University of Virginia, Charlottesville, Virginia, USA.
Diabetes. 2009 Nov;58(11):2457-63. doi: 10.2337/db08-1077. Epub 2009 Aug 12.
Insulin and contraction each increase muscle microvascular blood volume (MBV) and glucose uptake. Inhibiting nitric oxide synthase blocks insulin's but not contraction's effects. We examined whether contraction could augment the MBV increase seen with physiologic hyperinsulinemia and whether free fatty acid (FFA)-induced insulin resistance differentially affects contraction- versus insulin-mediated increases in MBV.
Rats were fasted overnight. Plasma FFAs were increased by intralipid/heparin infusion (3 h), insulin was increased with a euglycemic clamp (3 mU x min(-1) x kg(-1)), and hindlimb muscle contraction was electrically stimulated. Muscle MBV was measured using contrast-enhanced ultrasound. Insulin transport into muscle was measured using (125)I-insulin. BQ-123 (0.4 mg/h) was used to block the endothelin-1 (ET-1) receptor A.
Superimposing contraction on physiologic hyperinsulinemia increased MBV within 10 min by 37 and 67% for 0.1 or 1 Hz, respectively (P < 0.01). FFA elevation alone did not affect MBV, whereas 0.1 Hz stimulation doubled MBV (P < 0.05) and increased muscle insulin uptake (P < 0.05) despite high FFA. Physiologic hyperinsulinemia during FFA elevation paradoxically decreased MBV (P < 0.05). This MBV decrease was reversed by either 0.1 Hz contraction or ET-1 receptor A antagonism, and the combination raised MBV above basal.
Contraction recruits microvasculature beyond that seen with physiologic hyperinsulinemia by a distinct mechanism that is not blocked by FFA-induced vascular insulin resistance. The paradoxical MBV decline seen with insulin plus FFA may result from differential inhibition of insulin-stimulated nitric oxide-dependent vasodilation relative to ET-1 vasoconstriction. Our results implicate ET-1 as a potential mediator of FFA-induced vascular insulin resistance.
胰岛素和收缩都会增加肌肉微血管血液体积（MBV）和葡萄糖摄取。抑制一氧化氮合酶可阻断胰岛素的作用，但不阻断收缩的作用。我们研究了收缩是否可以增强生理高胰岛素血症引起的 MBV 增加，以及游离脂肪酸（FFA）引起的胰岛素抵抗是否会对收缩与胰岛素介导的 MBV 增加产生不同的影响。
大鼠隔夜禁食。通过静脉内脂肪乳剂/肝素输注（3 小时）增加血浆 FFAs，通过正葡萄糖钳夹（3 mU x min(-1) x kg(-1)）增加胰岛素，并用电刺激刺激后肢肌肉收缩。使用对比增强超声测量肌肉 MBV。使用 (125)I-胰岛素测量胰岛素向肌肉的转运。用 BQ-123（0.4 mg/h）阻断内皮素-1（ET-1）受体 A。
在生理高胰岛素血症的基础上叠加收缩在 10 分钟内分别使 0.1 或 1 Hz 的 MBV 增加了 37%和 67%（P < 0.01）。单独升高 FFA 不影响 MBV，而 0.1 Hz 刺激使 MBV 增加一倍（P < 0.05）并增加肌肉胰岛素摄取（P < 0.05），尽管 FFA 水平较高。在升高 FFA 的同时，生理高胰岛素血症反而使 MBV 降低（P < 0.05）。0.1 Hz 收缩或 ET-1 受体 A 拮抗作用可逆转这种 MBV 降低，并且联合作用使 MBV 高于基础水平。
收缩通过一种不同于生理高胰岛素血症的机制招募微血管，这种机制不受 FFA 引起的血管胰岛素抵抗的阻断。胰岛素加 FFA 时观察到的 MBV 下降可能是由于胰岛素刺激的一氧化氮依赖性血管舒张与 ET-1 血管收缩的差异抑制所致。我们的结果表明 ET-1 可能是 FFA 引起的血管胰岛素抵抗的潜在介质。
