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

  • Ilan Gabriely
    Affiliations
    Institute for Aging Research, Department of Medicine, Diabetes Research and Training Center, Albert Einstein College of Medicine, Belfer Bld.#701 1300, Morris Park Avenue, Bronx, NY 10461, USA
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  • Xiao Man Yang
    Affiliations
    Institute for Aging Research, Department of Medicine, Diabetes Research and Training Center, Albert Einstein College of Medicine, Belfer Bld.#701 1300, Morris Park Avenue, Bronx, NY 10461, USA
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  • Jane A Cases
    Affiliations
    Institute for Aging Research, Department of Medicine, Diabetes Research and Training Center, Albert Einstein College of Medicine, Belfer Bld.#701 1300, Morris Park Avenue, Bronx, NY 10461, USA
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  • Xiao Hui Ma
    Affiliations
    Institute for Aging Research, Department of Medicine, Diabetes Research and Training Center, Albert Einstein College of Medicine, Belfer Bld.#701 1300, Morris Park Avenue, Bronx, NY 10461, USA
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  • Luciano Rossetti
    Affiliations
    Institute for Aging Research, Department of Medicine, Diabetes Research and Training Center, Albert Einstein College of Medicine, Belfer Bld.#701 1300, Morris Park Avenue, Bronx, NY 10461, USA
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  • Nir Barzilai
    Correspondence
    Corresponding author. Tel.: +1-718-430-3344; fax: +1-718-430-8557
    Affiliations
    Institute for Aging Research, Department of Medicine, Diabetes Research and Training Center, Albert Einstein College of Medicine, Belfer Bld.#701 1300, Morris Park Avenue, Bronx, NY 10461, USA
    Search for articles by this author

      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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