Liraglutide prevents microvascular insulin resistance and preserves muscle capillary density in high-fat diet-fed rats
Liraglutide prevents microvascular insulin resistance and preserves muscle capillary density in high-fat diet-fed rats
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DOI：
10.1152/ajpendo.00205.2016
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发表时间：
2016-09-01
影响因子：
5.1
通讯作者：
Liu, Zhenqi
中科院分区：
文献类型：
--
作者：
Chai, Weidong;Fu, Zhuo;Liu, Zhenqi
肌肉微血管系统严格地调节内皮交换表面积，以促进胰岛素、营养物质和氧气向肌细胞的跨内皮递送。胰岛素抵抗使胰岛素介导的微血管募集变钝，并降低肌肉毛细血管密度;两者都有助于降低微血管血容量。胰高血糖素样肽1（GLP-1）及其类似物能够扩张血管并刺激内皮细胞增殖。在本研究中，我们旨在确定持续刺激GLP-1受体对胰岛素介导的毛细血管募集和代谢胰岛素反应、小动脉内皮功能和肌肉毛细血管密度的影响。对大鼠喂食高脂饲料（HFD）4周，同时给予或不给予利拉鲁肽，并在禁食过夜后进行正常血糖高胰岛素钳夹试验120 min。胰岛素介导的肌肉微血管募集和肌肉氧合在胰岛素输注前和输注过程中进行了测定。测定肌肉毛细血管密度，并使用远端隐动脉测定内皮功能和胰岛素介导的血管舒张。高脂饮食可引起肌肉微血管胰岛素抵抗和小动脉内皮功能障碍，并降低肌肉毛细血管密度。同时给予HFD喂养大鼠利拉鲁肽可预防所有这些变化，并改善胰岛素刺激的葡萄糖处置。这些与AMPK磷酸化和VEGF及其受体的表达显著增加有关。结论：GLP-1受体激动剂可能通过改善胰岛素抵抗过程中微血管胰岛素敏感性和肌毛细血管密度发挥其有益的血糖调节作用，早期应用GLP-1受体激动剂可减轻代谢性胰岛素抵抗，预防糖尿病心血管并发症。
Muscle microvasculature critically regulates endothelial exchange surface area to facilitate trans-endothelial delivery of insulin, nutrients, and oxygen to myocytes. Insulin resistance blunts insulin-mediated microvascular recruitment and decreases muscle capillary density; both contribute to lower microvascular blood volume. Glucagon-like peptide 1 (GLP-1) and its analogs are able to dilate blood vessels and stimulate endothelial cell proliferation. In this study, we aim to determine the effects of sustained stimulation of the GLP-1 receptors on insulin-mediated capillary recruitment and metabolic insulin responses, small arterial endothelial function, and muscle capillary density. Rats were fed a high-fat diet (HFD) for 4 wk with or without simultaneous administration of liraglutide and subjected to a euglycemic hyperinsulinemic clamp for 120 min after an overnight fast. Insulin-mediated muscle microvascular recruitment and muscle oxygenation were determined before and during insulin infusion. Muscle capillary density was determined and distal saphenous artery used for determination of endothelial function and insulin-mediated vasodilation. HFD induced muscle microvascular insulin resistance and small arterial vessel endothelial dysfunction and decreased muscle capillary density. Simultaneous treatment of HFD-fed rats with liraglutide prevented all of these changes and improved insulin-stimulated glucose disposal. These were associated with a significantly increased AMPK phosphorylation and the expressions of VEGF and its receptors. We conclude that GLP-1 receptor agonists may exert their salutary glycemic effect via improving microvascular insulin sensitivity and muscle capillary density during the development of insulin resistance, and early use of GLP-1 receptor agonists may attenuate metabolic insulin resistance as well as prevent cardiovascular complications of diabetes.