Von Willebrand Factor, Dysfunction of the Vascular Endothelium, and the Development of Renal and Vascular Complications in Diabetes

  • Coen D. A. Stehouwer


Both in IDDM [1–4] and in NIDDM [5–11], the presence of microalbuminuria or clinical proteinuria identifies a group of patients at very high risk of developing severe vascular complications, ie, proliferative retinopathy, renal insufficiency, and cardiovascular disease. Several hypotheses have been advanced to explain why an increased urinary albumin excretion rate should be associated with an excess of extrarenal complications [1,12–14]. This chapter will discuss the role of von Willebrand factor (vWF), a haemostatic glycoprotein synthesised by endothelial cells and megakaryocytes, and of dysfunction of the vascular endothelium.


Endothelial Dysfunction Platelet Adhesion Urinary Albumin Excretion Endothelial Injury Insulin Resistance Syndrome 
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  1. 1.
    Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, Jensen T, Kofoed-Enevoldsen A. Albuminuria reflects widespread vascular damage. The Steno hypothesis. Diabetologia 1989; 32: 219–226.Google Scholar
  2. 2.
    Parving HH, Hommel E, Mathiesen ER, et al. Prevalence of microalbuminuria, arterial hypertension, retinopathy and neuropathy in patients with insulin-dependent diabetes. BMJ 1988; 296: 156–160.PubMedCrossRefGoogle Scholar
  3. 3.
    Krolewski AS, Kosinski EJ, Warram JH, et al. Magnitude and determinants of coronary artery disease in juvenile-onset insulin-dependent diabetes mellitus. Am J Cardiol 1987; 59: 750–755.PubMedCrossRefGoogle Scholar
  4. 4.
    Messent JWC, Elliott TG, Hill RD, Jarrett RJ, Keen H, Viberti GC. Prognostic significance of microalbuminuria in insulin-dependent diabetes mellitus: A twenty-three year follow-up study. Kidney Int 1992; 41: 836–839.PubMedCrossRefGoogle Scholar
  5. 5.
    Schmitz A, Vaeth M. Microalbuminuria. A major risk factor in non-insulin-dependent diabetes. A 10-year follow-up study of 503 patients. Diabetic Med 1988; 5: 126–134.PubMedCrossRefGoogle Scholar
  6. 6.
    Nelson RG, Pettitt DJ, Carraher MJ, Baird HR, Knowler WC. Effect of proteinuria on mortality in non-insulin-dependent diabetes mellitus. Diabetes 1988; 37: 1499–1504.PubMedCrossRefGoogle Scholar
  7. 7.
    Gall MA, Rossing P, Skott P, et al. Prevalence of micro-and macroalbuminuria, arterial hypertension, retinopathy and large vessel disease in European Type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1991; 34: 655–661.PubMedCrossRefGoogle Scholar
  8. 8.
    Damsgaard EM, Froland A, Jorgensen OD, Mogensen CE. Eight-nine year mortality in known non-insulin-dependent diabetics and controls. A prospective study. Kidney Int 1992; 41: 731–735.Google Scholar
  9. 9.
    Mattock MB, Morrish NJ, Viberti GC, Keen H, Fitzgerald AP, Jackson G. Prospective study of microalbuminuria as predictor of mortality in non-insulin-dependent diabetes mellitus. Diabetes 1992; 41: 736–741.PubMedCrossRefGoogle Scholar
  10. 10.
    Stehouwer CDA, Nauta JJP, Zeldenrust GC, Hackeng WHL, Donker AJM, den Ottolander GJH. Albuminuria, cardiovascular disease, and endothelial dysfunction in non-insulin-dependent diabetes mellitus. Lancet 1992; 340: 319–323.PubMedCrossRefGoogle Scholar
  11. 11.
    Gall M-A, Borch-Johnsen K, Hougaard P, Nielsen FS, Parving H-H. Albuminuria and poor glycemic control predict mortality in non-insulin-dependent diabetes mellitus. Diabetes 1995; 44: 1301–1309.CrossRefGoogle Scholar
  12. 12.
    Viberti GC, Messent J. Hypertension and diabetes: Critical combination for micro-and macrovascular disease. Diabetes Care 1991; 11: Suppl. 4: 4–7.Google Scholar
  13. 13.
    DeFronzo RA, Ferranini E. Insulin resistance: A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991; 14: 173–194.PubMedCrossRefGoogle Scholar
  14. 14.
    Stehouwer CDA, Donker AJM. Urinary albumin excretion and cardiovascular disease risk in diabetes mellitus: Is endothelial dysfunction the missing link? J Nephrol 1993; 6: 72–92.Google Scholar
  15. 15.
    Jensen T. Increased plasma level of von Willebrand factor in type 1 (insulin-dependent) diabetic patients with incipient nephropathy. BMJ 1989; 298: 27–28.PubMedCrossRefGoogle Scholar
  16. 16.
    Stehouwer CDA, Stroes ESG, Hackeng WHL, Mulder PGH, den Ottolander GJH. von Willebrand factor and development of diabetic nephropathy in insulin-dependent diabetes mellitus. Diabetes 1991; 40: 971–976 [erratum, Diabetes 1991; 40: 1746].PubMedCrossRefGoogle Scholar
  17. 17.
