Gewebe, andererseits den Effekt veränderter Signalkaskaden (Phospholipide, Kinasen) durch die Produkte des Glukosestoffwechsels. Die hyperglykämie-induzierte vaskuläre Insuffizienz tritt beim Diabetiker bereits frühzeitig auf, entwickelt sich parallel zur progredienten neuronalen Dysfunktion und hält die schwerwiegenden strukturellen, funktionalen und klinischen Veränderungen der Erkrankung aufrecht.

Abstract

Polyneuropathy is a generalized disorder of the peripheral nervous system. Diabetes mellitus is the main cause of such neuropathies and neuropathy itself is the most frequent complication in diabetic patients. All forms of diabetes are characterized by hyperglycaemia and the development of specific micro-vascular alterations. Blood vessels consistently need neural regulation to maintain their function and nerve cells correspondingly require an appropriate nutrition through capillaries. The diabetic neuropathy probably results both directly from damaging hyperglycaemic effects on neural parenchyma, and indirectly from changes of the neurovascular blood flow with consecutive neuronal ischemia. Persisting hyperglycaemia of the organism is initiating cause and established risk factor for pathological changes and clinical complications in insufficiently treated diabetic patients. In case of hyperglycaemia most cells are able to reduce the transport into the cell. Some cells of retina, kidney and peripheral nerve lack this ability and therefore cannot compensate for ongoing hyperglycaemic states. Since pathological consequences depend on intracellular glucose levels, it seems reasonable that the underlying mechanisms take place inside the cell as well. Increasing flux through the polyol and hexosamine pathway, advanced glycosylation of molecules, activation of protein kinase C and finally oxidative stress seem to be of importance in this context. Those pathways describe toxic effects of the hyperglycemia and pathophysiological consequences on the tissue (oxidants, hyperosmolarity, advanced glycosylation end products), as well as the modification of signalling cascades by products of the glucose metabolism (phospholipids, kinases). Hyperglycaemically induced vascular insufficiency occurs early in diabetic patients, develops simultaneously to progressive neural dysfunction and maintains the severe structural, functional and clinical changes of the disease.

