Department of Medicine, Division of Endocrinology and Metabolism, University of Virginia Health System, Charlottesville, Virginia, USA.
Diabetes. 2011 Nov;60(11):2939-46. doi: 10.2337/db10-1691. Epub 2011 Sep 6.
Angiotensin (ANG) II interacts with insulin-signaling pathways to regulate insulin sensitivity. The type 1 (AT(1)R) and type 2 (AT(2)R) receptors reciprocally regulate basal perfusion of muscle microvasculature. Unopposed AT(2)R activity increases muscle microvascular blood volume (MBV) and glucose extraction, whereas unopposed AT(1)R 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 (AT(2)R blocker), or insulin plus losartan (AT(1)R blocker, intravenously). Muscle MBV, microvascular flow velocity, and microvascular blood flow (MBF) were determined. In protocol 2, rats received (125)I-insulin with or without PD123319, and muscle insulin uptake was determined.
Insulin significantly increased muscle MBV and MBF. AT(2)R 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 AT(1)Rs and AT(2)Rs regulate insulin's microvascular and metabolic action in muscle. Although AT(1)R activity restrains muscle metabolic responses to insulin via decreased microvascular recruitment and insulin delivery, AT(2)R activity is required for normal microvascular responses to insulin. Thus, pharmacologic manipulation aimed at increasing the AT(2)R-to-AT(1)R activity ratio may afford the potential to improve muscle insulin sensitivity and glucose metabolism.
血管紧张素（ANG）II 与胰岛素信号通路相互作用，调节胰岛素敏感性。1 型（AT(1)R）和 2 型（AT(2)R）受体相互调节肌肉微血管基础灌注。无拮抗的 AT(2)R 活性增加肌肉微血管血液体积（MBV）和葡萄糖摄取，而无拮抗的 AT(1)R 活性则降低两者。本研究探讨了血管紧张素 II 受体是否调节肌肉胰岛素的输送和敏感性。
对 overnight-fasted 大鼠进行研究。在方案 1 中，大鼠接受 2 小时盐水、胰岛素（3 mU/kg/min）、胰岛素加 PD123319（AT(2)R 阻断剂）或胰岛素加氯沙坦（AT(1)R 阻断剂，静脉内）输注。测定肌肉 MBV、微血管血流速度和微血管血流（MBF）。在方案 2 中，大鼠接受（125）I-胰岛素加或不加 PD123319，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 阻断剂消除了胰岛素介导的肌肉 MBV 和 MBF 的增加，并使胰岛素刺激的葡萄糖摄取减少约 30%。相比之下，洛沙坦加胰岛素使肌肉 MBV 增加了两到三倍，而没有进一步增加胰岛素刺激的葡萄糖摄取。胰岛素和胰岛素加氯沙坦使血浆一氧化氮增加超过 50%，但胰岛素加 PD123319 则不然。PD123319 显著降低肌肉胰岛素摄取和胰岛素刺激的 Akt 磷酸化。
我们得出结论，AT(1)R 和 AT(2)R 均调节胰岛素在肌肉中的微血管和代谢作用。尽管 AT(1)R 活性通过减少微血管募集和胰岛素输送来抑制肌肉对胰岛素的代谢反应，但 AT(2)R 活性是正常的胰岛素对微血管反应所必需的。因此，旨在增加 AT(2)R 与 AT(1)R 活性比的药物干预可能有潜力改善肌肉胰岛素敏感性和葡萄糖代谢。
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