Angiotensin II receptors modulate muscle microvascular and metabolic responses to insulin in vivo.
Angiotensin II receptors modulate muscle microvascular and metabolic responses to insulin in vivo.
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作者：
Chai W;Wang W;Dong Z;Cao W;Liu Z
血管紧张素（ANG）II与胰岛素信号通路相互作用以调节胰岛素敏感性。1型（AT 1 R）和2型（AT 2 R）受体共同调节肌肉微血管的基础灌注。非对抗性AT 2 R活性增加肌肉微血管血容量（MBV）和葡萄糖提取，而非对抗性AT 1 R活性降低两者。目前的研究检查ANG II受体是否调节肌肉胰岛素输送和敏感性。研究了整夜禁食的大鼠。在方案1中，大鼠接受盐水、胰岛素（3 mU/kg/min）、胰岛素+PD 123319（AT 2 R阻断剂）或胰岛素+氯沙坦（AT 1 R阻断剂，静脉内）2小时输注。测定肌肉MBV、微血管流速和微血管血流量（MBF）。在方案2中，大鼠接受含或不含PD 123319的125 I-胰岛素，并测定肌肉胰岛素摄取。胰岛素显著增加肌肉MBV和MBF。AT 2 R阻断可消除胰岛素介导的肌肉MBV和MBF增加，并使胰岛素刺激的葡萄糖处置减少约30%。相比之下，氯沙坦加胰岛素使肌肉MBV增加2 - 3倍，而没有进一步增加胰岛素刺激的葡萄糖处置。胰岛素和胰岛素加氯沙坦使血浆一氧化氮增加>50%，但胰岛素加PD 123319则无此作用。PD 123319显著降低肌肉胰岛素摄取和胰岛素刺激的Akt磷酸化。我们的结论是AT 1 Rs和AT 2 Rs都调节胰岛素在肌肉中的微血管和代谢作用。虽然AT 1 R活性通过减少微血管募集和胰岛素递送来抑制肌肉对胰岛素的代谢反应，但AT 2 R活性是正常微血管对胰岛素反应所必需的。因此，旨在增加AT 2 R与AT 1 R活性比的药理学操作可能提供改善肌肉胰岛素敏感性和葡萄糖代谢的潜力。
Angiotensin (ANG) II interacts with insulin-signaling pathways to regulate insulin sensitivity. The type 1 (AT1R) and type 2 (AT2R) receptors reciprocally regulate basal perfusion of muscle microvasculature. Unopposed AT2R activity increases muscle microvascular blood volume (MBV) and glucose extraction, whereas unopposed AT1R activity decreases both. The current study examined whether ANG II receptors modulate muscle insulin delivery and sensitivity. Overnight-fasted rats were studied. In protocol 1, rats received a 2-h infusion of saline, insulin (3 mU/kg/min), insulin plus PD123319 (AT2R blocker), or insulin plus losartan (AT1R blocker, intravenously). Muscle MBV, microvascular flow velocity, and microvascular blood flow (MBF) were determined. In protocol 2, rats received 125I-insulin with or without PD123319, and muscle insulin uptake was determined. Insulin significantly increased muscle MBV and MBF. AT2R blockade abolished insulin-mediated increases in muscle MBV and MBF and decreased insulin-stimulated glucose disposal by ~30%. In contrast, losartan plus insulin increased muscle MBV by two- to threefold without further increasing insulin-stimulated glucose disposal. Plasma nitric oxide increased by >50% with insulin and insulin plus losartan but not with insulin plus PD123319. PD123319 markedly decreased muscle insulin uptake and insulin-stimulated Akt phosphorylation. We conclude that both AT1Rs and AT2Rs regulate insulin’s microvascular and metabolic action in muscle. Although AT1R activity restrains muscle metabolic responses to insulin via decreased microvascular recruitment and insulin delivery, AT2R activity is required for normal microvascular responses to insulin. Thus, pharmacologic manipulation aimed at increasing the AT2R-to-AT1R activity ratio may afford the potential to improve muscle insulin sensitivity and glucose metabolism.