罗格列酮可抑制胰岛素介导的人腹部皮下脂肪细胞中纤溶酶原激活物抑制因子-1（PAI-1）分泌增加。

Rosiglitazone inhibits the insulin-mediated increase in PAI-1 secretion in human abdominal subcutaneous adipocytes.

作者信息

Harte A L, McTernan P G, McTernan C L, Smith S A, Barnett A H, Kumar S

机构信息

Division of Medical Sciences, Department of Medicine, University of Birmingham and Heartlands Hospital, Edgbaston, Birmingham, UK.

出版信息

Diabetes Obes Metab. 2003 Sep;5(5):302-10. doi: 10.1046/j.1463-1326.2003.00276.x.

DOI:10.1046/j.1463-1326.2003.00276.x

PMID:12940867

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.

摘要

目的

本研究旨在探讨胰岛素及胰岛素增敏剂罗格列酮（RSG）对分离的腹部皮下脂肪细胞中纤溶酶原激活物抑制剂-1（PAI-1）生成的影响。同时检测人组织型纤溶酶原激活物（t-PA），以评估整体血栓形成风险的变化。

方法

检测腹部皮下（n = 21）、网膜（n = 10）和大腿（n = 11）脂肪组织库中PAI-1和t-PA mRNA的平均库特异性表达（n = 42）。此外，将皮下脂肪细胞用胰岛素、RSG以及胰岛素与RSG联合（10⁻⁸ m）处理48小时。收集条件培养基，进行PAI-1和t-PA（n = 12）抗原的酶联免疫吸附测定。同时评估PAI-1和t-PA mRNA水平。

结果

腹部皮下和网膜组织中PAI-1 mRNA水平显著高于大腿脂肪（p = 0.037和p = 0.014）。未观察到各脂肪组织库之间t-PA mRNA表达的变化。胰岛素以浓度依赖方式刺激脂肪细胞中PAI-1蛋白分泌（对照：68.3 ± 1.2 ng/ml（标准误）；10 nM胰岛素：73.7 ± 3.8 ng/ml↑；100 nM胰岛素：86.8 ± 4.1 ng/ml↑；1000 nM胰岛素：102.0 ± 4.8 ng/ml↑*；**p < 0.01，p < 0.001）。相反，胰岛素 + RSG（10⁻⁸ m）相对于单独使用胰岛素降低了PAI-1的生成（p < 0.001），而单独使用RSG以浓度依赖方式降低PAI-1蛋白分泌（10⁻¹⁰ m的RSG：50.4 ± 2.87 ng/ml↓；10⁻⁵ m的RSG：30.3 ± 2.0 ng/ml↓；p < 0.001）。t-PA分泌在对照与各处理组之间未观察到差异（范围7 - 11 ng/ml）。