Hyperglycemia induces PAI-1 gene expression in adipose tissue by activation of the hexosamine biosynthetic pathway

We examined whether acute in vivo increases in either plasma glucose or insulin concentrations stimulate PAI-1 gene expression in fat tissue. We studied chronically catheterized unstressed and awake. lean ( similar to 300 g, n = 12) and obese ( similar to 450 g, n = 12) Sprague-Dawley rats. Hyperglycemia ( similar to 18mM) was induced for 3 It by glucose infusion during a pancreatic clamp (somatostatin inhibited endogenous insulin secretion). Compared with equivalent saline infusion. hyperglycemia induced a 6-7 fold increase in PAI-1 gene expression in both lean and obese rats (P < 0.001). When the rate of cellular glucose uptake was matched during a euglycemic hyperinsulinemic ( similar to 60 muU/ml) clamp, PAI-1 gene expression in both obese and lean rats was proportionately and significantly increased (P < 0.001). We further examined whether induction of the hexosamine biosynthetic pathway would mimic the effects of hyperglycemia and hyperinsulinemia on PAI-1 gene expression. Indeed. infusion of glucosamine (GlcN, 30 mumol/kg/min), induced a similar to 3-4 fold increase (P < 0.01) in PAI-1 gene expression in both lean and obese animals. While obese rats had a four times greater fat mass then the lean rats. PAI-1 gene expression remained significantly higher when expressed as per gram fat. Our results support the hypothesis that increased glucose uptake induces PAI-1 gene expression in adipose tissue, probably through the activation of the hexosamine biosynthetic pathway. These findings may account for some of the fibrinolytic alterations seen in obese type 2 diabetic humans. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.