Metformin Decreases the High Plasminogen Activator Inhibition Capacity, Plasma Insulin and Triglyceride Levels in Non-Diabetic Obese Subjects

Vague, P; Juhan‐Vague, I.; Alessi, Marie‐Christine; Badier, C; Valadier, J

doi:10.1055/s-0038-1651126

Cited by 177 publications

(67 citation statements)

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“…50 Furthermore, the dissimilar effects on fibrinolysis of imidapril and candesartan might depend on their different effects on insulin sensitivity, whose relationship with PAI-1 level, observed in crosssectional studies, has been confirmed by interventional studies aimed at reducing insulin resistance, which have demonstrated a parallel decrease in plasma insulin and PAI-1 levels. 45,46,54 In the present study, imidapril significantly increased insulin sensitivity, as assessed by euglycemic-hyperinsulinemic clamp, whereas candesartan did not. These findings, which are in agreement with previous observations by ourselves and other authors, 35,[55][56][57] besides providing another possible explanation for the different effects of the two drugs on the fibrinolytic balance, also suggest that mechanisms other than Ang II inhibition, such as the increase in endogenous kinins because of ACE inhibition, might be responsible for the observed different influences of imidapril and candesartan on insulin sensitivity.…”

Section: Discussioncontrasting

confidence: 41%

Fibrinolysis and insulin sensitivity in imidapril and candesartan (FISIC study) recipients with hypertension

et al. 2010

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The aim of this study was to evaluate the effects of imidapril and candesartan on fibrinolysis and insulin sensitivity in normoweight hypertensive patients. After a 2-week wash-out period, 61 patients with mild-to-moderate hypertension were randomized to imidapril or candesartan for 12 weeks. Blood pressure (BP), plasma tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) antigen activities were evaluated at baseline and during treatment. The patients underwent a euglycemic-hyperinsulinemic clamp (insulin sensitivity was evaluated as glucose infusion rate during the last 30 min) and a desmopressin test (with desmopressin infusion in the brachial artery) to evaluate endothelial ability to release t-PA. Imidapril and candesartan induced similar systolic/diastolic BP reductions (À16/12.6 and À16.1/12.2 mm Hg, respectively, Po0.001 vs. baseline). Imidapril increased glucose infusion rate (+1.1 mg min À1 per kg, Po0.02), whereas candesartan did not change it. Both drugs decreased PAI-1 antigen activity after 4 weeks of treatment; subsequently, only the decreasing effect of imidapril was sustained throughout the 12 weeks, whereas candesartan increased PAI-1 activity at week 12 (Po0.05 vs. baseline, Po0.01 vs. imidapril). Activity of t-PA decreased with candesartan (from 0.48 ± 0.16 to 0.43 ± 0.14 IU ml À1 , Po0.05) but not with imidapril. Activity of t-PA in response to desmopressin was increased more by imidapril (+4.45 IU ml À1 ) than by candesartan (+2.73 IU ml À1 , Po0.01 vs. imidapril). These results indicate that in normoweight hypertensive patients, despite similar BP reduction, imidapril but not candesartan improved the fibrinolytic balance, suggesting that mechanisms other than Ang II inhibition, possibly including bradykinin-mediated effects on insulin sensitivity and endothelial function, may be responsible for these different effects.

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Section: Discussioncontrasting

confidence: 41%

Fibrinolysis and insulin sensitivity in imidapril and candesartan (FISIC study) recipients with hypertension

et al. 2010

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“…In addition, metformin improves fibrinolysis in cardiovascular disease ( 14). We have also shown in a previous study that, in obese non diabetic women, recovery of fibrinolytic activity after Metformin treatment was mainly due to decreased PAI-1 levels ( 15 ).…”

Section: Introductionmentioning

confidence: 69%

Plasminogen activator inhibitor-1 synthesis in the human hepatoma cell line Hep G2. Metformin inhibits the stimulating effect of insulin.

