PDF(Pubmed)
Abstract：
BACKGROUND: Vascular insulin resistance is commonly observed in obesity and diabetes; yet, insulin action across the vascular tree and the relationship between insulin responses at different vascular locations remains incompletely defined.
OBJECTIVE: To elucidate the impact of elevated free fatty acids (FFAs) on insulin action across the arterial tree and define the relationship among insulin actions in the different arterial segments.
METHODS: This randomized crossover study assigned healthy lean adults to 2 separate admissions with euglycemic insulin clamp superimposed for the final 120 minutes of 5-hour lipid or matched-volume saline infusion. Vascular measures including peripheral and central arterial blood pressure, brachial artery flow-mediated dilation (FMD), carotid femoral pulse wave velocity (cfPWV), augmentation index (AIx), pulse wave separation analysis, subendocardial viability ratio (SEVR), and skeletal and cardiac muscle microvascular perfusion were determined before and after insulin clamp. Insulin-mediated whole body glucose disposal was calculated.
RESULTS: Insulin enhanced FMD, AIx, reflection magnitude, and cardiac and skeletal muscle microvascular perfusion. Elevation of plasma FFA concentrations to the levels seen in the postabsorptive state in people with insulin resistance suppressed SEVR, blunted insulin-induced increases in FMD and cardiac and skeletal muscle microvascular blood volume, and lowered insulin\'s ability to reduce AIx and reflection magnitude. In multivariate regression, insulin-mediated muscle microvascular perfusion was independently associated with insulin-mediated FMD and cfPWV.
CONCLUSIONS: Clinically relevant elevation of plasma FFA concentrations induces pan-arterial insulin resistance, the vascular insulin resistance outcomes are interconnected, and insulin-mediated muscle microvascular perfusion associates with cardiovascular disease predictors. Our data provide biologic plausibility whereby a causative relationship between FFAs and cardiovascular disease could exist, and suggest that further attention to interventions that block FFA-mediated vascular insulin resistance may be warranted.
OBJECTIVE: To elucidate the impact of elevated free fatty acids (FFAs) on insulin action across the arterial tree and define the relationship among insulin actions in the different arterial segments.
METHODS: This randomized crossover study assigned healthy lean adults to 2 separate admissions with euglycemic insulin clamp superimposed for the final 120 minutes of 5-hour lipid or matched-volume saline infusion. Vascular measures including peripheral and central arterial blood pressure, brachial artery flow-mediated dilation (FMD), carotid femoral pulse wave velocity (cfPWV), augmentation index (AIx), pulse wave separation analysis, subendocardial viability ratio (SEVR), and skeletal and cardiac muscle microvascular perfusion were determined before and after insulin clamp. Insulin-mediated whole body glucose disposal was calculated.
RESULTS: Insulin enhanced FMD, AIx, reflection magnitude, and cardiac and skeletal muscle microvascular perfusion. Elevation of plasma FFA concentrations to the levels seen in the postabsorptive state in people with insulin resistance suppressed SEVR, blunted insulin-induced increases in FMD and cardiac and skeletal muscle microvascular blood volume, and lowered insulin\'s ability to reduce AIx and reflection magnitude. In multivariate regression, insulin-mediated muscle microvascular perfusion was independently associated with insulin-mediated FMD and cfPWV.
CONCLUSIONS: Clinically relevant elevation of plasma FFA concentrations induces pan-arterial insulin resistance, the vascular insulin resistance outcomes are interconnected, and insulin-mediated muscle microvascular perfusion associates with cardiovascular disease predictors. Our data provide biologic plausibility whereby a causative relationship between FFAs and cardiovascular disease could exist, and suggest that further attention to interventions that block FFA-mediated vascular insulin resistance may be warranted.
摘要：
目的：阐明游离脂肪酸（FFA）升高对整个动脉树的胰岛素作用的影响，并确定不同动脉段中胰岛素作用之间的关系。
方法：这项随机交叉研究将健康的瘦成人分配到两个单独入院，并在最后120分钟的5小时脂质或匹配体积的盐水输注中叠加正常血糖胰岛素钳。血管测量包括外周和中心动脉血压，肱动脉血流介导的扩张（FMD），颈动脉股动脉脉搏波传导速度（cfPWV），增强指数(AIX)，脉搏波分离分析，心内膜下活力比（SEVR），测定胰岛素钳夹前后骨骼肌和心肌微血管灌注。计算胰岛素介导的全身葡萄糖处置。
结果：胰岛素增强口蹄疫，AIx,反射幅度，和心肌和骨骼肌微血管灌注。胰岛素抵抗患者血浆FFA浓度升高至吸收后状态时的水平抑制了SEVR，胰岛素诱导的FMD和心肌和骨骼肌微血管血容量的增加，并降低了胰岛素减少AIx和反射幅度的能力。在多元回归中，胰岛素介导的肌肉微血管灌注与胰岛素介导的FMD和cfPWV独立相关.
结论：临床相关的血浆FFA浓度升高可诱导全动脉胰岛素抵抗，血管胰岛素抵抗结果是相互关联的，胰岛素介导的肌肉微血管灌注与心血管疾病预测因子相关。我们的数据提供了生物学合理性，即FFA和心血管疾病之间可能存在因果关系，并提示可能需要进一步关注阻断FFA介导的血管胰岛素抵抗的干预措施.
方法：这项随机交叉研究将健康的瘦成人分配到两个单独入院，并在最后120分钟的5小时脂质或匹配体积的盐水输注中叠加正常血糖胰岛素钳。血管测量包括外周和中心动脉血压，肱动脉血流介导的扩张（FMD），颈动脉股动脉脉搏波传导速度（cfPWV），增强指数(AIX)，脉搏波分离分析，心内膜下活力比（SEVR），测定胰岛素钳夹前后骨骼肌和心肌微血管灌注。计算胰岛素介导的全身葡萄糖处置。
结果：胰岛素增强口蹄疫，AIx,反射幅度，和心肌和骨骼肌微血管灌注。胰岛素抵抗患者血浆FFA浓度升高至吸收后状态时的水平抑制了SEVR，胰岛素诱导的FMD和心肌和骨骼肌微血管血容量的增加，并降低了胰岛素减少AIx和反射幅度的能力。在多元回归中，胰岛素介导的肌肉微血管灌注与胰岛素介导的FMD和cfPWV独立相关.
结论：临床相关的血浆FFA浓度升高可诱导全动脉胰岛素抵抗，血管胰岛素抵抗结果是相互关联的，胰岛素介导的肌肉微血管灌注与心血管疾病预测因子相关。我们的数据提供了生物学合理性，即FFA和心血管疾病之间可能存在因果关系，并提示可能需要进一步关注阻断FFA介导的血管胰岛素抵抗的干预措施.
