血管紧张素II受体活性对骨骼肌微循环胰岛素抵抗的调节作用

To exert its biological actions on muscle cells, insulin first has to reach the muscle interstitium. Insulin promotes its own access to muscle interstitum by recruiting microvasculature. In the state of diabetes or obesity, insulin resistance is present in multiple insulin responsive tissues, including the microvasculature. Microvascular insulin resistance contributes significantly to metabolic insulin resistance. In the preliminary study, we have demonstrated that angiotensin II type 1 receptor (AT1R) and type 2 receptor (AT2R) modulate basal microvascular tone and insulin responses in muscle microvasculature. Basal AT1R tone restricts muscle microvascular recruitment and glucose extraction, whereas basal AT2R activity increases muscle microvascular recruitment and glucose uptake. We further demonstrated that AT2R activity is required for normal microvascular responses to insulin. Base on our preliminary findings, we conduct the present study to further exam weather AT1R and AT2R activity regulate insulin's action on microvascular recruitment, insulin delivery and glucose use in insulin-resistant states. We exam weather the AT1R blocker losartan rescue insulin's metabolic action via improving microvascular insulin sensitivity in an experimental insulin-resistance state induced by lipid infusion and, if so, whether this improvement depended on AT2R activity. We speculate pharmacological manipulation aimed at increasing AT2R/AT1R activity ratio may affords the potential to improve microvascular insulin sensitivity, insulin delivery and glucose metabolism, and to reduce the complications associated with diabetes nd insulin resistance.

胰岛素通过增加骨骼肌微循环灌注量，促进自身转运至骨骼肌组织间隙，进而发挥调节糖代谢的作用。在微循环胰岛素抵抗的状态下，胰岛素增加骨骼肌微循环灌注量的能力降低，限制了胰岛素自身的转运，影响其促进骨骼肌细胞摄取葡萄糖的能力，是导致葡萄糖利用异常的重要因素。本课题组前期研究发现：正常大鼠中，血管紧张素Ⅱ1型受体（AT1R）和2型受体（AT1R）活性与微循环胰岛素敏感性密切相关；AT1R拮抗后，AT2R的活化，可增加大鼠骨骼肌微循环灌注量及葡萄糖摄取，而阻滞AT2R使微循环胰岛素敏感性下降。本课题拟在胰岛素抵抗大鼠模型中进一步研究，观察能否通过对AT1R和/或AT2R活性的调节，达到增加骨骼肌微循环灌注量，促进胰岛素自身转运，改善骨骼肌微循环胰岛素抵抗，治疗糖代谢紊乱的作用。为明确微循环胰岛素抵抗的发生机制，探寻改善微循环胰岛素抵抗的治疗靶点，找到更有效的策略来防治糖尿病及其并发症提供理论支持。

胰岛素可通过增加骨骼肌微循环灌注，促进自身转运至骨骼肌组织间隙，进而发挥调节糖代谢的作用。在微循环胰岛素抵抗的情况下，胰岛素增加微循环灌注的能力受损，限制自身的转运，进而影响其调节糖代谢的能力。微循环胰岛素抵抗是导致葡萄糖利用异常和糖尿病微血管、大血管病变发生发展的重要因素。本课题组前期研究发现：正常大鼠中，血管紧张素Ⅱ1型受体（AT1R）和2型受体（AT2R）的活性与骨骼肌微循环灌注及胰岛素敏感性密切相关；AT1R拮抗后，可增加正常大鼠微循环灌注及骨骼肌葡萄糖摄取，而阻滞AT2R可使微循环胰岛素敏感性下降。本课题在脂质输注诱导的胰岛素抵抗大鼠模型中，观察AT1R拮抗剂氯沙坦是否能够改善骨骼肌微循环胰岛素抵抗状态，进而改善代谢性胰岛素抵抗，并初步探讨其作用机制。研究发现：（1）与对照组相比，脂质输注模型组大鼠胰岛素刺激的葡萄糖处置率（GIR）明显下降，存在代谢性胰岛素抵抗，给予氯沙坦治疗后可显著提高GIR，改善代谢性敏感性；（2）与对照组相比，模型组大鼠胰岛素刺激的骨骼肌微循环灌注量（MBV）没有明显增加，存在微循环胰岛素抵抗，给予氯沙坦治疗后，可观察到骨骼肌MBV较基础值显著升高，改善微循环胰岛素敏感性；（3）L-NAME输注抑制氯沙坦增加骨骼肌MBV的作用，同时氯沙坦改善GIR的作用也受到抑制，提示氯沙坦对代谢性胰岛素敏感性的改善依赖于其微循环作用；（4）对照组、模型组及氯沙坦治疗组骨骼肌对125-碘标记胰岛素的摄取未发现差别；（5）使用AT2R抑制剂PD123319阻滞AT2R的作用后，氯沙坦升高骨骼肌MBV的作用被抑制，AT2R受体直接激动剂C21有升高骨骼肌MBV及调节葡萄糖代谢的作用。综上所述，该研究提示在胰岛素抵抗大鼠模型中，AT1R拮抗剂氯沙坦治疗能改善大鼠微循环胰岛素抵抗状态，进而改善代谢性胰岛素抵抗，AT1R拮抗剂对胰岛素抵抗的改善作用可能依赖于AT1R阻滞后AT2R的活化。