Inorganic nitrite improves components of the metabolic syndrome independent of weight change in a murine model of obesity and insulin resistance.
Inorganic nitrite improves components of the metabolic syndrome independent of weight change in a murine model of obesity and insulin resistance.
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无机亚硝酸盐可改善代谢综合征的各个组成部分，与肥胖和胰岛素抵抗小鼠模型中的体重变化无关。
DOI：
10.1113/jp270386
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
O'Donnell,ChristopherP
中科院分区：
文献类型：
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作者：
Singamsetty,Srikanth;Watanabe,Yoshio;Guo,Lanping;Corey,Catherine;Wang,Yinna;Tejero,Jesus;McVerry,BryanJ;Gladwin,MarkT;Shiva,Sruti;O'Donnell,ChristopherP
要点亚硝酸盐是生物可利用的一氧化氮的内分泌来源，可以改善代谢功能。对遗传性肥胖小鼠外源施用亚硝酸盐可增强葡萄糖耐量并提高胰岛素敏感性，而与体重变化无关。外源性亚硝酸盐解偶联线粒体呼吸，减少 ATP 的生成，并增加骨骼肌中 AMP 激活蛋白激酶的磷酸化。外源性亚硝酸盐对代谢功能的不依赖于体重的改善与罗格列酮，表明亚硝酸盐对肥胖、胰岛素抵抗或糖尿病患者具有治疗功效的潜力。摘要亚硝酸盐作为生物活性一氧化氮的内分泌来源，影响血管反应性、血管生成和细胞保护。亚硝酸盐最近被证明具有代谢作用，尽管其在肥胖胰岛素抵抗状态下的作用和作用机制尚不清楚。我们使用频繁采样的静脉内葡萄糖耐量试验检查了葡萄糖耐量和胰岛素分泌，并使用高胰岛素正常血糖钳夹对肥胖男性患者进行了亚硝酸盐（100 mg kg−1day−1）或生理盐水（对照）7天的胰岛素敏感性检查，并比较了与罗格列酮（6 mg kg−1day−1）已知胰岛素增敏作用的反应。在体重匹配的条件下，亚硝酸盐相对于盐水和罗格列酮降低了血压，而只有罗格列酮能够有效降低肝葡萄糖输出和基础血糖。相对于生理盐水，亚硝酸盐和罗格列酮均改善了葡萄糖耐量（分别为 12,524 ± 602、12,811 ± 692vs.14,428 ± 335 mg（dl min）−1；P < 0.05）和胰岛素敏感性（8.6 ± 0.7、7.9 ± 0.3 vs.分别为 6.6 ± 0.5 mg kg−1min−1；P< 0.001)，但对胰岛素分泌没有影响。亚硝酸盐表现出线粒体呼吸的解偶联和肌肉中 ATP 生成的减少，这与线粒体生物发生或解偶联蛋白的激活无关。没有胰岛素刺激的 Akt 磷酸化，但亚硝酸盐增加了 AMP 激活蛋白激酶的磷酸化。我们得出的结论是，亚硝酸盐可以改善代谢综合征的两个关键组成部分，即血压和胰岛素敏感性，与体重无关，并且其有效性与罗格列酮相当。
Key pointsNitrite acts as an endocrine source of bioavailable nitric oxide that can improve metabolic function.Exogenous administration of nitrite to genetically obese mice enhanced glucose tolerance and increased insulin sensitivity independent of weight change.Exogenous nitrite uncoupled mitochondrial respiration, decreased the generation of ATP, and increased phosphorylation of AMP‐activated protein kinase in skeletal muscle.The weight‐independent improvements in metabolic function from exogenous nitrite were comparable to rosiglitazone, suggesting the potential for therapeutic efficacy of nitrite in obese, insulin‐resistant, or diabetic patients.AbstractNitrite acts as an endocrine source of bioactive nitric oxide, impacting vascular reactivity, angiogenesis and cytoprotection. Nitrite has recently been shown to have a metabolic role although its effects and mechanisms of action in the obese insulin‐resistant state are unknown. We examined glucose tolerance and insulin secretion using the frequently sampled intravenous glucose tolerance test and insulin sensitivity using the hyperinsulinaemic euglycaemic clamp in obese male oblepmice administered nitrite (100 mg kg−1day−1) or saline (control) for 7 days and compared responses to the known insulin‐sensitizing effects of rosiglitazone (6 mg kg−1day−1). Under weight‐matched conditions, nitrite lowered blood pressure relative to saline and rosiglitazone, whereas only rosiglitazone was effective at reducing hepatic glucose output and basal blood glucose. Both nitrite and rosiglitazone produced improvements, relative to saline, in glucose tolerance (12,524 ± 602, 12,811 ± 692vs.14,428 ± 335 mg (dl min)−1, respectively;P< 0.05) and insulin sensitivity (8.6 ± 0.7, 7.9 ± 0.3vs. 6.6 ± 0.5 mg kg−1min−1, respectively;P< 0.001), but there was no effect on insulin secretion. Nitrite exhibited an uncoupling of mitochondrial respiration and a decrease in ATP generation in muscle that was independent of mitochondrial biogenesis or activation of uncoupling proteins. There was no insulin‐stimulated phosphorylation of Akt, but nitrite increased the phosphorylation of AMP‐activated protein kinase. We conclude that nitrite improves two key components of the metabolic syndrome, blood pressure and insulin sensitivity, independent of weight and with effectiveness comparable to rosiglitazone.