Steinberg H O, Paradisi G, Hook G, Crowder K, Cronin J, Baron A D
Department of Medicine, Indiana University School of Medicine, and the Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, USA.
Diabetes. 2000 Jul;49(7):1231-8. doi: 10.2337/diabetes.49.7.1231.
The effect and time course of free fatty acid (FFA) elevation on insulin-mediated vasodilation (IMV) and the relationship of FFA elevation to changes in insulin-mediated glucose uptake was studied. Two groups of lean insulin-sensitive subjects underwent euglycemic-hyperinsulinemic (40 mU x m(-2) x min(-1)) clamp studies with and without superimposed FFA elevation on 2 occasions approximately 4 weeks apart. Groups differed only by duration of FFA elevation, either short (2-4 h, n = 12) or long (8 h, n = 7). On both occasions, rates of whole-body glucose uptake were measured, and changes in leg blood flow (LBF) and femoral vein nitric oxide nitrite plus nitrate (NOx) flux in response to the clamps were determined. Short FFA infusion did not have any significant effect on the parameters of interest. In contrast, long FFA infusion decreased rates of whole-body glucose uptake from 47.7 +/-2.8 to 32.2 +/- 0.6 micromol x kg(-1) x min(-1) (P < 0.01), insulin-mediated increases in LBF from 66 +/- 8 to 37 +/- 7% (P < 0.05), and insulin-induced increases in NOx flux from 25 +/- 9 to 5 +/- 9% (P < 0.05). Importantly, throughout all groups, FFA-induced changes in whole-body glucose uptake correlated significantly with FFA-induced changes in insulin-mediated increases in LBF (r = 0.706, P < 0.001), which indicates coupling of metabolic and vascular effects. In a different protocol, short FFA elevation blunted the LBF response to NG-monomethyl-L-arginine (L-NMMA), which is an inhibitor of NO synthase. LBF in response to L-NMMA decreased by 17.3 +/- 2.4 and 9.0 +/- 1.4% in the groups without and with FFA elevation, respectively (P < 0.05), which indicates that FFA elevation interferes with shear stress-induced NO production. Thus, impairment of shear stress-induced vasodilation and IMV by FFA elevation occurs with different time courses, and impairment of IMV occurs only if glucose metabolism is concomitantly reduced. These findings suggest that NO production in response to the different stimuli may be mediated via different signaling pathways. FFA-induced reduction in NO production may contribute to the higher incidence of hypertension and macrovascular disease in insulin-resistant patients.
研究了游离脂肪酸（FFA）升高对胰岛素介导的血管舒张（IMV）的影响及时间进程，以及FFA升高与胰岛素介导的葡萄糖摄取变化之间的关系。两组瘦型胰岛素敏感受试者接受了正常血糖-高胰岛素血症（40 mU·m⁻²·min⁻¹）钳夹研究，在大约相隔4周的两个时间点分别进行了有无叠加FFA升高的实验。两组仅在FFA升高的持续时间上有所不同，即短时间（2 - 4小时，n = 12）或长时间（8小时，n = 7）。在两个时间点，均测量了全身葡萄糖摄取率，并测定了钳夹后腿部血流量（LBF）和股静脉一氧化氮亚硝酸盐加硝酸盐（NOx）通量的变化。短时间FFA输注对所关注的参数没有任何显著影响。相比之下，长时间FFA输注使全身葡萄糖摄取率从47.7±2.8降至32.2±0.6 μmol·kg⁻¹·min⁻¹（P < 0.01），胰岛素介导的LBF增加从66±8%降至37±7%（P < 0.05），胰岛素诱导的NOx通量增加从25±9%降至5±9%（P < 0.05）。重要的是，在所有组中，FFA诱导的全身葡萄糖摄取变化与FFA诱导的胰岛素介导的LBF增加变化显著相关（r = 0.706，P < 0.001），这表明代谢和血管效应之间存在耦合。在另一个方案中，短时间FFA升高减弱了对NO合酶抑制剂NG-单甲基-L-精氨酸（L-NMMA）的LBF反应。在无FFA升高组和有FFA升高组中，对L-NMMA的LBF反应分别下降了17.3±2.4%和9.0±1.4%（P < 0.05），这表明FFA升高干扰了剪切应力诱导的NO生成。因此，FFA升高对剪切应力诱导的血管舒张和IMV的损害具有不同的时间进程，并且只有在葡萄糖代谢同时降低时才会发生IMV损害。这些发现表明，对不同刺激的NO生成可能通过不同的信号通路介导。FFA诱导的NO生成减少可能导致胰岛素抵抗患者高血压和大血管疾病的发生率更高。
