Tack C J, Ong M K, Lutterman J A, Smits P
Department of Internal Medicine, University Hospital Nijmegen, The Netherlands. c.tackdaig.azn.nz.
Diabetologia. 1998 May;41(5):569-76. doi: 10.1007/s001250050948.
Insulin resistance is associated with a decreased vasodilator response to insulin. Because insulin's vasodilator effect is nitric oxide dependent, this impairment may reflect endothelial dysfunction. Troglitazone, an insulin-sensitiser, might thus improve insulin-dependent and/or endothelium-dependent vascular function in insulin resistant obese subjects. For 8 weeks, fifteen obese subjects were treated with either 400 mg troglitazone once daily or placebo, in a randomised, double-blind, cross-over design. At the end of each treatment period, we measured forearm vasodilator responses (plethysmography) to intra-arterial administered acetylcholine and sodium nitroprusside; insulin sensitivity and insulin-induced vascular and neurohumoral responses (clamp); vasoconstrictor responses to NC-monomethyl-L-arginine (L-NMMA) during hyperinsulinaemia; and ambulatory 24-h blood pressure (ABPM). Baseline data (placebo) of obese subjects were compared with those obtained in lean control subjects. Obese subjects were insulin resistant compared with leans (whole-body glucose uptake: 26.8+/-3.0 vs. 53.9+/-4.3 [tmol kgl min-, p < 0.001). Troglitazone improved whole-body glucose uptake (to 31.9+/-3.3 micromol x kg(-1) x min(-1) , p=0.028), and forearm glucose uptake (from 1.09+/-0.54 to 2.31+/-0.69 micromol dL(-1) x min(-1), p=0.006). Insulin-induced vasodilatation was blunted in obese subjects (percent increase in forearm blood flow (FBF) in lean 66.5+/-23.0%, vs. 10.1+/-11.3% in obese, p=0.04), but did not improve during troglitazone. Vascular responses to acetylcholine, sodium nitroprusside and L-NMMA did not differ between the obese and lean group, nor between both treatment periods in the obese individuals. In conclusion, in insulin resistant obese subjects, endothelial vascular function is normal despite impaired vasodilator responses to insulin. Troglitazone improved insulin sensitivity but it had no effects on endothelium-dependent and -independent vascular responses. These data do not support an association between insulin resistance and endothelial function.
胰岛素抵抗与胰岛素介导的血管舒张反应减弱有关。由于胰岛素的血管舒张作用依赖于一氧化氮，这种损害可能反映了内皮功能障碍。因此，胰岛素增敏剂曲格列酮可能改善胰岛素抵抗肥胖受试者的胰岛素依赖性和/或内皮依赖性血管功能。15名肥胖受试者采用随机、双盲、交叉设计，接受每日一次400mg曲格列酮或安慰剂治疗，为期8周。在每个治疗期结束时，我们测量了前臂对动脉内注射乙酰胆碱和硝普钠的血管舒张反应（体积描记法）；胰岛素敏感性以及胰岛素诱导的血管和神经体液反应（钳夹试验）；高胰岛素血症期间对N(G)-单甲基-L-精氨酸（L-NMMA）的血管收缩反应；以及动态24小时血压（ABPM）。将肥胖受试者的基线数据（安慰剂）与瘦对照受试者的数据进行比较。与瘦人相比，肥胖受试者存在胰岛素抵抗（全身葡萄糖摄取：26.8±3.0对53.9±4.3[tmol·kg-1·min-1，p<0.001]）。曲格列酮改善了全身葡萄糖摄取（至31.9±3.3μmol·kg-1·min-1，p=0.028）以及前臂葡萄糖摄取（从1.09±0.54至2.31±0.69μmol·dL-1·min-1，p=0.006）。肥胖受试者中胰岛素诱导的血管舒张减弱（瘦人前臂血流量（FBF）增加百分比为66.5±23.0%，肥胖者为10.1±11.3%，p=0.04），但在曲格列酮治疗期间未得到改善。肥胖组与瘦组之间以及肥胖个体的两个治疗期之间，对乙酰胆碱、硝普钠和L-NMMA的血管反应无差异。总之，在胰岛素抵抗肥胖受试者中，尽管对胰岛素的血管舒张反应受损，但内皮血管功能正常。曲格列酮改善了胰岛素敏感性，但对内皮依赖性和非依赖性血管反应均无影响。这些数据不支持胰岛素抵抗与内皮功能之间存在关联。
