Effects of troglitazone on blood concentrations of plasminogen activator inhibitor 1 in patients with type 2 diabetes and in lean and obese normal subjects
Effects of troglitazone on blood concentrations of plasminogen activator inhibitor 1 in patients with type 2 diabetes and in lean and obese normal subjects
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DOI：
10.2337/diabetes.49.4.633
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发表时间：
2000-04-01
期刊：
影响因子：
7.7
通讯作者：
Sobel, BE
中科院分区：
文献类型：
--
作者：
Kruszynska, YT;Yu, JG;Sobel, BE
低血浆纤溶活性与血浆纤溶酶原激活物抑制物1（派-1）水平升高相关，与肥胖和2型糖尿病患者动脉粥样硬化风险增加有关。我们检验了这样一个假设，即曲格列酮可以提高胰岛素敏感性，降低胰岛素抵抗性肥胖受试者和2型糖尿病患者的血浆胰岛素水平，也可以降低循环派-1抗原浓度和活性。我们评估了胰岛素敏感性（5小时，80 mU。m（-2）。14例2型糖尿病患者和20例正常对照者（10例瘦型，10例肥胖）在曲格列酮（600 mg/d）治疗前和治疗3个月后测定血浆派-1抗原和活性及组织纤溶酶原激活物（tPA）。在基线时，肥胖者（33.5 +/- 4.7 μ g/l）和2型糖尿病受试者（54.9 +/- 6.3 μ g/l）过夜禁食后的血浆派-1抗原水平显著高于瘦对照受试者（16.3 +/- 3.2 μ g/l;分别为P < 0.01和P < 0.001）。曲格列酮降低糖尿病患者血浆派-1抗原浓度（36.8 ± 5.0 μ g/l;与基线相比P < 0.001），但肥胖受试者的降低没有达到统计学显著性（基线，33.5 ± 4.7;曲格列酮后，25.6 ± 5.2 μ g/l）。血浆派-1活性的变化与派-1抗原的变化一致。糖尿病患者接受曲格列酮治疗后血浆派-1抗原浓度的降低程度与空腹血浆胰岛素水平的降低相关（r = 0.60，P < 0.05），非酯化脂肪酸（r = 0.63，P < 0.02）和葡萄糖浓度（r = 0.64，P < 0.02），但与葡萄糖钳夹期间葡萄糖处置率的改善无关。三名曲格列酮对胰岛素敏感性、空腹血糖和胰岛素水平无反应者的循环派-1也没有降低。总之，曲格列酮可增强胰岛素抵抗2型糖尿病患者的纤溶系统活性。这种作用似乎与其通过外周组织胰岛素增敏作用降低血浆胰岛素水平和改善血糖控制的潜力密切相关。
Low plasma fibrinolytic activity in association with increased plasma plasminogen activator inhibitor 1 (PAI-1) levels has been linked to an increased risk of atherosclerosis in obesity and type 2 diabetes. We tested the hypothesis that troglitazone, which improves insulin sensitivity and lowers plasma insulin levels in insulin-resistant obese subjects and patients with type 2 diabetes, would also lower circulating PAI-1 antigen concentrations and activity. We assessed insulin sensitivity (5-h, 80 mU . m(-2) . min(-1) hyperinsulinemic-euglycemic damp) and measured plasma PAI-1 antigen and activities and tissue plasminogen activator (tPA) in 14 patients with type 2 diabetes and 20 normal control subjects (10 lean, 10 obese) before and after 3 months of treatment with troglitazone (600 mg/day). At baseline, plasma PAI-1 antigen levels after an overnight fast were significantly higher in the obese (33.5 +/- 4.7 mu g/l) and type 2 diabetic subjects (54.9 +/- 6.3 mu g/l) than in the lean control subjects (16.3 +/- 3.2 mu g/l; P < 0.01 and P < 0.001, respectively). Troglitazone decreased plasma PAI-1 antigen concentrations in the diabetic patients (36.8 +/- 5.0 mu g/l; P < 0.001 vs. baseline), but the reduction in the obese subjects did not reach statistical significance (baseline, 33.5 +/- 4.7; after troglitazone, 25.6 +/- 5.2 mu g/l). Changes in plasma PAI-1 activity paralleled those of PAI-1 antigen. The extent of the reduction in plasma PAI-1 antigen concentrations in the diabetic patients after troglitazone correlated with the reductions in fasting plasma insulin (r = 0.60, P < 0.05), nonesterified fatty acid (r = 0.63, P < 0.02), and glucose concentrations (r = 0.64, P < 0.02) but not with the improvement in glucose disposal rates during the glucose clamps. Three nonresponders to troglitazone with respect to effects on insulin sensitivity and fasting glucose and insulin levels also had no reduction in circulating PAI-1. In conclusion, troglitazone enhances fibrinolytic system activity in insulin-resistant type 2 diabetic patients. This effect appears to be intimately linked to its potential to lower plasma insulin levels and improve glycemic control through its peripheral tissue insulin-sensitizing effects.