Metformin prevents endothelial oxidative stress and microvascular insulin resistance during obesity development in male rats.
Metformin prevents endothelial oxidative stress and microvascular insulin resistance during obesity development in male rats.
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二甲双胍可预防雄性大鼠肥胖发展过程中的内皮氧化应激和微血管胰岛素抵抗。
DOI：
10.1152/ajpendo.00240.2021
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Liu,Zhenqi
中科院分区：
文献类型：
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作者：
Liu,Jia;Aylor,KevinW;Chai,Weidong;Barrett,EugeneJ;Liu,Zhenqi
胰岛素增加肌肉微血管灌注，这有助于其在肌肉中的代谢作用，但这种作用在肥胖症中受损。二甲双胍改善内皮功能超出其降糖作用。我们的目的是研究二甲双胍是否可以预防肥胖发展过程中的微血管胰岛素抵抗和内皮功能障碍。对成年雄性大鼠喂食高脂饲料（HFD），同时给予或不给予二甲双胍，持续2或4周。胰岛素的代谢和微血管作用，确定使用联合正常血糖-高胰岛素钳夹和超声造影方法。与普通饲料喂养的对照组相比，HFD喂养增加了身体肥胖，但没有额外的体重增加，这与胰岛素介导的全身葡萄糖处置的显着减少和胰岛素诱导的肌肉微血管募集的废除有关。二甲双胍同时给药早在2周时就完全挽救了胰岛素诱导的肌肉微血管募集，并在第4周时使胰岛素介导的全身葡萄糖处置正常化。在二甲双胍治疗的大鼠中，第2周胰岛素微血管和代谢作用之间的不同反应伴随着内皮氧化应激和血管炎症的减少，以及内皮功能和血管胰岛素信号的改善。总之，二甲双胍可以通过减轻肥胖发展过程中的内皮氧化应激和血管炎症来预防微血管胰岛素抵抗和内皮功能障碍的发展。新&值得注意的是肌肉微血管胰岛素作用有助于胰岛素介导的葡萄糖使用。微血管胰岛素抵抗是饮食诱导肥胖的早期事件，与血管炎症相关。二甲双胍有效降低内皮氧化应激，改善内皮功能，并防止肥胖发展过程中的微血管胰岛素抵抗。这些可能有助于二甲双胍有益的糖尿病预防和心血管保护作用。
Insulin increases muscle microvascular perfusion, which contributes to its metabolic action in muscle, but this action is impaired in obesity. Metformin improves endothelial function beyond its glucose lowering effects. We aim to examine whether metformin could prevent microvascular insulin resistance and endothelial dysfunction during the development of obesity. Adult male rats were fed a high-fat diet (HFD) with or without simultaneous metformin administration for either 2 or 4 wk. Insulin’s metabolic and microvascular actions were determined using a combined euglycemic-hyperinsulinemic clamp and contrast-enhanced ultrasound approach. Compared with chow-fed controls, HFD feeding increased body adiposity without excess body weight gain, and this was associated with a marked decrease in insulin-mediated whole body glucose disposal and abolishment of insulin-induced muscle microvascular recruitment. Simultaneous administration of metformin fully rescued insulin-induced muscle microvascular recruitment as early as 2 wk and normalized insulin-mediated whole body glucose disposal atweek 4. The divergent responses between insulin’s microvascular and metabolic actions seen atweek 2were accompanied with reduced endothelial oxidative stress and vascular inflammation, and improved endothelial function and vascular insulin signaling in metformin-treated rats. In conclusions, metformin could prevent the development of microvascular insulin resistance and endothelial dysfunction by alleviating endothelial oxidative stress and vascular inflammation during obesity development.NEW & NOTEWORTHYMuscle microvascular insulin action contributes to insulin-mediated glucose use. Microvascular insulin resistance is an early event in diet-induced obesity and is associated with vascular inflammation. Metformin effectively reduces endothelial oxidative stress, improves endothelial function, and prevents microvascular insulin resistance during obesity development. These may contribute to metformin’s salutary diabetes prevention and cardiovascular protective actions.