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

Ilan Gabriely, Xiao Man Yang, Jane A. Cases, Xiao Hui Ma, Luciano Rossetti, Nir Barzilai

Research output: Contribution to journalArticle

54 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)115-122
Number of pages8
JournalAtherosclerosis
Volume160
Issue number1
DOIs
StatePublished - Jan 1 2002

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Keywords

  • Diabetes mellitus
  • Glucose
  • Hexosamine biosynthetic pathway
  • Insulin resistance
  • Obesity
  • Plasminogen activator inhibitor type-1

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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