Metformin improves putative longevity effectors in peripheral mononuclear cells from subjects with prediabetes. A randomized controlled trial
Metformin improves putative longevity effectors in peripheral mononuclear cells from subjects with prediabetes. A randomized controlled trial
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DOI：
10.1016/j.numecd.2015.03.007
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发表时间：
2015-07-01
影响因子：
3.9
通讯作者：
Avogaro, A.
中科院分区：
文献类型：
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作者：
de Kreutzenberg, S. Vigili;Ceolotto, G.;Avogaro, A.
背景和目的：糖尿病前期增加心血管风险，并与过高的死亡率相关。在临床前模型中，二甲双胍已被证明具有延缓衰老的作用。方法与结果：在一项随机、单盲、安慰剂对照试验中，38名糖尿病前期受试者接受二甲双胍(1500 mg/天)或安慰剂治疗2个月。在基线和治疗后，我们收集人体测量和代谢参数。检测外周血单个核细胞(PBMC)中SIRT1、mTOR、P53、p66Shc、SIRT1活性、AMPK活性、端粒长度和SIRT1启动子染色质可及性的基因和蛋白水平。与基线相比，二甲双胍显著改善代谢参数和胰岛素敏感性，增加SIRT1基因/蛋白表达和SIRT1启动子染色质可及性，增加受试者外周血单个核细胞mTOR基因表达并伴随p70S6K磷酸化降低，并改变血浆N-糖链分布。与安慰剂相比，二甲双胍增加了SIRT1蛋白的表达，降低了p70S6K的磷酸化(mTOR活性的替代指标)。与安慰剂相比，二甲双胍对血浆N-葡聚糖的修饰也更有利。结论：在糖尿病前期患者中，二甲双胍改善了动物模型中已被证明可调节寿命的效应通路。(C)2015爱思唯尔B.V.保留所有权利。
Background and aims: Prediabetes increases cardiovascular risk and is associated with excess mortality. In preclinical models, metformin has been shown to exert anti-ageing effects. In this study, we sought to assess whether metformin modulates putative effector longevity programs in prediabetic subjects.Methods and results: In a randomized, single-blind, placebo-controlled trial, 38 prediabetic subjects received metformin (1500 mg/day) or placebo for 2 months. At baseline and after treatment, we collected anthropometric and metabolic parameters. Gene and protein levels of SIRT1, mTOR, p53, p66Shc, SIRT1 activity, AMPK activation, telomere length, and SIRT1 promoter chromatin accessibility were determined in peripheral blood mononuclear cells (PBMCs). Plasma N-glycans, non-invasive surrogate markers of ageing, were also analysed.Compared to baseline, metformin significantly improved metabolic parameters and insulin sensitivity, increased SIRT1 gene/protein expression and SIRT1 promoter chromatin accessibility, elevated mTOR gene expression with concomitant reduction in p70S6K phosphorylation in subjects' PBMCs, and modified the plasma N-glycan profile. Compared to placebo, metformin increased SIRT1 protein expression and reduced p70S6K phosphorylation (a proxy of mTOR activity). Plasma N-glycans were also favourably modified by metformin compared to placebo.Conclusion: In individuals with prediabetes, metformin ameliorated effector pathways that have been shown to regulate longevity in animal models. (C) 2015 Elsevier B.V. All rights reserved.