Cameron Amy R, Morrison Vicky L, Levin Daniel, Mohan Mohapradeep, Forteath Calum, Beall Craig, McNeilly Alison D, Balfour David J K, Savinko Terhi, Wong Aaron K F, Viollet Benoit, Sakamoto Kei, Fagerholm Susanna C, Foretz Marc, Lang Chim C, Rena Graham
From the Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School (A.R.C., D.L., M.M., C.F., C.B., A.D.M., A.K.F.W., C.C.L., G.R.) and Division of Neuroscience, Ninewells Hospital and Medical School (D.J.K.B.), MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences (K.S.), University of Dundee, Scotland, United Kingdom; Institute of Biotechnology, University of Helsinki, Finland (V.L.M., T.S., S.C.F.); INSERM U1016, Institut Cochin, CNRS UMR8104, Université Paris Descartes, Sorbonne Paris Cité, France (B.V., M.F.); and Institute of Infection, Immunity, and Inflammation, University of Glasgow, United Kingdom (V.L.M.).
Circ Res. 2016 Aug 19;119(5):652-65. doi: 10.1161/CIRCRESAHA.116.308445. Epub 2016 Jul 14.
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.
糖尿病药物二甲双胍正在心血管疾病领域接受研究，但其潜在益处的分子机制尚不清楚。
在此，我们研究了该药物的抗炎作用及其与降血糖特性的关系。
在来自健康动物的原代肝细胞中，二甲双胍和IKKβ（κB激酶抑制剂）抑制剂BI605906均抑制肿瘤坏死因子-α依赖性IκB降解以及促炎介质白细胞介素-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，这一作用可与某些代谢作用区分开来，因为BI605906无法模拟二甲双胍对脂肪生成基因表达、葡萄糖生成和AMP激活的蛋白激酶激活的影响。同样，线粒体对IκB降解的抑制也不需要AMP激活的蛋白激酶。与离散的抗炎作用一致，在巨噬细胞中，二甲双胍特异性地减弱促炎细胞因子的分泌，而不抑制M1/M2分化或激活。在一个未经治疗的大型糖尿病患者队列中，我们观察到在接受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值存在差异。与磺脲类药物相比，二甲双胍在8至16个月后将平均对数转换后的中性粒细胞与淋巴细胞比值降低了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值低于基线的可能性（比值比，1.83；95%置信区间，1.22 - 2.75；P = 0.00364）。在一项针对非糖尿病心力衰竭患者的双盲安慰剂对照试验（试验注册号：NCT00473876）中对这些发现进行随访时，二甲双胍抑制血浆细胞因子，包括与衰老相关的细胞因子CCL11（C-C基序趋化因子配体11）。
我们得出结论，二甲双胍的抗炎特性与糖尿病状态无关。这可能会加速对该药物在非糖尿病心血管疾病群体中效用的研究。
试验注册机构名称：泰赛德试验（二甲双胍治疗胰岛素抵抗性左心室功能障碍）。网址：https://www.clinicaltrials.gov。唯一标识符：NCT00473876。