Anfosso

Chomiki²,

Alessi³

et al. 1993

J. Clin. Invest.

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High plasma plasminogen activator inhibitor-i (PAI-1) activity is associated with insulin resistance and is correlated with hyperinsulinemia. The cellular origin of plasma PAI-1 in insulin resistance is not known. The hepatoma cell line Hep G2 has been shown to synthesize PAI-1 in response to insulin. The aim of this study was to analyze the insulin-mediated response of PAI-1 and lipid synthesis in Hep G2 cells after producing an insulin-resistant state by decreasing insulin receptor numbers. The effect of metformin, a dimethyl-substituted biguanide, known to lower plasma insulin and PAI-I levels in vivo was concomitantly evaluated. Preincubation by an 18-h exposure of Hep G2 cells to 1i-7 M insulin aimed at reducing the number of insulin receptors, was followed by a subsequent 24-h stimulation with 10-9 M insulin. The decrease in insulin receptors was accompanied as expected, by a reduction in I14Clacetate incorporation, an index of lipid synthesis, whereas PAI-i secretion and PAI-i mRNA expression were enhanced. The addition of metformin did not modify the effect of insulin on insulin receptors or I14C acetate incorporation. In contrast, the drug (i0-4 M) inhibited insulin-mediated PAI-1 synthesis. The results indicate that PAI-1 synthesis in presence of insulin is markedly increased in down-regulated cells, and that metformin inhibits this effect by acting at the cellular level. These in vitro data are relevant with those found in vivo in insulin-resistant patients. Hep G2 cells may be a suitable model to study PAI-1 regulation in response to hyperinsulinemia. (J. Clin. Invest. 1993. 91:2185-2193 Key words: fibrinolysis* insulin * insulin resistance -metformin-plasminogen activator inhibitor 1

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“…A strong positive association between PAI-1 activity and fasting insulin has been demonstrated in normal subjects, obese women and type 2 diabetic patients [16,25]. This relation is independent of body mass [16] and probably reflects insulin stimulated hepatic PAI-1 production [26].…”

Section: Discussionmentioning

confidence: 91%

The Plasminogen Activator System in Young and Lean Women with Polycystic Ovary Syndrome

et al. 2004

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Abstract. The purpose of the study was to evaluate the plasminogen activator inhibitor-1 (PAI-1) levels and PAI-1 activity in young and lean women with PCOS and to compare with controls matched for age and weight. Thirty two women with PCOS and 25 weight and age-matched healthy controls participated in this study. Patients were evaluated clinically and by pelvic ultrasound and fasting blood samples were taken for hematological and biochemical tests. Fasting insulin, glucose, lipid profile, FSH, LH, PRL, testosterone, SHBG, 17-hydroxyprogesterone, androstenedione, PAI-1 antigen; PAI-1 activity, insulin sensitivity indices (HOMA and QUICKI) were measured. PAI-1 Ag and activity were significantly higher in PCOS women than healthy control group. PAI-1 levels were directly correlated with BMI, insulin levels and insulin sensitivity indices. PAI-1 activity was also correlated with insulin levels and insulin resistance. As a conclusion PAI-1 Ag levels and activity were increased in lean PCOS women and these were directly correlated with insulin resistance. The finding may contribute to evidence of increase risk of cardiovascular disease and anovulatory infertility in PCOS women. Plasminogen activator inhibitor-1 (PAI-1) is a 52 kD glycoprotein whose main role is in the inhibition of plasmin formation during plasminogen activation and fibrinolysis [9]. The relationship between PAI-1 levels and cardiovascular risk is not clear [10,11]. Moreover, some studies speculated that overproduction of PAI-1 leads to distortions in the ovarian plasminogenplasmin pathway and anovulation in women with PCOS [12,13]. PAI-1 levels and metabolic parameters that can affect the PAI-1 concentrations in women with PCOS are still under debate. Insulin resistance is found in women with PCOS independent of body mass index (BMI) [14]. In diabetic patients, insulin resistance correlated linearly with plasma concentrations of PAI-1 [15,16]. Elevated PAI-1 levels have been demonstrated in some studies of women with PCOS [13,17,18]. Therefore it has been suggested that insulin mediated elevation of PAI-1 may contribute to anovulatory infertility and increased risk of cardiovascular disease those were determined in women with PCOS. However most of these studies included obese or over-weight patient and control groups, so it was not clear from these studies whether the finding of raised PAI-1 levels in women with PCOS was independent of obesity or not. The present study was designed to evaluate PAI-1 levels and activity in young and lean women with PCOS and compare with

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Metformin Decreases the High Plasminogen Activator Inhibition Capacity, Plasma Insulin and Triglyceride Levels in Non-Diabetic Obese Subjects

Cited by 177 publications

References 24 publications

Fibrinolysis and insulin sensitivity in imidapril and candesartan (FISIC study) recipients with hypertension

Fibrinolysis and insulin sensitivity in imidapril and candesartan (FISIC study) recipients with hypertension

Plasminogen activator inhibitor-1 synthesis in the human hepatoma cell line Hep G2. Metformin inhibits the stimulating effect of insulin.

The Plasminogen Activator System in Young and Lean Women with Polycystic Ovary Syndrome

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