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

Low plasma fibrinolytic activity in association with increased plasma plasm inogen activator inhibitor 1 (PAI-1) levels has been linked to an increased risk of atherosclerosis in obesity and type 2 diabetes. We tested the hypo thesis that troglitazone, which improves insulin sensitivity and lowers pla sma insulin levels in insulin-resistant obese subjects and patients with ty pe 2 diabetes, would also lower circulating PAI-1 antigen concentrations an d activity. We assessed insulin sensitivity (5-h, 80 mU . m(-2) . min(-1) h yperinsulinemic-euglycemic damp) and measured plasma PAI-1 antigen and acti vities and tissue plasminogen activator (tPA) in 14 patients with type 2 di abetes and 20 normal control subjects (10 lean, 10 obese) before and after 3 months of treatment with troglitazone (600 mg/day). At baseline, plasma P AI-1 antigen levels after an overnight fast were significantly higher in th e obese (33.5 +/- 4.7 mu g/l) and type 2 diabetic subjects (54.9 +/- 6.3 mu g/l) than in the lean control subjects (16.3 +/- 3.2 mu g/l; P < 0.01 and P < 0.001, respectively). Troglitazone decreased plasma PAI-1 antigen conce ntrations in the diabetic patients (36.8 +/- 5.0 mu g/l; P < 0.001 vs. base line), but the reduction in the obese subjects did not reach statistical si gnificance (baseline, 33.5 +/- 4.7; after troglitazone, 25.6 +/- 5.2 mu g/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 diabe tic patients after troglitazone correlated with the reductions in fasting p lasma 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 im provement in glucose disposal rates during the glucose clamps. Three nonres ponders 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 in sulin-resistant type 2 diabetic patients. This effect appears to be intimat ely linked to its potential to lower plasma insulin levels and improve glyc emic control through its peripheral tissue insulin-sensitizing effects.