Abstract
Biguanides and thiazolidinediones (TZDs), which are primarily used as anti-diabetic
drugs, are also associated with other beneficial effects on cardiovascular risk factors
such as reduced plasma plasminogen activator inhibitor-1 (PAI-1) concentration in
both diabetic and non-diabetic obese subjects. Since human adipose tissue is of importance
for the production of PAI-1, the aim of the present study was to investigate the possible
direct effects of these anti-diabetic agents on PAI-1 mRNA and secretion by human
adipose tissue. Adipose tissue was obtained from biopsies taken from the subcutaneous
abdominal depot. Adipose tissue fragments, isolated mature adipocytes, and preadipocytes
were incubated in vitro with metformin and various TZDs. Metformin (0.1 - 10 mM) dose-dependently decreased
PAI-1 production (and PAI-1 mRNA) under both basal (43 % inhibition at 10 mM, p <
0.05) and interleukin-1β (IL-1β)-stimulated conditions where the levels were inhibited
by 47.8 % at 1 mM metformin (p < 0.05) and by 100 % at 10 mM (p < 0.01). None of the
TZDs tested (PPAR-γ agonists: troglitazone, pioglitazone, or ciglitazone) had any
effects on PAI-1 production. Moreover, no effects on PAI-1 production were observed
using various PPAR-α agonists such as 5, 8, 11, 14-eicosatetraynoic acid (ETYA), Wy14643
and fenofibrate. Our findings indicate no direct effects of TZDs on PAI-1 secretion,
whereas metformin was able to directly inhibit PAI-1 production in human adipose tissue.
Key words
Plasminogen Activator Inhibitor-1 - Human Adipose Tissue - Metformin - Thiazolidinediones
- Gene Expression - Obesity
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Dr. B. Richelsen
Department of Endocrinology and Metabolism · Aarhus Amtssygehus, Aarhus University
Hospital
Tage Hansensgade 2 · 8000 Aarhus C. · Denmark ·
Phone: + 45 (89) 497 679
Fax: + 45 (89) 497 659
Email: br@aas.auh.dk
