Div. of Endocrinology and Metabolism, Dept. of Medicine, Univ. of Virginia Health System, Charlottesville, VA 22908, USA.
Am J Physiol Endocrinol Metab. 2013 Mar 1;304(5):E538-45. doi: 10.1152/ajpendo.00537.2012. Epub 2013 Jan 8.
Insulin delivery and transendothelial insulin transport are two discrete steps that limit muscle insulin action. Angiotensin II type 1 receptor (AT1R) blockade recruits microvasculature and increases glucose use in muscle. Increased muscle microvascular perfusion is associated with increased muscle delivery and action of insulin. To examine the effect of acute AT1R blockade on muscle insulin uptake and action, rats were studied after an overnight fast to examine the effects of losartan on muscle insulin uptake (protocol 1), microvascular perfusion (protocol 2), and insulin's microvascular and metabolic actions in the state of insulin resistance (protocol 3). Endothelial cell insulin uptake was assessed, using (125)I-insulin as tracer. Systemic lipid infusion was used to induce insulin resistance. Losartan significantly increased muscle insulin uptake (∼60%, P < 0.03), which was associated with a two- to threefold increase in muscle microvascular blood volume (MBV; P = 0.002) and flow (MBF; P = 0.002). Losartan ± angiotensin II had no effect on insulin internalization in cultured endothelial cells. Lipid infusion abolished insulin-mediated increases in muscle MBV and MBF and lowered insulin-stimulated whole body glucose disposal (P = 0.0001), which were reversed by losartan administration. Inhibition of nitric oxide synthase abolished losartan-induced muscle insulin uptake and reversal of lipid-induced metabolic insulin resistance. We conclude that AT1R blockade increases muscle insulin uptake mainly via microvascular recruitment and rescues insulin's metabolic action in the insulin-resistant state. This may contribute to the clinical findings of decreased cardiovascular events and new onset of diabetes in patients receiving AT1R blockers.
胰岛素的输送和跨内皮胰岛素转运是两个限制肌肉胰岛素作用的独立步骤。血管紧张素 II 型 1 型受体（AT1R）阻断剂募集微血管并增加肌肉中的葡萄糖利用。肌肉微血管灌注增加与胰岛素的肌肉输送和作用增加有关。为了研究急性 AT1R 阻断对肌肉胰岛素摄取和作用的影响，在隔夜禁食后研究了大鼠，以研究氯沙坦对肌肉胰岛素摄取（方案 1）、微血管灌注（方案 2）和胰岛素在胰岛素抵抗状态下的微血管和代谢作用（方案 3）的影响。使用 (125)I-胰岛素作为示踪剂评估内皮细胞胰岛素摄取。全身脂质输注用于诱导胰岛素抵抗。氯沙坦显著增加肌肉胰岛素摄取（约 60%，P < 0.03），这与肌肉微血管血液体积（MBV；P = 0.002）和流量（MBF；P = 0.002）增加两到三倍相关。氯沙坦±血管紧张素 II 对培养的内皮细胞中胰岛素的内化没有影响。脂质输注消除了胰岛素介导的肌肉 MBV 和 MBF 的增加，并降低了胰岛素刺激的全身葡萄糖处置（P = 0.0001），而氯沙坦给药则逆转了这一作用。一氧化氮合酶抑制剂消除了氯沙坦诱导的肌肉胰岛素摄取和脂质诱导的代谢性胰岛素抵抗的逆转。我们得出结论，AT1R 阻断主要通过微血管募集增加肌肉胰岛素摄取，并挽救胰岛素在胰岛素抵抗状态下的代谢作用。这可能有助于接受 AT1R 阻滞剂的患者心血管事件减少和新发糖尿病的临床发现。
