Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status.
Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status.
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DOI：
10.1161/circresaha.116.308445
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发表时间：
2016-08-19
影响因子：
20.1
通讯作者：
Rena G
中科院分区：
文献类型：
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作者：
Cameron AR;Morrison VL;Levin D;Mohan M;Forteath C;Beall C;McNeilly AD;Balfour DJ;Savinko T;Wong AK;Viollet B;Sakamoto K;Fagerholm SC;Foretz M;Lang CC;Rena G
文本中提供了补充数字内容。糖尿病药物二甲双胍正在研究其在心血管疾病中的作用，但其潜在益处的分子机制尚不清楚。在这里，我们研究了该药物的抗炎作用及其与抗高血糖特性的关系。在健康动物的原代肝细胞中，二甲双胍和 IKKβ（κ B 激酶抑制剂）抑制剂 BI605906 均能抑制肿瘤坏死因子-α 依赖性 IκB 降解以及促炎介质白介素-6、白细胞介素-1β 和 CXCL1/2（C-X-C 基序配体 1/2）的表达。二甲双胍抑制 IKKα/β 激活，这种效应可以与某些代谢作用分开，因为 BI605906 没有模拟二甲双胍对脂肪生成基因表达、葡萄糖生成和 AMP 激活蛋白激酶激活的影响。同样，线粒体抑制 IκB 降解也不需要 AMP 激活的蛋白激酶。与离散的抗炎作用一致，在巨噬细胞中，二甲双胍特异性减弱促炎细胞因子的分泌，而不抑制 M1/M2 分化或激活。在一个大型的初治糖尿病人群队列中，我们观察到用二甲双胍或磺脲类单药治疗后全身炎症标志物、中性粒细胞与淋巴细胞比率的差异。与磺脲类暴露相比，二甲双胍使 8 至 16 个月后的平均对数转化中性粒细胞与淋巴细胞比率降低了 0.09 U（95% 置信区间，0.02-0.17；P=0.013），并增加了 8 至 16 个月后中性粒细胞与淋巴细胞比率低于基线的可能性（比值比，1.83；95% 置信度） 区间，1.22–2.75； P=0.00364）。在非糖尿病心力衰竭双盲安慰剂对照试验（试验注册号：NCT00473876）中跟踪这些发现后，二甲双胍抑制了血浆细胞因子，包括与衰老相关的细胞因子 CCL11（C-C 基序趋化因子配体 11）。我们的结论是，无论糖尿病状况如何，二甲双胍都具有抗炎特性。这可能会加速非糖尿病心血管疾病组药物效用的研究。试验注册名称：TAYSIDE 试验（二甲双胍治疗胰岛素抵抗左心室 [LV] 功能障碍）。网址：https://www.clinicaltrials.gov。唯一标识符：NCT00473876。
Supplemental Digital Content is available in the text. The diabetes mellitus drug metformin is under investigation in cardiovascular disease, but the molecular mechanisms underlying possible benefits are poorly understood. Here, we have studied anti-inflammatory effects of the drug and their relationship to antihyperglycemic properties. In primary hepatocytes from healthy animals, metformin and the IKKβ (inhibitor of kappa B kinase) inhibitor BI605906 both inhibited tumor necrosis factor-α–dependent IκB degradation and expression of proinflammatory mediators interleukin-6, interleukin-1β, and CXCL1/2 (C-X-C motif ligand 1/2). Metformin suppressed IKKα/β activation, an effect that could be separated from some metabolic actions, in that BI605906 did not mimic effects of metformin on lipogenic gene expression, glucose production, and AMP-activated protein kinase activation. Equally AMP-activated protein kinase was not required either for mitochondrial suppression of IκB degradation. Consistent with discrete anti-inflammatory actions, in macrophages, metformin specifically blunted secretion of proinflammatory cytokines, without inhibiting M1/M2 differentiation or activation. In a large treatment naive diabetes mellitus population cohort, we observed differences in the systemic inflammation marker, neutrophil to lymphocyte ratio, after incident treatment with either metformin or sulfonylurea monotherapy. Compared with sulfonylurea exposure, metformin reduced the mean log-transformed neutrophil to lymphocyte ratio after 8 to 16 months by 0.09 U (95% confidence interval, 0.02–0.17; P=0.013) and increased the likelihood that neutrophil to lymphocyte ratio would be lower than baseline after 8 to 16 months (odds ratio, 1.83; 95% confidence interval, 1.22–2.75; P=0.00364). Following up these findings in a double-blind placebo controlled trial in nondiabetic heart failure (trial registration: NCT00473876), metformin suppressed plasma cytokines including the aging-associated cytokine CCL11 (C-C motif chemokine ligand 11). We conclude that anti-inflammatory properties of metformin are exerted irrespective of diabetes mellitus status. This may accelerate investigation of drug utility in nondiabetic cardiovascular disease groups. Name of the trial registry: TAYSIDE trial (Metformin in Insulin Resistant Left Ventricular [LV] Dysfunction). URL: https://www.clinicaltrials.gov. Unique identifier: NCT00473876.