Ayala Julio E, Bracy Deanna P, Julien Brianna M, Rottman Jeffrey N, Fueger Patrick T, Wasserman David H
Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, 2200 Pierce Ave., 702 Light Hall, Nashville, TN 37232, USA.
Diabetes. 2007 Apr;56(4):1025-33. doi: 10.2337/db06-0883. Epub 2007 Jan 17.
Stimulation of nitric oxide-cGMP signaling results in vascular relaxation and increased muscle glucose uptake. We show that chronically inhibiting cGMP hydrolysis with the phosphodiesterase-5 inhibitor sildenafil improves energy balance and enhances in vivo insulin action in a mouse model of diet-induced insulin resistance. High-fat-fed mice treated with sildenafil plus L-arginine or sildenafil alone for 12 weeks had reduced weight and fat mass due to increased energy expenditure. However, uncoupling protein-1 levels were not increased in sildenafil-treated mice. Chronic treatment with sildenafil plus L-arginine or sildenafil alone increased arterial cGMP levels but did not adversely affect blood pressure or cardiac morphology. Sildenafil treatment, with or without l-arginine, resulted in lower fasting insulin and glucose levels and enhanced rates of glucose infusion, disappearance, and muscle glucose uptake during a hyperinsulinemic (4 mU x kg(-1) x min(-1))-euglycemic clamp in conscious mice. These effects occurred without an increase in activation of muscle insulin signaling. An acute treatment of high fat-fed mice with sildenafil plus l-arginine did not improve insulin action. These results show that phosphodiesterase-5 is a potential target for therapies aimed at preventing diet-induced energy imbalance and insulin resistance.
一氧化氮 - 环磷酸鸟苷（NO - cGMP）信号通路的激活会导致血管舒张以及肌肉葡萄糖摄取增加。我们发现，使用磷酸二酯酶 - 5抑制剂西地那非长期抑制cGMP水解，可改善饮食诱导的胰岛素抵抗小鼠模型的能量平衡并增强体内胰岛素作用。高脂喂养的小鼠，用西地那非加L - 精氨酸或单独使用西地那非治疗12周后，由于能量消耗增加，体重和脂肪量减少。然而，西地那非治疗的小鼠中解偶联蛋白 - 1水平并未升高。西地那非加L - 精氨酸或单独使用西地那非长期治疗可提高动脉cGMP水平，但对血压或心脏形态无不良影响。在清醒小鼠的高胰岛素血症（4 mU x kg(-1) x min(-1)） - 正常血糖钳夹实验中，无论是否添加L - 精氨酸，西地那非治疗均可降低空腹胰岛素和葡萄糖水平，并提高葡萄糖输注、消失及肌肉葡萄糖摄取率。这些作用在肌肉胰岛素信号激活未增加的情况下发生。高脂喂养的小鼠急性给予西地那非加L - 精氨酸并不能改善胰岛素作用。这些结果表明，磷酸二酯酶 - 5是旨在预防饮食诱导的能量失衡和胰岛素抵抗的治疗的潜在靶点。
