De novo synthesis of diacylglycerol in endothelium may mediate the association between PAI-1 and the insulin resistance syndrome

Abstract 

Increased free fatty acid flux, giving rise to increased de novo synthesis of diacylglycerol (DAG) and activation of protein kinase C (PKC) in vascular endothelium, may be largely responsible for the endotheliopathy and increased vascular risk associated with insulin resistance syndrome. This mechanism may also mediate, in large part, the increase in plasminogen activator inhibitor-1 (PAI-1) observed in this syndrome. PKC activation promotes transcription of PAI-1 in endothelial cells and other tissues, apparently by boosting the activity of Sp1 transcription factors that bind to the PAI-1 promoter. Plasma PAI-1 correlates inversely with the ability of insulin infusion to suppress free fatty acid levels. Moreover, infusion of triglycerides with heparin – inducing a marked increase in free fatty acids – has been shown to induce a rapid increase in plasma PAI-1. Alternatively, hyperinsulinemia and hypertriglyceridemia have been suggested as mediators of PAI-1 excess in insulin resistance, inasmuch as insulin and VLDL can stimulate PAI-1 production in cell cultures. However, plasma PAI-1 tends to decline in response to hyperinsulinemic clamps and insulin treatment of type 2 diabetes, and gemfibrozil treatment of hypertriglyceridemia does not decrease PAI-1 – suggesting that elevations of insulin or triglycerides are not likely to mediate PAI-1 excess in vivo. Hypertrophied adipose mass can secrete PAI-1, and is likely to contribute to the plasma PAI-1 pool in obese insulin-resistant subjects, but current evidence suggests that this is not likely to be the primary source of the elevated plasma PAI-1 in insulin resistance syndrome. Plasma PAI-1 can be decreased in insulin resistant subjects by improving adipocyte insulin sensitivity (with weight loss and thiazolidinediones), by consuming a very-low-fat diet that minimizes postprandial free fatty acid flux, and by administering activators of AMP-activated kinase (e.g., metformin), which can be expected to lessen tissue DAG synthesis.