Relaxin Treatment Reverses Insulin Resistance in Mice Fed a High-Fat Diet
Relaxin Treatment Reverses Insulin Resistance in Mice Fed a High-Fat Diet
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DOI：
10.2337/db13-0033
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发表时间：
2013-09-01
期刊：
影响因子：
7.7
通讯作者：
Wasserman, David H.
中科院分区：
文献类型：
--
作者：
Bonner, Jeffrey S.;Lantier, Louise;Wasserman, David H.
内源性激素松弛素增加血管反应性和血管生成。我们证明，在高胰岛素-正常血糖钳夹过程中，瘦 C57BL/6J 小鼠中的急性松弛素输注可增强骨骼肌灌注并增加肌肉葡萄糖摄取。然而，在喂食高脂肪 (HF) 饮食 13 周的小鼠中，并未出现急性效应。相比之下，喂食 HF 饮食 13 周并在饮食的最后 3 周持续使用松弛素治疗的小鼠表现出空腹血糖下降。胰岛素刺激的全身葡萄糖消失和肝葡萄糖产生的百分比抑制可通过慢性松弛素来纠正。外周葡萄糖利用率的增加是体内骨骼肌葡萄糖摄取增加的结果。松弛素干预可改善内皮依赖性血管反应性，并诱导骨骼肌毛细血管的两倍增殖。治疗的代谢效应并非归因于肌细胞胰岛素信号传导的变化。松弛素干预可逆转肝脏中III型胶原蛋白以及心脏中III型胶原蛋白和IV型胶原蛋白的积累；这是由高频喂食引起的。这些研究表明松弛素在治疗饮食引起的胰岛素抵抗和血管功能障碍方面具有潜力。松弛素提供了一种针对胰岛素作用的肌细胞外障碍的新型治疗方法，这对于胰岛素抵抗的发病机制至关重要。
The endogenous hormone relaxin increases vascular reactivity and angiogenesis. We demonstrate that acute relaxin infusion in lean C57BL/6J mice enhances skeletal muscle perfusion and augments muscle glucose uptake during a hyperinsulinemic-euglycemic clamp. However, an acute effect was absent in mice fed a high-fat (HF) diet for 13 weeks. In contrast, mice fed an HF diet for 13 weeks and continuously treated with relaxin for the final 3 weeks of the diet exhibited decreased fasting blood glucose. Insulin-stimulated whole-body glucose disappearance and percent suppression of hepatic glucose production are corrected by chronic relaxin. The increase in peripheral glucose utilization is a result of augmented in vivo skeletal muscle glucose uptake. Relaxin intervention improves endothelial-dependent vascular reactivity and induces a two-fold proliferation in skeletal muscle capillarity. The metabolic effects of the treatment are not attributed to changes in myocellular insulin signaling. Relaxin intervention reverses the accumulation of collagen III in the liver and collagen III and collagen IV in the heart; this is induced by HF feeding. These studies show the potential of relaxin in the treatment of diet-induced insulin resistance and vascular dysfunction. Relaxin provides a novel therapeutic approach targeting the extramyocellular barriers to insulin action, which are critical to the pathogenesis of insulin resistance.