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Epidemiological and clinical data suggest a relationship between hyperinsulinism and macroangiopathy in non insulin-dependent diabetes. On the other hand, a relationship between the plasma free insulin level and macroangiopathy has not been documented in insulin-dependent diabetes. Other abnormalities in addition to hyperinsulinism and glucose intolerance are frequently associated in the presence of insulin resistance and have been grouped by Reaven under the term syndrome X: raised VLDL triglycerides, decreased HDL, and raised blood pressure. Iatrogenic hyperinsulinism appears to be an arterial risk factor, but by what mechanism may it also constitute an independent risk factor? The following theoretical aspects of a possible atherogenic role of hyperinsulinism are currently being investigated: a) insulin stimulates the proliferation and migration of smooth muscle cells either directly or via a rise in IGF1; b) insulin induces lipogenesis in the intima-media, but it has not been demonstrated that this in situ lipogenesis is atherogenic; c) insulin raises the VLDL production, decreases HDL and modifies the clearance of LDL; d) insulin increases blood pressure by stimulating both the renal reabsorption of sodium and the sympathetic nervous system; insulin resistance may also be expressed at the level of the Na-K-ATPase of vascular smooth muscle cells by decreasing the vasodilator effect of the hormone; e) lastly, insulin induces a defect of fibrinolysis mediated by an increase in the level of plasminogen activator inhibitors (PAI1). In conclusion, the combination of hyperglycemia and hyperinsulinism is probably damaging to the artery. Therapeutic intervention studies are necessary to confirm and define the role of hyperinsulinism in macroangiopathy and to answer the unresolved questions: direct or indirect role? effect of endogenous and/or exogenous hyperinsulinism?
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PMID:[Theoretical aspects of the relationship between diabetic macroangiopathy and hyperinsulinism]. 143 1

Plasminogen activator inhibitor-1 (PAI-1) is an important physiological inhibitor of fibrinolysis. It circulates in blood both in free active form and in inactive form complexed with tissue type plasminogen activator (t-PA). Control mechanisms for its synthesis and release from hepatocytes and endothelial cells are important in the pathogenesis of thrombosis. Possible risk factors for myocardial infarction include high insulin and PAI-1 levels, which correlate with one another in healthy subjects, and fibrinogen, which together with PAI-1, is an acute-phase reactant. We therefore studied the interrelationships between PAI-1, plasma insulin, and acute-phase proteins in 67 patients with angina pectoris. Plasma insulin correlated strongly (r = 0.59, p less than 0.001) with PAI activity, free PAI-1 antigen (r = 0.60, p less than 0.001), and total PAI-1 antigen (r = 0.58, p less than 0.001). The acute-phase proteins, fibrinogen and C-reactive protein, correlated significantly with t-PA antigen, total PAI-1 antigen, and PAI-1/t-PA complexes but not with PAI activity or free PAI-1. The results suggest that insulin stimulates synthesis and release of free PAI-1 (probably via hepatocytes as previously shown with cell culture) and that endothelial cell synthesis and release of t-PA, together with PAI-1, reflects a nonspecific acute-phase response to chronic vascular disease. Hyperinsulinemia found in patients with angina pectoris could play a role in the development of myocardial infarction via the induction of high plasma PAI-1 activity.
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PMID:Plasma plasminogen activator inhibitor-1 in angina pectoris. Influence of plasma insulin and acute-phase response. 247 Mar 43

We have previously demonstrated that a short period of normoglycaemia obtained through an artificial pancreas in uncontrolled insulin-dependent diabetics improves parameters of the functional microangiopathy such as erythrocyte deformability and platelet aggregation. Because recently an immunoradiometric assay for tissue plasminogen activator (t-PA) was developed we measured t-PA levels in 18 uncontrolled insulin-dependent diabetics before and after 24 hr of normoglycaemia induced by insulin to look for a modification of endothelial cells function. After 24 hr of strict control, plasma free insulin levels rose significantly, total t-PA R-Ag, its active fibrin binding fraction and euglobulin fibrinolytic activity were significantly decreased. These results suggest a responsibility for insulin in the decrease in t-PA blood level and could explain at least partially the relation between hyperinsulinism, thrombosis and atherogenesis.
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PMID:Effect of 24 hours of normoglycaemia on tissue-type plasminogen activator plasma levels in insulin-dependent diabetes. 637 55

