Original article:
Effects of troglitazone on blood concentrations of plasminogen activator inhibitor 1 in patients with type 2 diabetes and in lean and obese normal subjects. Kruszynska YT, Yu JG, Olefsky JM, Sobel BE. Diabetes 2000; 49: 633–9.

Summary
Low plasma fibrinolytic activity in association with increased levels of plasma plasminogen activator inhibitor-1 (PAI-1) is linked to an increased risk of atherothrombosis and appears to be part of the insulin resistance (or plurimetabolic) syndrome. This study was aimed at testing whether troglitazone, an insulin sensitizer, would decrease PAI-1 levels and improve the low fibrinolytic activity and various other parameters associated with insulin resistance, in non-diabetic and diabetic obese patients.
Twenty non-diabetic control subjects (10 obese and 10 lean) and 14 obese subjects with Type 2 diabetes were given 600 mg/day troglitazone for 3 months. At baseline, the diabetic patients demonstrated higher plasma insulin, triglyceride, non-esterified fatty acid and PAI-1 levels and lower insulin sensitivity (during a 5-h euglycaemic-hyperinsulinaemic clamp) than the lean controls. The obese controls had intermediate values for these parameters.
During troglitazone treatment, body weight did not change significantly in any group. In the diabetic group, the treatment was followed by a marked fall in plasma glucose, insulin, triglyceride and PAI-1 and an increase in insulin sensitivity. Fructosamine levels were only slightly, but not significantly, ameliorated. Interestingly, three non-responders to troglitazone with respect to effects on insulin sensitivity, fasting glucose and insulin levels also had no reduction in circulating PAI-1. In the obese controls, the changes were less marked and did not reach statistical significance. There was no treatment effect among the lean controls.
Acute hyperinsulinaemia induced by the eu-glycaemic-hyperinsulinaemic clamp was accompanied by a reduction in PAI-1 levels in all subjects, but the fall did not differ from the spontaneous diurnal decrease in PAI-1 levels.
The authors concluded that troglitazone enhances fibrinolytic system activity in insulin-resistant Type 2 diabetic patients.

Comment
It has been abundantly demonstrated by epidemiological studies that high PAI-1 levels and consequent low fibrinolytic activity are a risk marker for coronary heart disease. Animals with a PAI-1 gene deletion or given anti-PAI-1 antibodies have a reduced tendency to thrombosis. However, there have been no intervention studies in humans attempting specifically to decrease PAI-1 levels and thus demonstrate that high PAI-1 levels are in themselves a risk factor for coronary heart disease. High PAI-1 levels are closely linked to the various abnormalities that characterize the plurimetabolic syndrome and in the vast majority of studies high PAI-1 levels do not appear to be an independent risk factor. The mechanisms linking increased production of PAI-1 to insulin resistance in obese subjects, whether diabetic or non-diabetic, have not been elucidated. It has been proposed that there is enhanced production by the adipose tissue under the influence of various inducers such as insulin, glucocorticoids and cytokines like tumour necrosis factor-alpha.
In Type 2 diabetic patients, PAI-1 levels are elevated; however, they do not appear to be linked to glycaemic control but are related to plasma insulin levels. This was also observed in the present study.
The administration of an insulin sensitizer, i.e. troglitazone 600 mg/day for 3 months, in Type 2 obese diabetic patients reduced insulin resistance, plasma insulin, triglyceride, blood glucose and PAI-1 levels. The decrease in PAI-1 levels induced by troglitazone was not directly linked to the decrease in insulin resistance but was closely linked to plasma insulin, non-esterified fatty acid and glucose levels. The three non-responders to troglitazone in terms of insulin sensitivity, fasting glucose and insulin levels also had no reduction in their PAI-1 levels. It should be noted that at a lower titration (200 mg/day for 8 weeks), Sironi et al. [1] did not observe any effect of troglitazone on PAI-1 levels in diabetic patients.
Among the obese controls in the present study, the effect of troglitazone was not significant, but insulin resistance and plasma levels of insulin, triglyceride, free fatty acid and PAI-1 were less elevated than among the diabetic patients.
These results may be compared with those of a study by Ehrmann et al. [2] which showed a similar effect of troglitazone treatment in obese women with polycystic ovary syndrome and insulin resistance. It has been shown that another insulin sensitizer, metformin, which has a different mechanism of action to that of troglitazone, also decreases raised PAI-1 levels and improves fibrinolytic activity in obese Type 2 diabetic patients [3] and in obese women with polycystic ovary syndrome [4].
Taken together all of these results demonstrate that in obese patients with severe insulin resistance, whether or not they are diabetic, treatment with an insulin sensitizer, troglitazone, or to some extent metformin, diminishes the otherwise markedly inhibited fibrinolytic activity. This effect appears to be due to an enhancement of insulin sensitivity and, probably more directly, to the preceding decrease in chronic hyperinsulinaemia.

References
1. Sironi AM, Vichi S, Gastaldelli A et al. Effects of troglitazone on insulin action and cardiovascular risk factors in patients with non-insulin-dependent diabetes. Pharmacol Ther 1997; 62: 194–202.
2. Ehrmann DA, Schneider DJ, Sobel BE et al. Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1997; 82: 2108–16.
3. Grant PJ. The effects of high- and medium-dose metformin therapy on cardiovascular risk factors in patients with type II diabetes. Diabetes Care 1996; 19: 64–6.
4. Velazquez EM, Mendoza SG, Wang P, Glueck CJ. Metformin therapy is associated with a decrease in plasma plasminogen activator inhibitor-1, lipoprotein (a), and immunoreactive insulin levels in patients with the polycystic ovary syndrome. Metabolism 1997; 46: 454–7.

Summary and Comment:
Philippe Vague, Marseille, France