Fibrinolysis And Diabetes

Decreased fibrinolytic system capacity is observed consistently as judged from analysis of blood from patients with diabetes mellitus, particularly those with type 2 diabetes. We have found that impaired fibrinolysis in subjects with type |

2 diabetes mellitus, not only under baseline conditions but also in response to £

physiological (transitory venous occlusion) challenge, is attributable to augmented concentrations in blood of circulating plasminogen activator inhibitor type-1 (PAI-1). Increased PAI-1 is seen also in blood from patients with other M

insulin-resistant states such as obesity, hypertension, and the polycystic ovarian syndrome.

Increased expression of PAI-1 is a marker of increased risk of acute myo-cardial infarction as judged from its presence in relatively young, long-term survivors of acute myocardial infarction compared with age-matched subjects who had not experienced any manifestations of overt coronary artery disease. Because the endogenous fibrinolytic system influences the evolution and persistence of thrombosis and the rapidity and extent of lysis of thrombi associated with vascular damage and its repair, overexpression of PAI-1 is likely to exacerbate both development and persistence of thrombi. Results of laboratory studies of transgenic mice deficient in PAI-1 compared with wild-type animals are consistent with this hypothesis. Twenty-four hours after arterial injury, persistence of thrombosis and the residual thrombus burden are greater in wild-type mice that are not deficient in PAI-1. Analogous observations are seen in analyses of human tissues after fatal pulmonary embolism. Increased expression of PAI-1 in association with pulmonary thromboembolism is evident. Thus, increased expression of PAI-1 typical of that seen in type 2 diabetes is likely to be a determinant of increased and persistent thrombosis.

Increased expression of PAI-1 in diabetes is likely to be multifactorial. A direct effect of insulin and of proinsulin on the expression of PAI-1 has been suggested by positive correlations between the concentrations of both with those of PAI-1 in vivo. Glucose, triglycerides, and circulating free fatty acids as well as those liberated by hydrolysis of triglycerides appear to contribute to the overexpression of PAI-1. Insulin and its precursors directly augment expression of PAI-1 in vitro. Insulin and triglycerides in combination exert a synergistic increase in accumulation of PAI-1 in conditioned media of diverse cells in culture when both are present in pathophysiological concentrations. Thus, the combination of hyperinsulinemia, hyperglycemia, and hypertriglyceridemia appears to be a major determinant of the increased PAI-1 in blood in vivo in subjects with diabetes. Accordingly, it is not surprising that experimentally induced hyperinsulinemia combined with hypertriglyceridemia and hyperglycemia increases the concentration of PAI-1 in blood in normal subjects. Both phenomena, hormonal (hyperin-sulinemia) and metabolic (hyperglycemia and hypertriglyceridemia) derangements typical of type 2 diabetes mellitus contribute together to elevations of the concentration of PAI-1 in blood. Other constituents known to be capable of increasing PAI-1 expression include glycated LDL and oxidized LDL, both of which are often increased in blood in patients with insulin resistance and type 2

diabetes. In addition to potentiating elevation of PAI-1 in blood, insulin increases |

expression of PAI-1 in vessel walls. We have shown that pathophysiological £

concentrations of insulin increase the expression of PAI-1 by human arteries in c vitro, an effect seen both in segments that appear to be grossly normal and in those that exhibit atherosclerotic changes. The increased PAI-1 expression is seen Ja in arterial segments from subjects with or without insulin-resistant states in vivo.

Augmented expression of PAI-1 is seen in response to insulin with vascular a

& u smooth muscle cells in culture and with cocultured endothelial cells and smooth muscle cells. The insulin-dependent increase in vessel wall PAI-1 may alter the evolution of atherosclerotic plaques favoring development of vulnerable as opposed to relatively stable plaques as discussed below. It may also contribute to elevation of PAI-1 in blood via release of PAI-1 from the vascular smooth muscle and endothelial cells themselves. Vulnerable, as opposed to relatively stable, atherosclerotic plaques are characterized by large lipid cores within thin relatively acellular fibrous caps. Increased expression of PAI-1 in the vessel wall may potentiate the development of such atherosclerotic plaques in the setting of any atherogenic stimulus. Stable plaques are characterized by a high ratio of vascular smooth muscle cells to lipid and thicker caps rendering them less prone to rupture. Falk and Davies demonstrated that lethal acute coronary syndromes are generally associated with vulnerable rather than stable plaques. We have hypothesized that migration of vascular smooth muscle cells into the neointima during the evolution of plaques is one factor contributing to their stability. Migration depends on cell surface expression and activity of plasminogen activators, particularly urokinase. Accordingly, in diabetes, the overexpression of PAI-1 by vascular smooth muscle cells may limit their migration and hence promote formation of vulnerable plaques that are relatively acellular and particularly prone to rupture.

Therapy designed to reduce insulin resistance and the often-associated hyperinsulinemia reduces concentrations of PAI-1 in blood. Thus, treatment of women with polycystic ovarian syndrome with metformin or with troglitazone decreases both blood insulin and PAI-1. Changes in the concentration of PAI-1 in blood correlate significantly with those of insulin. The concordance supports the view that hyperinsulinemia contributes to the increased PAI-1 expression in vivo. The changes in PAI-1 expression are likely to be secondary at least in part to the decrease in concentrations of insulin in blood rather than the direct effects of the pharmacological agents used to reduce them on PAI-1 expression per se. Thus, troglitazone decreases PAI-1 expression in vascular smooth muscle and endothelial cells in vitro, yet lowers PAI-1 in blood in vivo in diabetic and obese nondiabetic subjects with pretreatment hyperinsulinemia. Metformin, not itself an insulin sensitizer, decreases hepatic gluconeogenesis and hence concentrations of insulin in vivo. PAI-1 decreases as well.

The exposure of human hepatoma cells to gemfibrozil decreases basal and insulin-stimulated secretion of PAI-1. This inhibitory effect is seen in vitro. How- -o ever, gemfibrozil does not lower PAI-1 in blood in vivo despite reducing the |

concentration of triglycerides in blood by 50 to 60%. No changes in insulin sensi- £

tivity or plasma concentrations of insulin are seen after treatment of patients with gemfibrozil. Thus, unlike therapy with agents that reduce insulin resistance and lower concentrations of insulin, therapy with gemfibrozil that reduces triglycerides without affecting concentrations of insulin does not lower PAI-1 in vivo. J These observations support the likelihood that insulin per se is a critical determi-

& u nant of altered expression of PAI-1 in subjects with insulin resistance such as those with type 2 diabetes mellitus. As judged from results in studies in which human hepatoma cells were exposed to insulin and triglycerides in vitro, modest elevations in the concentration of triglycerides and free fatty acids in the setting of hyperinsulinemia may be sufficient to augment expression of PAI-1. Thus, although the concentration of triglycerides in blood in patients treated with gem-fibrozil was decreased by 50%, the prevailing concentration of triglycerides may have been sufficient to lead to persistent elevation of PAI-1 in blood in the setting of hyperinsulinemia. Recent results in studies with several statins, including ator-vastatin, fail to show reduction of PAI-1 in blood, despite diminution of concentrations of triglycerides consistent with this possibility.

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