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Rosiglitazone inhibits the insulin-mediated increase in PAI-1 secretion in human abdominal subcutaneous adipocytes.
Diabetes Obes Metab 2003; 5(5):302-10DO

Abstract

OBJECTIVE

The aim of this study was to investigate the effect of insulin and an insulin-sensitizing agent, rosiglitazone (RSG), on the production of plasminogen-activator inhibitor-1 (PAI-1) in isolated subcutaneous abdominal adipocytes. Human tissue-type plasminogen activator (t-PA) was also measured to assess changes in overall thrombotic risk.

METHODS

The mean depot-specific expression of PAI-1 and t-PA mRNA (n = 42) in subcutaneous abdominal (n = 21), omental (n = 10) and thigh (n = 11) adipose tissue depots was examined. Furthermore, subcutaneous adipocytes were treated with insulin, RSG and insulin in combination with RSG (10-8 m) for 48 h. Conditioned media were collected and enzyme-linked immunosorbent assays performed for PAI-1 and t-PA (n = 12) antigen. PAI-1 and t-PA mRNA levels were also assessed.

RESULTS

PAI-1 mRNA levels were significantly higher in subcutaneous and omental abdominal tissue than in thigh fat (p = 0.037 and p = 0.014). No change in t-PA mRNA expression between the adipose tissue depots was observed. Insulin stimulated PAI-1 protein secretion in a concentration-dependent manner in adipocytes (control: 68.3 +/- 1.2 ng/ml (s.e.m.); 10 nm insulin: 73.7 +/- 3.8 ng/ml upward arrow; 100 nm insulin: 86.8 +/- 4.1 ng/ml upward arrow **; 1000 nm insulin: 102.0 +/- 4.8 ng/ml upward arrow ***; **p < 0.01, ***p < 0.001). In contrast, insulin + RSG (10-8 m) reduced PAI-1 production relative to insulin alone (***p < 0.001), whilst RSG alone reduced PAI-1 protein secretion in a concentration-dependent manner (RSG at 10-10 m: 50.4 +/- 2.87 ng/ml downward arrow ***; RSG at 10-5 m: 30.3 +/- 2.0 ng/ml downward arrow ***; p < 0.001). No difference was observed between control and treatments for t-PA secretion (range 7-11 ng/ml).

CONCLUSIONS

Insulin stimulated PAI-1 secretion, whilst RSG reduced both PAI-1 secretion alone and in combination with insulin. These data suggest that adipose tissue may contribute significantly to the elevated circulating PAI-1 in obesity. Therefore, RSG's effects on PAI-1 production in adipose tissue may contribute to the fall in circulating PAI-1 levels observed in patients receiving RSG therapy.

Authors+Show Affiliations

Division of Medical Sciences, Department of Medicine, University of Birmingham and Heartlands Hospital, Edgbaston, Birmingham, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12940867

Citation

Harte, A L., et al. "Rosiglitazone Inhibits the Insulin-mediated Increase in PAI-1 Secretion in Human Abdominal Subcutaneous Adipocytes." Diabetes, Obesity & Metabolism, vol. 5, no. 5, 2003, pp. 302-10.
Harte AL, McTernan PG, McTernan CL, et al. Rosiglitazone inhibits the insulin-mediated increase in PAI-1 secretion in human abdominal subcutaneous adipocytes. Diabetes Obes Metab. 2003;5(5):302-10.
Harte, A. L., McTernan, P. G., McTernan, C. L., Smith, S. A., Barnett, A. H., & Kumar, S. (2003). Rosiglitazone inhibits the insulin-mediated increase in PAI-1 secretion in human abdominal subcutaneous adipocytes. Diabetes, Obesity & Metabolism, 5(5), pp. 302-10.
Harte AL, et al. Rosiglitazone Inhibits the Insulin-mediated Increase in PAI-1 Secretion in Human Abdominal Subcutaneous Adipocytes. Diabetes Obes Metab. 2003;5(5):302-10. PubMed PMID: 12940867.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Rosiglitazone inhibits the insulin-mediated increase in PAI-1 secretion in human abdominal subcutaneous adipocytes. AU - Harte,A L, AU - McTernan,P G, AU - McTernan,C L, AU - Smith,S A, AU - Barnett,A H, AU - Kumar,S, PY - 2003/8/28/pubmed PY - 2003/12/16/medline PY - 2003/8/28/entrez SP - 302 EP - 10 JF - Diabetes, obesity & metabolism JO - Diabetes Obes Metab VL - 5 IS - 5 N2 - OBJECTIVE: The aim of this study was to investigate the effect of insulin and an insulin-sensitizing agent, rosiglitazone (RSG), on the production of plasminogen-activator inhibitor-1 (PAI-1) in isolated subcutaneous abdominal adipocytes. Human tissue-type plasminogen activator (t-PA) was also measured to assess changes in overall thrombotic risk. METHODS: The mean depot-specific expression of PAI-1 and t-PA mRNA (n = 42) in subcutaneous abdominal (n = 21), omental (n = 10) and thigh (n = 11) adipose tissue depots was examined. Furthermore, subcutaneous adipocytes were treated with insulin, RSG and insulin in combination with RSG (10-8 m) for 48 h. Conditioned media were collected and enzyme-linked immunosorbent assays performed for PAI-1 and t-PA (n = 12) antigen. PAI-1 and t-PA mRNA levels were also assessed. RESULTS: PAI-1 mRNA levels were significantly higher in subcutaneous and omental abdominal tissue than in thigh fat (p = 0.037 and p = 0.014). No change in t-PA mRNA expression between the adipose tissue depots was observed. Insulin stimulated PAI-1 protein secretion in a concentration-dependent manner in adipocytes (control: 68.3 +/- 1.2 ng/ml (s.e.m.); 10 nm insulin: 73.7 +/- 3.8 ng/ml upward arrow; 100 nm insulin: 86.8 +/- 4.1 ng/ml upward arrow **; 1000 nm insulin: 102.0 +/- 4.8 ng/ml upward arrow ***; **p < 0.01, ***p < 0.001). In contrast, insulin + RSG (10-8 m) reduced PAI-1 production relative to insulin alone (***p < 0.001), whilst RSG alone reduced PAI-1 protein secretion in a concentration-dependent manner (RSG at 10-10 m: 50.4 +/- 2.87 ng/ml downward arrow ***; RSG at 10-5 m: 30.3 +/- 2.0 ng/ml downward arrow ***; p < 0.001). No difference was observed between control and treatments for t-PA secretion (range 7-11 ng/ml). CONCLUSIONS: Insulin stimulated PAI-1 secretion, whilst RSG reduced both PAI-1 secretion alone and in combination with insulin. These data suggest that adipose tissue may contribute significantly to the elevated circulating PAI-1 in obesity. Therefore, RSG's effects on PAI-1 production in adipose tissue may contribute to the fall in circulating PAI-1 levels observed in patients receiving RSG therapy. SN - 1462-8902 UR - https://www.unboundmedicine.com/medline/citation/12940867/Rosiglitazone_inhibits_the_insulin_mediated_increase_in_PAI_1_secretion_in_human_abdominal_subcutaneous_adipocytes_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&amp;sid=nlm:pubmed&amp;issn=1462-8902&amp;date=2003&amp;volume=5&amp;issue=5&amp;spage=302 DB - PRIME DP - Unbound Medicine ER -