The aim of this study was to characterize the acute effect of euglycemic (glucose 5.2 +/- 0.6 mmol/l) hyperinsulinemia (mean 118 +/- 32 mU/l) on fibrinolytic variables, free fatty acids (FFA) and counterregulatory hormones. In addition, the effect of chronic treatment with metformin, an oral antidiabetic agent which enhances insulin action, and metoprolol CR, a relatively beta 1-selective adrenergic antagonist, was also evaluated. A randomized, double-blind, placebo-controlled, cross-over study including 18 non-obese men, aged 53 +/- 6 years, was performed. The investigations were performed after each treatment period of 6 weeks in both the postabsorptive state and during a euglycemic, hyperinsulinemic clamp. Compared to the postabsorptive state, plasminogen activator inhibitor (PAI-1) activity and antigen, tissue plasminogen activator (t-PA) antigen and FFA decreased (p < 0.001) after 120 min of euglycemic hyperinsulinemia. In addition, t-PA activity increased (p < 0.01) while blood levels of lipoprotein (a), catecholamines and cortisol remained unchanged. Growth hormone increased during the clamps and this was most pronounced after treatment with metoprolol CR. When the effect of treatment was compared, postabsorptive levels of C-peptide, FFA and t-PA antigen were lower after metformin than after the placebo period (p < 0.05). t-PA antigen also remained lower during the clamp after metformin treatment. No significant effects of metformin or metoprolol CR were seen on insulin-stimulated glucose uptake during the clamps or on postabsorptive levels of counterregulatory hormones, PAI-1 or Lp(a).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of metformin and metoprolol CR on hormones and fibrinolytic variables during a hyperinsulinemic, euglycemic clamp in man. 797 48

The present study was performed to investigate the acute effects of physiologically induced hyperinsulinemia on plasminogen activator inhibitor 1 (PAI-1), tissue plasminogen activator (t-PA) and triglycerides (TG). Forty-one male patients with chronic coronary heart disease (CHD) and moderate hypertriglyceridemia were studied for 3 h; 33 of them during an oral glucose tolerance test (OGTT), whereas eight patients served as controls, receiving water only. All subjects in the OGTT group were adequate responders to glucose administration, giving peak values of glucose (median 6.90 mmol l-1) and insulin (median 123 mU l-1) after 1 h. TG were unchanged throughout the test period in both groups. After 1 h PAI-1 activity and antigen decreased significantly more in the OGTT group than in the controls (median values: PAI-1 act 23-12 vs. 12-12 U ml-1; (p < 0.001). PAI-ag 45-35 vs. 18-16 ng ml-1 (p < 0.05)). t-PA increased more in the OGTT group (0.70-1.20 vs. 0.50-0.63 IU ml-1 (p = 0.08)). These differences tailored off after 3 h. We conclude that acute hyperinsulinemia, when generated during an OGTT, stimulates fibrinolysis with a consequent decrease in PAI-1 activity, but give no change in TG. The postulated regulating role of insulin for the steady state levels of PAI-1 could probably not be elucidated in the present dynamic model.
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PMID:Insulin and PAI-1 levels during oral glucose tolerance test in patients with coronary heart disease. 803 49

This report reviews the major haemostatic deviations associated with the evolution of ischaemic heart disease (IHD) and also such deviations, which might be of importance for the evolution of the acute ischaemic heart syndrome. It is demonstrated that deviation in the t-PA/PAI-1 system indicate endothelial cell dysfunction in patients with IHD. Different factors which have the capability to induce such an endothelial cell dysfunction are proposed, i.e. hyperinsulinemia, mediators of chronic disease phase response, and thrombin. Finally, the intimate interrelation between coagulation and fibrinolysis in patients with IHD is discussed. The experimental and clinical studies reviewed provide good evidence that the endothelial cell response of t-PA and PAI-1 is coupled and that there is an intimate interrelation between generation of thrombin and production/release of t-PA and PAI-1 in IHD patients.
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PMID:The fibrinolysis and coagulation systems in ischaemic heart disease. Risk markers and their relation to metabolic dysfunction of the arterial intima. 822 71

Patients with hyperinsulinemia, defined by increased concentrations of IRI in plasma, experience increased cardiovascular mortality. In type II diabetic patients, the increase in IRI may reflect, in part, not only insulin but also proinsulinemia as a result of impaired conversion of proinsulin to insulin by pancreatic beta-cells. High IRI is accompanied by attenuation of endogenous fibrinolytic activity and increased plasma PAI-1, the primary physiological inhibitor of t-PA. Concordant increases of plasma PAI-1 and plasma IRI appear to reflect direct effects of insulin and proinsulin on the synthesis and secretion of PAI-1 by endothelial and liver cells as judged from results of studies in vitro. Because attenuated fibrinolysis may predispose to thrombosis, the increased exposure of luminal surfaces of vessels to atherogenic, clot-associated mitogens and chemoattractants may activate macrophages and potentiate proliferation of vascular smooth muscle cells. Accordingly, increased concentrations of plasma IRI may contribute to macrovascular disease in diabetic patients by impairing endogenous fibrinolysis.
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PMID:Attenuated fibrinolysis and accelerated atherogenesis in type II diabetic patients. 842 Aug 6

