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Horm Metab Res 2003; 35(1): 18-23
DOI: 10.1055/s-2003-38386
Original Basic
© Georg Thieme Verlag Stuttgart · New York

Metformin, but not Thiazolidinediones, Inhibits Plasminogen Activator Inhibitor-1 Production in Human Adipose Tissue in Vitro

G.  He1 , S.  B.  Pedersen1 , J.  M.  Bruun1 , A.  S.  Lihn1 , B.  Richelsen1
  • 1Department of Endocrinology and Metabolism C, Aarhus Amtssygehus, Aarhus University Hospital, Aarhus, Denmark
Further Information

Publication History

Received 14 February 2002

Accepted after revision 8 July 2002

Publication Date:
01 April 2003 (online)

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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

References

  • 1 Juhan-Vague I, Alessi M C. PAI-1, obesity, insulin resistance and risk of cardiovascular events.  Thromb Haemost. 1997;  78 656-660
    PubMedSearch in Google Scholar
  • 2 Bastard J P, Pieroni L, Hainque B. Relationship between plasma plasminogen activator inhibitor 1 and insulin resistance.  Diabetes Metab Res Rev. 2000;  16 192-201
    CrossrefPubMedSearch in Google Scholar
  • 3 Saltiel A R, Olefsky J M. Thiazolidinediones in the treatment of insulin resistance and type II diabetes.  Diabetes. 1996;  45 1661-1669
    CrossrefPubMedSearch in Google Scholar
  • 4 Nolan J J, Ludvik B, Beerdsen P, Joyce M, Olefsky J. Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone.  N Engl J Med. 1994;  331 1188-1193
    CrossrefPubMedSearch in Google Scholar
  • 5 Kruszynska Y T, Yu J G, Olefsky J M, Sobel B E. Effects of troglitazone on blood concentrations of plasminogen activator inhibitor 1 in patients with type 2 diabetes and in lean and obese normal subjects.  Diabetes. 2000;  49 633-639
    PubMedSearch in Google Scholar
  • 6 Bailey C J. Biguanides and NIDDM.  Diabetes Care. 1992;  15 755-772
    CrossrefPubMedSearch in Google Scholar
  • 7 Bailey C J, Turner R C. Metformin.  N Engl J Med. 1996;  334 574-579
    CrossrefPubMedSearch in Google Scholar
  • 8 Matthaei S, Hamann A, Klein H H, Benecke H, Kreymann G, Flier J S, Greten H. Association of Metformin's effect to increase insulin-stimulated glucose transport with potentiation of insulin-induced translocation of glucose transporters from intracellular pool to plasma membrane in rat adipocytes.  Diabetes. 1991;  40 850-857
    PubMedSearch in Google Scholar
  • 9 Abbasi F, Carantoni M, Chen Y D, Reaven G M. Further evidence for a central role of adipose tissue in the antihyperglycemic effect of metformin.  Diabetes Care. 1998;  21 1301-1305
    PubMedSearch in Google Scholar
  • 10 UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).  Lancet. 1998;  352 854-865
    CrossrefPubMedSearch in Google Scholar
  • 11 Grant P J. The effects of high- and medium-dose metformin therapy on cardiovascular risk factors in patients with type II diabetes.  Diabetes Care. 1996;  19 64-66
    PubMedSearch in Google Scholar
  • 12 Alessi M C, Peiretti F, Morange P, Henry M, Nalbone G, Juhan-Vague I. Production of plasminogen activator inhibitor-1 by human adipose tissue: possible link between visceral fat accumulation and vascular disease.  Diabetes. 1997;  46 860-867
    CrossrefPubMedSearch in Google Scholar
  • 13 Mavri A, Stegnar M, Krebs M, Sentocnik J T, Geiger M, Binder B R. Impact of adipose tissue on plasma plasminogen activator inhibitor-1 in dieting obese women.  Arterioscler Thromb Vasc Biol. 1999;  19 1582-1587
    CrossrefPubMedSearch in Google Scholar
  • 14 Gottschling-Zeller H, Rohrig K, Hauner H. Troglitazone reduces plasminogen activator inhibitor-1 expression and secretion in cultured human adipocytes.  Diabetologia. 2000;  43 377-383
    CrossrefPubMedSearch in Google Scholar
  • 15 Anfosso F, Chomiki N, Alessi M C, Vague P, Juhan-Vague I. Plasminogen activator inhibitor-1 synthesis in the human hepatoma cell line Hep G2. Metformin inhibits the stimulating effect of insulin.  J Clin Invest. 1993;  91 2185-2193
    CrossrefPubMedSearch in Google Scholar
  • 16 Kristensen K, Pedersen S B, Richelsen B. Regulation of leptin by steroid hormones in rat adipose tissue.  Biochem Biophys Res Commun . 1999;  259 624-630
