Kruszynska Y T, Yu J G, Olefsky J M, Sobel B E
Department of Endocrinology and Metabolism, University of California San Diego, Veterans Administration Center, La Jolla 92093, USA.
Diabetes. 2000 Apr;49(4):633-9. doi: 10.2337/diabetes.49.4.633.
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 x m(-2) x min(-1) hyperinsulinemic-euglycemic clamp) 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 microg/l) and type 2 diabetic subjects (54.9 +/- 6.3 microg/l) than in the lean control subjects (16.3 +/- 3.2 microg/l; P < 0.01 and P < 0.001, respectively). Troglitazone decreased plasma PAI-1 antigen concentrations in the diabetic patients (36.8 +/- 5.0 microg/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 microg/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.
血浆纤溶活性降低与血浆纤溶酶原激活物抑制剂1（PAI-1）水平升高有关，这已被证明与肥胖和2型糖尿病患者动脉粥样硬化风险增加相关。我们验证了这样一个假设：曲格列酮可改善胰岛素抵抗的肥胖受试者和2型糖尿病患者的胰岛素敏感性并降低血浆胰岛素水平，它也能降低循环中PAI-1抗原浓度和活性。我们评估了14例2型糖尿病患者和20例正常对照受试者（10例瘦人，10例肥胖者）在接受曲格列酮（600毫克/天）治疗3个月前后的胰岛素敏感性（5小时，80 mU x m(-2) x min(-1)高胰岛素-正常血糖钳夹法），并检测了血浆PAI-1抗原、活性以及组织纤溶酶原激活物（tPA）。基线时，肥胖受试者（33.5 +/- 4.7微克/升）和2型糖尿病受试者（54.9 +/- 6.3微克/升）过夜禁食后的血浆PAI-1抗原水平显著高于瘦对照受试者（16.3 +/- 3.2微克/升；P分别< 0.01和P < 0.001）。曲格列酮降低了糖尿病患者的血浆PAI-1抗原浓度（36.8 +/- 5.0微克/升；与基线相比P < 0.001），但肥胖受试者的降低未达到统计学意义（基线时为33.5 +/- 4.7；曲格列酮治疗后为25.6 +/- 5.2微克/升）。血浆PAI-1活性的变化与PAI-1抗原的变化平行。曲格列酮治疗后糖尿病患者血浆PAI-1抗原浓度的降低程度与空腹血浆胰岛素的降低（r = 0.60，P < 0.05）、非酯化脂肪酸的降低（r = 0.63，P < 0.02）和血糖浓度的降低（r = 0.64，P < 0.02）相关，但与葡萄糖钳夹期间葡萄糖处置率的改善无关。3例对曲格列酮在胰岛素敏感性、空腹血糖和胰岛素水平方面无反应的患者，其循环中的PAI-1也没有降低。总之，曲格列酮增强了胰岛素抵抗的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。