The fibrinolytic system is thought to be impaired in older hypertensive adults, thus contributing to the elevated risk of atherothrombosis, stroke, and acute myocardial infarction in this population. However, studies that have examined the fibrinolytic system in hypertensive individuals have failed to control for the confounding effects of other metabolic risk factors, making it difficult for one to determine the independent effect of hypertension on the fibrinolytic system. The purpose of the present study was to test the hypothesis that the fibrinolytic system is not impaired in older sedentary hypertensive men when the confounding effects of cardiovascular disease, diabetes, and dyslipidemia are controlled. Plasma concentrations of tissue-type plasminogen activator antigen and activity as well as plasminogen activator inhibitor-1 antigen and activity were measured under resting conditions in 12 hypertensive (69.4 +/- 1.4 years) and 11 normotensive 65.2 +/- 1.3 years) older men. The hypertensive and normotensive subjects had similar anthropometric and metabolic characteristics. There were no significant differences between the hypertensive and normotensive men in tissue-type plasminogen antigen (7.3 +/- 0.5 versus 6.1 +/- 0.6 ng/mL) and activity (1.8 +/- 0.3 versus 1.7 +/- 0.2 IU/mL) or plasminogen activator inhibitor-1 antigen (14.1 +/- 2.3 versus 10.8 +/- 2.2 ng/mL) and activity (17.4 +/- 1.2 versus 17.5 +/- 1.8 arbitrary units [AU]/mL) levels. In addition, the molar concentration ratio of active tissue type plasminogen activator to active plasminogen activator inhibitor-1 did not differ between the hypertensive (1:9.7 +/- 2.3) mmol/L) and normotensive (1:10.5 +/- 2.2 mmol/L) subjects, indicative of no impairment in fibrinolytic potential in either group. These results support the hypothesis that hypertension does not directly result in impaired fibrinolytic function in older adults. Furthermore, our findings suggest that abnormalities in fibrinolytic function in older hypertensive men are likely due to the primary effects of other metabolic disorders that usually accompany hypertension, such as hyperinsulinemia and dyslipidemia.
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PMID:The fibrinolytic system is not impaired in older men with hypertension. 862 Nov 96

In Denmark, clinicians conducted clinical and metabolic evaluations on 17 healthy women, 21-26 years old, within the last 10 days of their menstrual cycle preceding intake with a triphasic oral contraceptive (OC) (ethinyl estradiol + norgestimate) and during the last 7 days of the sixth period of OC treatment. They aimed to examine the effect of proinsulin and insulin on fasting secretion of plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator (t-PA). OCs have a well-defined effect on plasma levels of PAI-1 and t-PA. The clinical researchers also studied the antigen concentrations of PAI-1 and t-PA during slow and fast changes in proinsulin and insulin levels induced by oral and intravenous glucose tolerance tests. They did not find consistent correlations between fasting values of proinsulin, insulin, PAI-1, and t-PA either before or during OC treatment. During the glucose tolerance test induced hyperproinsulinemia and hyperinsulinemia and before OC treatment, PAI-1 and t-PA antigen levels fell (p 0.05). After 6 months of OC treatment, t-PA levels fell only during the oral glucose tolerance test (p 0.05) even though proinsulin and insulin responded similarly to the glucose loads. These findings suggest that neither proinsulin nor insulin regulate plasma levels of PAI-1 and t-PA in young healthy women regardless of OC use status.
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PMID:No influence of proinsulin and insulin on plasma levels of plasminogen activator inhibitor type 1 and tissue plasminogen activator in young women before and during intake of contraceptive steroids. 869 17

Troglitazone, a novel oral insulin sensitizer, normalizes increased plasma activity of plasminogen activator inhibitor type 1 (PAI-1) in hyperinsulinemic patients such as women with polycystic ovary syndrome and patients with type 2 diabetes mellitus. However, underlying mechanisms have not yet been fully elucidated. Human hepatic and vascular cells, the main sources of circulating PAI-1, were studied in cell culture. In human hepatic cells, PAI-1 accumulated in conditioned medium by 23% within 24 h after exposure to 3 microg/mL troglitazone (P = 0.001). The accumulation depended on the concentration of troglitazone, but not that of insulin (known to stimulate PAI-1 synthesis). By contrast, in human aortic smooth muscle cells, 3 microg/mL troglitazone decreased basal PAI-1 expression by 23% (P = 0.037) and decreased transforming growth factor-beta-induced expression by 34% (P = 0.026). Concomitant insulin had no effect. Tissue-type plasminogen activator was decreased by 38% (P = 0.002). In human endothelial cells, PAI-1 was diminished by 32% (P < 0.001), whereas tissue-type plasminogen activator was unaffected. The results suggest that the reduction in plasma activity of PAI-1 induced by troglitazone in patients may reflect both directly mediated diminution of its elaboration from vessel walls and indirectly mediated reduction of its hepatic synthesis secondary to attenuation of hyperinsulinemia (known to increase the hepatic synthesis of PAI-1).
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PMID:Differential regulation by troglitazone of plasminogen activator inhibitor type 1 in human hepatic and vascular cells. 1077 Jan 98


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