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 (approximately 300 g, n=12) and obese (approximately 450 g, n=12) Sprague-Dawley rats. Hyperglycemia (approximately 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 (approximately 60 microU/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 micromol/kg/min), induced a approximately 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.
Gabriely
Ilan
I
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.
Yang
Xiao Man
XM
Cases
Jane A
JA
Ma
Xiao Hui
XH
Rossetti
Luciano
L
Barzilai
Nir
N
D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation / Q000187:drug effects*; D001786:Blood Glucose / Q000032:analysis / Q000187:drug effects; D001823:Body Composition / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D005944:Glucosamine / Q000493:pharmacokinetics; D006595:Hexosamines / Q000096:biosynthesis*; D006943:Hyperglycemia / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride / Q000493:pharmacokinetics
D001786:Blood Glucose; D006595:Hexosamines; D007328:Insulin; D017395:Plasminogen Activator Inhibitor 1; D012965:Sodium Chloride; D005944:Glucosamine