    Schmitz A, Ingerslev J. Haemostatic measures in Type 2 diabetic patients with microalbuminuria. Diabetic Med 1990; 7: 521–525.PubMedCrossRefGoogle Scholar
  18. 18.
    Collier A, Rumley A, Rumley AG, et al. Free radical activity and hemostatic factors in NIDDM patients with and without microalbuminuria. Diabetes 1992; 41: 909–913.PubMedCrossRefGoogle Scholar
  19. 19.
    Stehouwer CDA, Fischer HRA, van Kuijk AWR, Polak BCP, Donker AJM. Endothelial dysfunction precedes development of microalbuminuria in insulin-dependent diabetes mellitus. Diabetes 1995; 44: 561–564.PubMedCrossRefGoogle Scholar
  20. 20.
    Chen JW, Gall M-A, Deckert M, Jensen JS, Parving H-H. Increased serum concentration of von Willebrand factor in non-insulin-dependent diabetic patients with and without diabetic nephropathy. BMJ 1995; 311: 1405–1406.PubMedCrossRefGoogle Scholar
  21. 21.
    Stehouwer CDA, Zellenrath P, Polak BCP, et al. von Willebrand factor and early diabetic retinopathy: no evidence for a relationship in patients with Type 1 (insulin-dependent) diabetes mellitus and normal urinary albumin excretion. Diabetologia 1992; 35: 555–559.PubMedCrossRefGoogle Scholar
  22. 22.
    Meyer D, Girma JP. von Willebrand factor: Structure and function. Thromb Haemost 1993; 70: 111–118.Google Scholar
  23. 23.
    Wagner DD. The Weibel-Palade body: The storage granule for von Willebrand factor and P-selectin. Thromb Haemost 1993; 70: 105–110.PubMedGoogle Scholar
  24. 24.
    Gruden G, Cavallo-Perin P, Bazzab M, Stella S, Vuolo A, Pagano G. PAI-1 and factor VII activity are higher in insulin-dependent diabetes mellitus patients with microalbuminuria. Diabetes 1994; 43: 426–429.PubMedCrossRefGoogle Scholar
  25. 25.
    Collier A, Leach JP, McLellan A, Jardine A, Morton JJ, Small M. Plasma endothelinlike immunoreactivity levels in insulin-dependent diabetes mellitus patients with microalbuminuria. Diabetes Care 1992; 15: 1038–1040.PubMedCrossRefGoogle Scholar
  26. 26.
    Elliott TG, Cockcroft JR, Groop PH, Viberti GC, Ritter JM. Inhibition of nitric oxide synthesis in forearm vasculature of insulin-dependent diabetic patients: blunted vasoconstriction in patients with microalbuminuria. Clin Sci 1993; 83: 687–693.Google Scholar
  27. 27.
    Ross R. The pathogenesis of atherosclerosis: A perspective for the 1990s. Nature 1993; 362: 801–809.PubMedCrossRefGoogle Scholar
  28. 28.
    Diamond JR, Karnovsky MJ. Focal and segmental glomerulosclerosis: analogies to atherosclerosis. Kidney Int 1988; 33: 917–924.PubMedCrossRefGoogle Scholar
  29. 29.
    Vane JR, Ånggård EE, Botting RM. Mechanisms of disease: regulatory functions of the vascular endothelium. N Engl J Med 1990; 323: 27–36.PubMedCrossRefGoogle Scholar
  30. 30.
    Nawroth PP, Handley D, Stern DM. The multiple levels of endothelial cell-coagulation factor interactions. Clin Haematol 1986; 15: 293–321.PubMedGoogle Scholar
  31. 31.
    McVeigh GE, Brennan GM, Johnston GD, et al. Impaired endothelium-dependent and independent vasodilation in patients with Type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1992; 35: 771–776.PubMedGoogle Scholar
  32. 32.
    Juhan-Vague I, Vague P. »Hyperinsulinemia and its effects on coagulation and fibrinolysis in cardiovascular disease.« In Atherosclerotic Cardiovascular Disease, Hemostasis, and Endothelial Function. Francis RB, ed. New York: Marcel Dekker, 1992; pp 141–182.Google Scholar
  33. 33.
    Calver A, Collier J, Vallance P. Inhibition and stimulation of nitric oxide synthesis in the human forearm arterial bed of patients with insulin-dependent diabetes. J Clin Invest 1992; 90: 2548–2554.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Smits P, Kapma J, Jacobs MC, Lutterman J, Thien T. Endothelium-dependent vascular relaxation in patients with Type 1 diabetes. Diabetes 1993; 42: 148–153.PubMedCrossRefGoogle Scholar
  35. 35.
    Jensen T, Bjerre-Knudsen J, Feldt-Rasmussen B, Deckert T. Features of endothelial dysfunction in early diabetic nephropathy. Lancet 1989; i: 461–463.CrossRefGoogle Scholar
  36. 36.
