Abstract
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 (∼300 g, n=12) and obese (∼450 g, n=12) Sprague–Dawley rats. Hyperglycemia (∼ 18mM) was induced for 3 h 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 (∼60 μU/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 μmol/kg/min), induced a ∼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.
Keywords
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Article info
Publication history
Accepted:
May 11,
2001
Received in revised form:
May 10,
2001
Received:
November 22,
2000
Identification
Copyright
© 2002 Elsevier Science Ireland Ltd. Published by Elsevier Inc. All rights reserved.