Literatur

  • 1 Diener H C. Leitlinien für Diagnostik und Therapie in der Neurologie. 3., aktualisierte und erweiterte Auflage. Stuttgart, New York; Thieme 2005
  • 2 Boulton A J, Gries F A, Jervell J A. Guidelines for the diagnosis and outpatient management of diabetic peripheral neuropathy.  Diabet Med. 1998;  15 508-514
  • 3 American Diabetes Association, American Academy of Neurology . Report and recommendations of the San Antonio Conference on Diabetic Neuropathy (Consensus Statement).  Diabetes Care. 1988;  11 592-597
  • 4 Dyck P J. Severity and staging of diabetic polyneuropathy. In: Gries FA, Cameron NE, Low PA, Ziegler D (eds) Textbook of diabetic neuropathy. 1. Auflage. Stuttgart; Thieme 2003: 170-175
  • 5 Vinik A I, Vinik E. Prevention of the complications of diabetes.  Am J Manag Care. 2003;  9 63-80
  • 6 Shaw J E, Zimmet P Z. The epidemiology of diabetic neuropathy.  Diabetes Rev. 1999;  7 245-252
  • 7 Pirart J. Diabetes mellitus and its degenerative complications: a prospective study of 4,400 patients observed between 1947 and 1973 (3rd and last part).  Diabetes Metab. 1977;  3 245-256
  • 8 Vinik A I, Holland M T, LeBeau J M. et al . Diabetic neuropathies.  Diabetes Care. 1992;  15 1926-1975
  • 9 Duby J J, Campbell R K, Setter S M. et al . Diabetic neuropathy: an intensive review.  Am J Health Syst Pharm. 2004;  61 160-173
  • 10 Boulton A J, Ward J D. Diabetic neuropathies and pain.  Clin Endocrinol Metab. 1986;  15 917-931
  • 11 Boulton A J, Malik R A. Diabetic neuropathy.  Med Clin North Am. 1998;  82 909-929
  • 12 Thomas P K. Classification, differential diagnosis, and staging of diabetic peripheral neuropathy.  Diabetes. 1997;  46 54-57
  • 13 Dyck P J, Kratz K M, Karnes J L. et al . The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study.  Neurology. 1993;  43 817-824
  • 14 Dyck P J, Giannini C. Pathologic alterations in the diabetic neuropathies of humans: a review.  J Neuropathol Exp Neurol. 1996;  55 1181-1193
  • 15 Malik R A, Tesfaye S, Thompson S D. et al . Endoneurial localisation of microvascular damage in human diabetic neuropathy.  Diabetologia. 1993;  36 454-459
  • 16 Sugimoto K, Murakawa Y, Sima A A. Diabetic neuropathy - a continuing enigma.  Diabetes Metab Res Rev. 2000;  16 408-433
  • 17 Brownlee M. Biochemistry and molecular cell biology of diabetic complications.  Nature. 2001;  414 813-820
  • 18 Shaw J E, Hodge A M, Courten M de. et al . Isolated post-challenge hyperglycaemia confirmed as a risk factor for mortality.  Diabetologia. 1999;  42 1050-1054
  • 19 Kaiser N, Sasson S, Feener E P. et al . Differential regulation of glucose transport and transporters by glucose in vascular endothelial and smooth muscle cells.  Diabetes. 1993;  42 80-89
  • 20 Heilig C W, Concepcion L A, Riser B L. et al . Overexpression of glucose transporters in rat mesangial cells cultured in a normal glucose milieu mimics the diabetic phenotype.  J Clin Invest. 1995;  96 1802-1814
  • 21 Brownlee M. The pathobiology of diabetic complications: a unifying mechanism.  Diabetes. 2005;  54 1615-1625
  • 22 Gabbay K H, Merola L O, Field R A. Sorbitol pathway: presence in nerve and cord with substrate accumulation in diabetes.  Science. 1966;  151 209-210
  • 23 Giardino I, Edelstein D, Brownlee M. Nonenzymatic glycosylation in vitro and in bovine endothelial cells alters basic fibroblast growth factor activity. A model for intracellular glycosylation in diabetes.  J Clin Invest. 1994;  94 110-117
  • 24 Shinohara R, Ohta Y, Yamauchi M, Ishiguro I. Improved fluorometric enzymatic sorbitol assay in human blood.  Clin Chim Acta. 1998;  273 171-184
  • 25 McLellan A C, Thornalley P J, Benn J, Sonksen P H. Glyoxalase system in clinical diabetes mellitus and correlation with diabetic complications.  Clin Sci. 1994;  87 21-29
  • 26 Koya D, King G L. Protein kinase C activation and the development of diabetic complications.  Diabetes. 1998;  47 859-866
