Rosiglitazone inhibits the insulin‐mediated increase in PAI‐1 secretion in human abdominal subcutaneous adipocytes

Objective:  The aim of this study was to investigate the effect of insulin and an insulin‐sensitizing agent, rosiglitazone (RSG), on the production of plasminogen‐activator inhibitor‐1 (PAI‐1) in isolated subcutaneous abdominal adipocytes. Human tissue‐type plasminogen activator (t‐PA) was also measured to assess changes in overall thrombotic risk.Methods:  The mean depot‐specific expression of PAI‐1 and t‐PA mRNA (n = 42) in subcutaneous abdominal (n = 21), omental (n = 10) and thigh (n = 11) adipose tissue depots was examined. Furthermore, subcutaneous adipocytes were treated with insulin, RSG and insulin in combination with RSG (10−8 m) for 48 h. Conditioned media were collected and enzyme‐linked immunosorbent assays performed for PAI‐1 and t‐PA (n = 12) antigen. PAI‐1 and t‐PA mRNA levels were also assessed.Results:  PAI‐1 mRNA levels were significantly higher in subcutaneous and omental abdominal tissue than in thigh fat (p = 0.037 and p = 0.014). No change in t‐PA mRNA expression between the adipose tissue depots was observed. Insulin stimulated PAI‐1 protein secretion in a concentration‐dependent manner in adipocytes (control: 68.3 ± 1.2  ng/ml (s.e.m.); 10 nm insulin: 73.7 ± 3.8 ng/ml↑; 100 nm insulin: 86.8 ± 4.1 ng/ml↑**; 1000 nm insulin: 102.0 ± 4.8  ng/ml↑***; **p < 0.01, ***p < 0.001). In contrast, insulin + RSG (10−8 m) reduced PAI‐1 production relative to insulin alone (***p < 0.001), whilst RSG alone reduced PAI‐1 protein secretion in a concentration‐dependent manner (RSG at 10−10 m: 50.4 ± 2.87 ng/ml↓***; RSG at 10−5 m: 30.3 ± 2.0 ng/ml↓***; p < 0.001). No difference was observed between control and treatments for t‐PA secretion (range 7–11 ng/ml).Conclusions:  Insulin stimulated PAI‐1 secretion, whilst RSG reduced both PAI‐1 secretion alone and in combination with insulin. These data suggest that adipose tissue may contribute significantly to the elevated circulating PAI‐1 in obesity. Therefore, RSG's effects on PAI‐1 production in adipose tissue may contribute to the fall in circulating PAI‐1 levels observed in patients receiving RSG therapy.