    Smulders RA, Stehouwer CDA, Olthof CG, et al. Plasma endothelin levels and vascular effects of intravenous L-arginine infusion in subjects with uncomplicated insulin-dependent diabetes mellitus. Clin Sci 1994; 87: 37–43.PubMedGoogle Scholar
  37. 37.
    Kool MJF, Lambert J, Stehouwer CDA, Hoeks APG, Sruijker Boudier HAJ, van Bortel LMAB. Vessel wall properties of large arteries in uncomplicated insulin-dependent diabetes mellitus. Diabetes Care 1995; 18: 618–624.PubMedCrossRefGoogle Scholar
  38. 38.
    Lambert J, Aarsen M, Donker AJM, Stehouwer CDA. Endothelium-dependent and-independent vasodilation of large arteries in normoalbuminuric insulin-dependent diabetes mellitus. Arteriosclerosis Thromb Vasc Biol 1996; in press.Google Scholar
  39. 39.
    Poston L, Taylor PD. Endothelium-mediated vascular function in insulin-dependent diabetes mellitus. Clin Sci 1995; 88: 245–255.PubMedGoogle Scholar
  40. 40.
    Jansson JH, Nilsson TK, Johnson O. von Willebrand factor in plasma: A novel risk factor for recurrent myocardial infarction and death. Br Heart J 1991; 66: 351–355.PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Thompson SG, Kienast J, Pyke SD, Haverkate F, van de Loo JC. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med 1995; 332: 635–641.PubMedCrossRefGoogle Scholar
  42. 42.
    Hamsten A. Hemostatic function and coronary artery disease. N Engl J Med 1995; 332: 677–678.PubMedCrossRefGoogle Scholar
  43. 43.
    Jorgensen JOL, Pedersen SA, Ingerslev J, Moller J, Skakkebaek NE, Christiansen JS. Growth hormone (GH) therapy in GH-deficient patients, the plasma factor VIII-von Willebrand factor complex, and capillary fragility. A double-blind, placebo-controlled crossover study. Scand J Clin Lab Invest 1990; 50: 417–420.PubMedCrossRefGoogle Scholar
  44. 44.
    Ribes JA, Francis CW, Wagner DD. Fibrin induces release of von Willebrand factor from endothelial cells. J Clin Invest 1987; 79: 117–123.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Lorenzi M. Glucose toxicity in the vascular complications of diabetes: the cellular perspective. Diabetes Metab Rev 1992; 8: 85–103.PubMedCrossRefGoogle Scholar
  46. 46.
    Hattori Y, Kasai K, Nakamura T, Emoto T, Shimodi SI. Effect of glucose and insulin on immunoreactive endothelin-1 release from cultured porcine aortic endothelial cells. Metabolism 1991; 40: 165–169.PubMedCrossRefGoogle Scholar
  47. 47.
    Takahashi K, Ghatei MA, Lam HC, O’Halloran DJ, Bloom SR. Elevated plasma endothelin in patients with diabetes mellitus. Diabetologia 1990; 33: 306–310.PubMedCrossRefGoogle Scholar
  48. 48.
    Conlan MG, Folsom AR, Finch A, et al. Associations of factor VIII and von Willebrand factor with age, race, sex, and risk factors for atherosclerosis. The Atherosclerosis Risk in Communities (ARIC) Study. Thromb Haemost 1993; 70: 380–385.Google Scholar
  49. 49.
    Baron AD. The coupling of glucose metabolism and perfusion in human skeletal muscle. The potential role of endothelium-derived nitric oxide. Diabetes 1996; 45: Suppl. 1: S105–S109.PubMedCrossRefGoogle Scholar
  50. 50.
    Niskanen L, Uusitupa M, Sarlund H, et al. Microalbuminuria predicts the development of serum lipoprotein abnormalities favouring atherogenesis in newly diagnosed Type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1990; 33: 237–243.PubMedCrossRefGoogle Scholar
  51. 51.
    Haffner SM, Morales PA, Gruber MK, Hazuda HP, Stern MP. Cardiovascular risk factors in non-insulin-dependent diabetic subjects with microalbuminuria. Arteriosclerosis Thromb 1993; 13: 205–210.CrossRefGoogle Scholar
  52. 52.
    Castillo C, Bogardus C, Bergman R, et al. Interstitial insulin concentrations determine glucose uptake rates but not insulin resistance in lean and obese men. J Clin Invest 1994; 93: 10–16.PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Parving HH, Gall MA, Skott P, et al. Prevalence and causes of albuminuria in non-insulin-dependent diabetic patients. Kidney Int 1992; 41: 758–762.PubMedCrossRefGoogle Scholar
  54. 54.
    Brocco E, Stehouwer C, van Hinsbergh V, Fioretto P, Mauer M, Trevisan M, Sfriso A, Bruseghin M, Crepaldi G, Nosadini R. Endothelial function in relation to renal structure in microalbuminuric type 2 diabetic patients (Abstract). Diabetologia 1996; 39: Suppl. 1: A303.Google Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Coen D. A. Stehouwer
    • 1
  1. 1.Department of MedicineFree University HospitalAmsterdamThe Netherlands

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