    CrossrefPubMedSearch in Google Scholar
  • 17 Hauner H, Entenmann G, Wabitsch M, Gaillard D, Ailhaud G, Negrel R, Pfeiffer E F. Promoting effect of glucocorticoids on the differentiation of human adipocyte precursor cells cultured in a chemically defined medium.  J Clin Invest. 1989;  84 1663-1670
    PubMedSearch in Google Scholar
  • 18 Pedersen S B, Børglum J, Jørgensen J, Richelsen B. Growth hormone treatment of obese premenopausal women: effects on isolated adipocyte metabolism.  Endocrinology and Metabolism. 1995;  2 251-258
    PubMedSearch in Google Scholar
  • 19 Bruun J M, Pedersen S B, Richelsen B. Interleukin-8 production in human adipose tissue. Inhibitory effects of anti-diabetic compounds, the thiazolidinedione ciglitazone, and the biguanide metformin.  Horm Metab Res . 2000;  32 537-541
    Thieme ConnectPubMedSearch in Google Scholar
  • 20 Pedersen S B, Kristensen K, Fisker S, Jorgensen J O, Christiansen J S, Richelsen B. Regulation of uncoupling protein-2 and -3 by growth hormone in skeletal muscle and adipose tissue in growth hormone-deficient adults.  J Clin Endocrinol Metab. 1999;  84 4073-4078
    CrossrefPubMedSearch in Google Scholar
  • 21 He G, Pedersen S B, Bruun J M, Richelsen B. Regulation of plasminogen activator inhibitor-1 in human adipose tissue: interaction between cytokines, cortisol, and estrogen.  Horm Metab Res . 2000;  32 515-520
    Thieme ConnectPubMedSearch in Google Scholar
  • 22 Eriksson P, Reynisdottir S, Lonnqvist F, Stemme V, Hamsten A, Arner P. Adipose tissue secretion of plasminogen activator inhibitor-1 in non- obese and obese individuals.  Diabetologia. 1998;  41 65-71
    CrossrefPubMedSearch in Google Scholar
  • 23 Kato K, Satoh H, Endo Y, Yamada D, Midorikawa S, Sato W, Mizuno K, Fujita T, Tsukamoto K, Watanabe T. Thiazolidinediones down-regulate plasminogen activator inhibitor type 1 expression in human vascular endothelial cells: A possible role for PPARgamma in endothelial function.  Biochem Biophys Res Commun . 1999;  258 431-435
    CrossrefPubMedSearch in Google Scholar
  • 24 Nilsson L, Takemura T, Eriksson P, Hamsten A. Effects of fibrate compounds on expression of plasminogen activator inhibitor-1 by cultured endothelial cells.  Arterioscler Thromb Vasc Biol. 1999;  19 1577-1581
    PubMedSearch in Google Scholar
  • 25 Ihara H, Urano T, Takada A, Loskutoff D J. Induction of plasminogen activator inhibitor-1 gene expression in adipocytes by thiazolidinediones.  FASEB J. 2001;  15 1233-1235
    PubMedSearch in Google Scholar
  • 26 Rieusset J, Auwerx J, Vidal H. Regulation of gene expression by activation of the peroxisome proliferator-activated receptor gamma with rosiglitazone (BRL 49653) in human adipocytes.  Biochem Biophys Res Commun. 1999;  265 265-271
    CrossrefPubMedSearch in Google Scholar
  • 27 Bailey C J. Metformin - an update.  Gen Pharmacol. 1993;  24 1299-1309
    PubMedSearch in Google Scholar
  • 28 Fischer Y, Thomas J, Rosen P, Kammermeier H. Action of metformin on glucose transport and glucose transporter GLUT1 and GLUT4 in heart muscle cells from healthy and diabetic rats.  Endocrinology. 1995;  136 412-420
    CrossrefPubMedSearch in Google Scholar
  • 29 Lenhard J M, Kliewer S A, Paulik M A, Plunket K D, Lehmann J M, Weiel J E. Effects of troglitazone and metformin on glucose and lipid metabolism: alterations of two distinct molecular pathways.  Biochem Pharmacol. 1997;  54 801-808
    CrossrefPubMedSearch in Google Scholar
  • 30 Yudkin J S, Coppack S W, Bulmer K, Rawesh A, Mohamed-Ali V. Lack of evidence for secretion of plasminogen activator inhibitor-1 by human subcutaneous adipose tissue in vivo.  Thromb Res . 1999;  96 1-9
    CrossrefPubMedSearch in Google Scholar
  • 31 Birgel M, Gottschling-Zeller H, Rohrig K, Hauner H. Role of cytokines in the regulation of plasminogen activator inhibitor-1 expression and secretion in newly differentiated subcutaneous human adipocytes.  Arterioscler Thromb Vasc Biol . 2000;  20 1682-1687
    PubMedSearch in Google Scholar

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