  • 27 Derubertis F R, Craven P A. Activation of protein kinase C in glomerular cells in diabetes. Mechanisms and potential links to the pathogenesis of diabetic glomerulopathy.  Diabetes. 1994;  43 1-8
  • 28 Xia P, Inoguchi T, Kern T S. et al . Characterization of the mechanism for the chronic activation of diacylglycerol-protein kinase C pathway in diabetes and hypergalactosemia.  Diabetes. 1994;  43 1122-1129
  • 29 Kolm-Litty V, Sauer U, Nerlich A. et al . High glucose-induced transforming growth factor beta1 production is mediated by the hexosamine pathway in porcine glomerular mesangial cells.  J Clin Invest. 1998;  101 160-169
  • 30 Sayeski P P, Kudlow J E. Glucose metabolism to glucosamine is necessary for glucose stimulation of transforming growth factor-alpha gene transcription.  J Biol Chem. 1996;  271 15237-15243
  • 31 Du X L, Edelstein D, Rossetti L. et al . Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation.  Proc Natl Acad Sci USA. 2000;  97 12222-12226
  • 32 Sheetz M J, King G L. Molecular understanding of hyperglycemia's adverse effects for diabetic complications.  JAMA. 2002;  288 2579-2588
  • 33 Duby J J, Campbell R K, Setter S M. et al . Diabetic neuropathy: an intensive review.  Am J Health Syst Pharm. 2004;  61 160-173
  • 34 Nishikawa T, Edelstein D, Brownlee M. The missing link: a single unifying mechanism for diabetic complications.  Kidney. 2000;  77 26-30
  • 35 Du X L, Matsumura T, Edelstein D. et al . Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells.  J Clin Invest. 2003;  112 1049-1057
  • 36 Oates P J. Polyol pathway and diabetic peripheral neuropathy.  Int Rev Neurobiol. 2002;  50 325-392
  • 37 Lee A Y, Chung S S. Contributions of polyol pathway to oxidative stress in diabetic cataract.  FASEB J. 1999;  13 23-30
  • 38 Verrotti A, Giuva P T, Morgese G, Chiarelli F. New trends in the etiopathogenesis of diabetic peripheral neuropathy.  J Child Neurol. 2001;  16 389-394
  • 39 Gooch C, Podwall D. The diabetic neuropathies.  Neurologist. 2004;  10 311-322
  • 40 Kihara M, Mitsui Y, Shioyama M. et al . Effect of zenarestat, an aldose reductase inhibitor, on endoneurial blood flow in experimental diabetic neuropathy of rat.  Neurosci Lett. 2001;  310 81-84
  • 41 Cameron N E, Jack A M, Cotter M A. Effect of alpha-lipoic acid on vascular responses and nociception in diabetic rats.  Free Radic Biol Med. 2001;  31 125-135
  • 42 Greene D A, Arezzo J C, Brown M B. Zenarestat Study Group . Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy.  Neurology. 1999;  53 580-591
  • 43 Hotta N, Toyota T, Matsuoka K. et al . SNK-860 Diabetic Neuropathy Study Group. Clinical efficacy of fidarestat, a novel aldose reductase inhibitor, for diabetic peripheral neuropathy: a 52-week multicenter placebo-controlled double-blind parallel group study.  Diabetes Care. 2001;  24 1776-1782
  • 44 Clark R J, McDonough P M, Swanson E. et al . Diabetes and the accompanying hyperglycemia impairs cardiomyocyte calcium cycling through increased nuclear O-GlcNAcylation.  J Biol Chem. 2003;  278 44230-44237
  • 45 Eichberg J. Protein kinase C changes in diabetes: is the concept relevant to neuropathy?.  Int Rev Neurobiol. 2002;  50 61-82
  • 46 Koya D, Jirousek M R, Lin Y W. et al . Characterization of protein kinase C beta isoform activation on the gene expression of transforming growth factor-beta, extracellular matrix components, and prostanoids in the glomeruli of diabetic rats.  J Clin Invest. 1997;  100 115-126
  • 47 Kuboki K, Jiang Z Y, Takahara N. et al . Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in vivo: a specific vascular action of insulin.  Circulation. 2000;  101 676-681
  • 48 Ishii H, Jirousek M R, Koya D. et al . Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor.  Science. 1996;  272 728-731
  • 49 Bishara N B, Dunlop M E, Murphy T V. et al . Matrix protein glycation impairs agonist-induced intracellular Ca2+ signaling in endothelial cells.  J Cell Physiol. 2002;  193 80-92
