Störung der Monozytenfunktion bei Diabetes mellitus Typ 1 und 2

Zusammenfassung

Monozyten sind an der Hämostase, der Wundheilung und der Arteriogenese, d. h. der Bildung von Kollateralarterien, beteiligt. Diabetes mellitus ist mit einer Reihe zellulärer und molekularer Defekte vergesellschaftet. Jüngst veröffentlichte Daten zeigen, dass der Diabetes mellitus mit einer Störung der durch Wachstumsfaktor VEGF-A induzierbaren Monozytenmigration vergesellschaftet ist. Allerdings ist die Migrationsfähigkeit der Monozyten nicht generell aufgehoben, denn andere chemotaktische Stimuli wie das Tripeptid fMLP sind in der Lage, die Migration von Monozyten, die von Diabetikern isoliert wurden, zu stimulieren. Als molekulare Basis der Monozytendysfunktion bei Diabetikern wurde ein Signaltransduktionsdefekt postuliert, denn die VEGF-Rezeptor Kinase Flt-1 ist in diesen Monozyten intakt. Die Charakterisierung der Monozytendysfunktion erscheint für das Verständnis der Diabetes-mellitusassoziierten Krankheitsprozesse wichtig.

Summary

Monocytes play a functional role during hemostasis, wound healing and arteriogenesis, i. e. the process leading to the growth of collateral arteries. Diabetes mellitus is associated with a number of cellular and molecular defects. Recent data demonstrate a diabetes mellitus-associated defect in monocyte migration, when monocytes are stimulated with vascular endothelial growth factor VEGF-A. The ability of monocytes to migrate, however, is not generally abolished since other chemotactic stimuli such as the tripeptide fMLP are still capable of inducing migration of monocytes isolated from diabetic individuals. The molecular basis of monocyte dysfunction in diabetes mellitus has been postulated to be a signal transduction defect, because the VEGF receptor kinase Flt-1 in monocytes appeares to be fully intact. The characterization of monocyte dysfunction provides an important task for the understanding of diabetes mellitus-related disease processes.

Schlüsselwörter

Monozyten - Diabetes mellitus - Wundheilung - Wachstumsfaktoren - VEGF - MCP-1 - Kollateralen - Zellmigration

Keywords

Monocytes - diabetes mellitus - wound healing - growth factors - VEGF - MCP-1 - collateral circulation - cell migration

• Literatur

• 1 Devalaraja RM, Nanney LB, Qian Q. et al. Delayed wound healing in CXCR2 knockout mice. J Invest Dermatol 2000; 115: 234-44.
• 2 Hiratsuka S, Minowa O, Kuno J, Noda T, Shibuya M. Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc Natl Acad Sci USA 1998; 95: 9349-54.
• 3 Chapman HA, Vavrin Z, Hibbs JB. Macrophage fibrinolytic activity: identification of two pathways of plasmin formation by intact cells and of a plasminogen activator inhibitor. Cell 1982; 28: 653-62.
• 4 Humphries J, McGuinness CL, Smith A, Waltham M, Poston R, Burnand KG. Monocyte chemotactic protein-1 (MCP-1) accelerates the organization and resolution of venous thrombi. J Vasc Surg 1999; 30: 894-9.
• 5 Burnand KG, Gaffney PJ, McGuinness CL, Humphries J, Quarmby JW, Smith A. The role of the monocyte in the generation and dissolution of arterial and venous thrombi. Cardiovasc Surg 1998; 6: 119-25.
• 6 Colucci M, Stramaglia AM, Mascolo E, Napoleone E, Lorenzet R, Semeraro N. Monocytes, but not endothelial cells, downregulate the anticoagulant activity of activated protein C. Br J Haematol 2001; 112: 519-26.
• 7 Arras M, Ito WD, Scholz D, Winkler B, Schaper J, Schaper W. Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb. J Clin Invest 1998; 101: 40-50.
• 8 Waltenberger J, Lange J, Kranz A. Vascular endothelial growth factor-A-induced chemo-taxis of monocytes is attenuated in patients with diabetes mellitus:A potential predictor for the individual capacity to develop collaterals. Circulation 2000; 102: 185-90.
• 9 Tanaka E, Ase K, Okuda T, Okumura M, Nogimori K. Mechanism of acceleration of wound healing by basic fibroblast growth factor in genetically diabetic mice. Biol Pharm Bull 1996; 19: 1141-8.
• 10 Aso Y, Fujiwara Y, Tayama K, Takebayashi K, Inukai T, Takemura Y. Relationship between soluble thrombomodulin in plasma and coagulation or fibrinolysis in type 2 diabetes. Clin Chim Acta 2000; 301: 135-45.
• 11 Bazzan M, Gruden G, Stella S. et al. Microalbuminuria in IDDM is associated with increased expression of monocyte procoagulant activity. Diabetologia 1998; 41: 767-71.
• 12 Reverter JL, Reverter JC, Tassies D. et al. Thrombomodulin and induced tissue factor expression on monocytes as markers of diabetic microangiopathy: a prospective study on hemostasis and lipoproteins in insulin-dependent diabetes mellitus. Am J Hematol 1997; 56: 93-9.
• 13 Abaci A, Oguzhan A, Kahraman S. et al. Effect of diabetes mellitus on formation of cornary collateral vessels. Circulation 1999; 99: 2239-42.