The Effect of Insulin Treatment on the Balance between Tissue Plasminogen Activator and Plasminogen Activator Inhibitor-1 in Type 2 Diabetic Patients

Summary

Beside hypercoagulation and hyperactivated platelets disturbances of the fibrinolytic system towards hypofibrinolysis have been reported to be associated with both glycemic and lipidemic derangement in diabetic patients. In the present prospective follow-up study the effect of 16 weeks insulin treatment and glycemic regulation on plasma levels of tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1), the main regulators of fibrinolysis, was investigated in 19 type-2 diabetic patients with secondary failure to sulphonylureas. A similar glycemic regulation was obtained in a control group of 10 type 2 diabetic patients with sufficient metabolic response to strict dietary treatment and continuation of sulphonylurea treatment. Compared to 27 healthy subjects levels of tPA and PAI-1 were not significantly increased in type 2 diabetic patients before metabolic intervention. Although a hypofibrinolytic state due to an increase of PAI-1 levels was previously reported in obese hyperinsulinemic patients, no effect of insulin treatment on both tPA- and PAI-1 levels was observed in the present study including patients with only slightly increased body mass index (median 26.0 kg/m²). By correlation analysis PAI-1 levels were significantly related to serum cholesterol (R = 0.52) and glycemic control (glucose R = 0.41) in the whole group of diabetic patients at entry and in both subgroups after 16 weeks of treatment (insulin group: cholesterol R = 0.46, HbA1c R = 0.51; sulphonylurea group: cholesterol R = 0.59, HbA1c R = 0.58). In healthy subjects tPA and PAI-1 was correlated to serum insulin (R = 0.54, R = 0.56) and triglycerides (R = 0.46, R = 0.40). In conclusion, our results indicate that insulin treatment associated with metabolic improvement has no adverse effect to fibrinolysis in type 2 diabetic patients.

• References

• 1 Jones RL, Peterson CM. The fluid phase of coagulation and the accelerated atherosclerosis in diabetes mellitus. Diabetes 1981; Suppl 1: 33-38
• 2 Vukovich T, Schernthaner G. Decreased protein C levels in patients with insulin-dependent type 1 diabetes mellitus. Diabetes 1986; 35: 617-619
• 3 Garzia Frade LJ, Calle H, Alava I, Navarro JL, Creighton LJ, Gaffney PJ. Diabetes mellitus as a hypercoagulable state: its relationship with fibrin fragments and vascular damage. Thromb Res 1987; 47: 533-540
• 4 Schernthaner G, Vukovich T, Knöbl P, Hay U, Müller M. The effect of near-normoglycaemic control on plasma levels of coagulation factor VII and the anticoagulant proteins C and S in insulin-dependent diabetic patients. Br J Haematol 1989; 73: 356-359
• 5 Vukovich T, Schernthaner G, Knöbl P, Hay U. The effect of nearnormoglycemic control on plasma factor VIII/von Willebrand factor and fibrin degradation products in insulin-dependent diabetic patients. J Clin Endocrinol Metab 1989; 69: 84-89
• 6 Juhan-Vague I, Vague P, Poisson C, Aillaud F, Mendez C, Collen D. Effect of 24 hours of normoglycaemia on tissue-type plasminogen activator plasma levels in insulin-dependent diabetes. Thromb Haemostas 1984; 51: 97-98
• 7 Auwerx J, Bouillon R, Collen D, Geboers J. Tissue-type plasminogen activator antigen and plasminogen activator inhibitor in diabetes mellitus. Arteriosclerosis 1988; 8: 68-72
• 8 Juhan-Vague I, Roul C, Alessi MC, Heim M, Vague P. Increased plasminogen activator inhibitor activity in non insulin dependent diabetic patients – Relationship with plasma insulin. Thromb Haemostas 1989; 61: 370-373
• 9 Garcia Frade LJ, de la Calle H, Torrado MC, Lara JI, Cuellar L, Garcia Avello A. Hypofibrinolysis associated with vasculopathy in non insulin dependent diabetes mellitus. Thromb Res 1990; 59: 51-59
• 10 Juhan-Vague I, Alessi MC, Vague P. Increased plasma plasminogen activator inhibitor 1 levels. A possible link between insulin resistance and atherothrombosis. Diabetologia 1991; 34: 457-462
• 11 Alessi MC, Juhan-Vague I, Kooistra T, Declerck PJ, Collen D. Insulin stimulates the synthesis of plasminogen activator inhibitor 1 by the human hepatocellular cell line Hep 62. Thromb Haemostas 1988; 60: 491-494
• 12 Rydzewski A, Kawamura H, Watanabe I, Takada Y, Takada A. Plasminogen activators and plasminogen activator inhibitor (PAI-1) in type II diabetes mellitus. Fibrinolysis 1990; 4: 183-188
• 13 Landin K, Tengborn L, Chmielewska J, von Schenck H, Smith U. The acute effect of insulin on tissue plasminogen activator and plasminogen activator inhibitor in man. Thromb Haemostas 1991; 65: 130-133
• 14 Grant MB, Fitzgerald C, Guay C, Lottenberg R. Fibrinolytic capacity following stimulation with desmopressin acetate in patients with diabetes mellitus. Metabolism 1989; 38: 901-907
• 15 Aimer LD, Nilsson IM. Fibrinolytic activity and treatment of diabetes. Lancet 1974; 1: 1342
• 16 Reaven GM. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595-1607
• 17 Vague P, Juhan-Vague I, Chabert V, Alessi MC, Atlan C. Fat distribution and plasminogen activator inhibitor activity in non diabetic obese women. Metabolism 1989; 38: 913-915
• 18 Reaven GM, Hoffman BB. A role for insulin in the aetiology and course of hypertension?. Lancet 1987; 2: 435-437
• 19 Kudlacek S, Schernthaner G. Longitudinal evaluation of the effect of insulin treatment in type 2 diabetic patients with secondary failure to treatment with sulphonylureas. Horm Metab Res 1992 in press