  • 50 Koya D, Haneda M, Nakagawa H. et al . Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC beta inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes.  FASEB J. 2000;  14 439-447
  • 51 Haitoglou C S, Tsilibary E C, Brownlee M, Charonis A S. Altered cellular interactions between endothelial cells and nonenzymatically glucosylated laminin/type IV collagen.  J Biol Chem. 1992;  267 12404-12407
  • 52 Vlassara H, Palace M R. Diabetes and advanced glycation endproducts.  J Intern Med. 2002;  251 87-101
  • 53 Abordo E A, Thornalley P J. Synthesis and secretion of tumour necrosis factor-alpha by human monocytic THP-1 cells and chemotaxis induced by human serum albumin derivatives modified with methylglyoxal and glucose-derived advanced glycation endproducts.  Immunol Lett. 1997;  58 139-147
  • 54 Doi T, Vlassara H, Kirstein M. et al . Receptor-specific increase in extracellular matrix production in mouse mesangial cells by advanced glycosylation end products is mediated via platelet-derived growth factor.  Proc Natl Acad Sci USA. 1992;  89 2873-2877
  • 55 Schmidt A M, Hori O, Chen J X. et al . Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice.  J Clin Invest. 1995;  96 1395-1403
  • 56 Krendel M, Zenke F T, Bokoch G M. Nucleotide exchange factor GEF-H1 mediates cross-talk between microtubules and the actin cytoskeleton.  Nat Cell Biol. 2002;  4 294-301
  • 57 Baynes J W, Thorpe S R. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm.  Diabetes. 1999;  48 1-9
  • 58 Singh R, Barden A, Mori T, Beilin L. Advanced glycation end-products: a review.  Diabetologia. 2001;  44 129-146
  • 59 Dickinson P J, Carrington A L, Frost G S, Boulton A J. Neurovascular disease, antioxidants and glycation in diabetes.  Diabetes Metab Res Rev. 2002;  18 260-272
  • 60 Newrick P G, Wilson A J, Jakubowski J. et al . Sural nerve oxygen tension in diabetes.  Br Med J. 1986;  293 1053-1054
  • 61 Srinivasan S, Stevens M, Wiley J W. Diabetic peripheral neuropathy: evidence for apoptosis and associated mitochondrial dysfunction.  Diabetes. 2000;  49 1932-1938
  • 62 Griffey R H, Eaton R P, Sibbitt R R. et al . Diabetic neuropathy. Structural analysis of nerve hydration by magnetic resonance spectroscopy.  JAMA. 1988;  260 2872-2878
  • 63 Dyck P J, Hansen S, Karnes J. et al . Capillary number and percentage closed in human diabetic sural nerve.  Proc Natl Acad Sci USA. 1985;  82 2513-2517
  • 64 Powell H C, Myers R R. Axonopathy and microangiopathy in chronic axonal diabetes.  Acta Neuropathol. 1984;  65 128-137
  • 65 Samii A, Unger J, Lange W. Vascular endothelial growth factor expression in peripheral nerves and dorsal root ganglia in diabetic neuropathy in rats.  Neurosci Lett. 1999;  262 159-162
  • 66 Kihara M, Low P A. Impaired vasoreactivity to nitric oxide in experimental diabetic neuropathy.  Exp Neurol. 1995;  132 180-185
  • 67 Maxfield E K, Cameron N E, Cotter M A. Effects of diabetes on reactivity of sciatic vasa nervorum in rats.  J Diabetes Complications. 1997;  11 47-55
  • 68 Hopfner R L, Gopalakrishnan V. Endothelin: emerging role in diabetic vascular complications.  Diabetologia. 1999;  42 1383-1394
  • 69 Giannini C, Dyck P J. Basement membrane reduplication and pericyte degeneration precede development of diabetic polyneuropathy and are associated with its severity.  Ann Neurol. 1995;  37 498-504
  • 70 Britland S T, Young R J, Sharma A K, Clarke B F. Relationship of endoneurial capillary abnormalities to type and severity of diabetic polyneuropathy.  Diabetes. 1990;  39 909-913
  • 71 Tesfaye S, Malik R, Ward J D. Vascular factors in diabetic neuropathy.  Diabetologia. 1994;  37 847-854

Dr. Sibylle Haußleiter

Neurologische Universitätsklinik Ruhr-Universität Bochum · BG-Kliniken Bergmannsheil

Bürkle-de-la-Camp-Platz 1

44789 Bochum

Email: ida@haussleiter.de

    >