Effects of troglitazone on blood concentrations of plasminogen activator inhibitor 1 in patients with type 2 diabetes and in lean and obese normal subjects.

Abstract

Low plasma fibrinolytic activity in association with increased plasma plasminogen activator inhibitor 1 ( PAI-1) levels has been linked to an increased risk of atherosclerosis in obesity and type 2 diabetes. We tested the hypothesis that troglitazone, which improves insulin sensitivity and lowers plasma insulin levels in insulin-resistant obese subjects and patients with t y p e 2 diabetes, would also lower circulating PA I -1 antigen concentrations and activity. We assessed insulin sensitivity (5-h, 80 mU · m -2 · min -1 h y p e r i n s ulinemic-euglycemic clamp) and measured plasma PA I -1 antigen and activities and tissue plasminogen activator ( t PA) in 14 patients with type 2 diabetes and 20 normal control subjects (10 lean, 10 obese) before and after 3 months of treatment with troglitazone (600 m g / d a y ) . At baseline, plasma PAI-1 antigen levels after an overnight fast were significantly higher in the obese (33.5 ± 4.7 µg/l) and type 2 diabetic subjects (54.9 ± 6.3 µg/l) than in the lean control subjects (16.3 ± 3.2 µg/l; P < 0.01 and P < 0.001, respectively). Troglitazone decreased plasma PAI-1 antigen concentrations in the diabetic patients (36.8 ± 5.0 µg/l; P < 0.001 vs. baseline), but the reduction in the obese subjects did not reach statistical significance (baseline, 33.5 ± 4.7; after troglitazone, 2 5 . 6 ± 5.2 µg/l). Changes in plasma PAI-1 activity paralleled those of PAI-1 antigen. The extent of the reduction in plasma PAI-1 antigen concentrations in the diabetic patients after troglitazone correlated with the reductions in fasting plasma insulin (r = 0.60, P < 0.05), nonesterified fatty acid (r = 0.63, P < 0.02), and glucose concentrations (r = 0.64, P < 0.02) but not with the improvement in glucose disposal rates during the glucose clamps. Three nonresponders to troglitazone with respect to effects on insulin sensitivity and fasting glucose and insulin levels also had no reduction in circulating PAI-1. In conclusion, troglitazone enhances fibrinolytic system activity in insulin-resistant type 2 diabetic patients. This effect appears to be intimately linked to its potential to lower plasma insulin levels and improve glycemic control through its peripheral tissue insulin-sensitizing effects. Diabetes 4 9 :6 3 3-639, 2000 A ccelerated atherosclerosis is an important cause of morbidity and mortality in insulin-resistant obese subjects and patients with type 2 diabetes (1,2). Low fibrinolytic activity in blood is a wellrecognized major risk factor not only for thrombosis, but also for atherosclerosis (3,4). Deficient fibrinolysis is due primarily to increased concentrations in blood of plasminogen activator inhibitor 1 (PAI-1), which rapidly binds to and inactivates tissue plasminogen activator (tPA) (5). PAI-1 concentrations and activity are increased in obese subjects (6-8) and patients with type 2 diabetes (8-13). The increases may contribute to an excess risk of cardiovascular disease (4,12-14).PAI-1 levels correlate with a number of variables that cosegregate in subjects with the insulin r...

Influence of diabetes on endothelial cell response during sepsis

“…Clinical studies have found increased levels of E-selectin, ICAM-1 and VCAM-1 in patients with diabetes, and higher levels were associated with a subsequent risk for cardiovascular events [16,27,28]. Similarly, high concentrations of PAI-1 and subsequent downregulation of fibrinolysis have been implicated in the increasing morbidity, mortality and risks for thrombotic disease in diabetic patients [18,19]. VEGF and sFLT-1 may also play a role in the pathophysiology of atherosclerosis by initiating and propagating angiogenesis, and thereby providing a passage for inflammatory cells to the site of injury [29].…”

“…Clinical studies have demonstrated increased levels of the adhesion markers E-selectin, ICAM-1 and VCAM-1 in patients with diabetes [15][16][17]. Increased levels of PAI-1 have also been found in patients with diabetes, increasing their risk for thrombotic disease [18,19]. Interestingly, these elevated levels of circulating markers are thought to play a role in the accelerated development of atherosclerotic plaques in patients with diabetes.…”

Rosiglitazone reduces urinary albumin excretion in type II diabetes

“…The activation of PPARg by thiazolidinediones has been shown to have a range of beneficial vascular effects, including vasorelaxation via blockade of K + channels 7 and reduction of voltage-gated Ca 2+ current, 8 inhibition of the proliferation and migration of vascular smooth muscle cells, 9,10 inhibition of angiogenesis, 11 and improvement in markers of inflammation and fibrinolysis. [12][13][14] These observations indicate a potential for thiazolidinediones to modify risk of vascular complications in diabetes.…”

Associations of Thrombotic-Hemostatic Factors with Cardiovascular Disease~!2009-10-29~!2009-12-22~!2010-04-08~!

“…Lipid lowering agents, pharmacologic inhibition of the RAS [161], improvement of insulin sensitivity and glucose metabolism [187,188] can reduce raised PAI-1 and enhance impaired fibrinolysis. Treatment with ACEI is associated with reductions in PAI-1 levels and a lower incidence of ischemic CV events [189].…”