dc.contributor.author | Cameron, AR | |
dc.contributor.author | Morrison, V | |
dc.contributor.author | Levin, D | |
dc.contributor.author | Mohan, M | |
dc.contributor.author | Forteath, C | |
dc.contributor.author | Beall, C | |
dc.contributor.author | McNeilly, AD | |
dc.contributor.author | Balfour, DJ | |
dc.contributor.author | Savinko, T | |
dc.contributor.author | Wong, AK | |
dc.contributor.author | Viollet, B | |
dc.contributor.author | Sakamoto, K | |
dc.contributor.author | Fagerholm, SC | |
dc.contributor.author | Foretz, M | |
dc.contributor.author | Lang, CC | |
dc.contributor.author | Rena, G | |
dc.date.accessioned | 2016-07-29T09:28:24Z | |
dc.date.issued | 2016-07-14 | |
dc.description.abstract | RATIONALE: The diabetes drug metformin is under investigation in cardiovascular disease but the molecular mechanisms underlying possible benefits are poorly understood. OBJECTIVE: Here we have studied anti-inflammatory effects of the drug and their relationship to anti-hyperglycaemic properties. METHODS AND RESULTS: In primary hepatocytes from healthy animals, metformin and the IKKβ inhibitor BI605906 both inhibited TNFα-dependent IκB degradation and expression of pro-inflammatory mediators IL-6, IL-1b, and CXCL1/2. Metformin suppressed IKKα/β activation, an effect which could be separated from some metabolic actions, in that BI605906 did not mimic effects of metformin on lipogenic gene expression, glucose production and AMPK activation. Equally AMPK was not required either for mitochondrial suppression of IκB degradation. Consistent with discrete anti-inflammatory actions, in macrophages metformin specifically blunted secretion of pro-inflammatory cytokines, without inhibiting M1/M2 differentiation or activation. In a large treatment naïve diabetes population cohort, we observed differences in the systemic inflammation marker, Neutrophil to Lymphocyte Ratio (NLR), following incident treatment with either metformin or sulfonylurea monotherapy. Compared to sulfonylurea exposure, metformin reduced the mean log-transformed NLR after 8-16 months by 0.09 units (95% CI=0.02-0.17, p=0.013), and increased the likelihood that NLR would be lower than baseline after 8-16 months (OR 1.83, 95% CI=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 ageing-associated cytokine CCL11. CONCLUSIONS: We conclude that anti-inflammatory properties of metformin are exerted irrespective of diabetes status. This may accelerate investigation of drug utility in non-diabetic cardiovascular disease groups. | en_GB |
dc.description.sponsorship | G.R. acknowledges funding from MRC (MR/K012924/1) and the Diabetes UK RW and JM Collins
studentship, supporting C.F. (12/0004625). S.F. acknowledges funding from the Academy of Finland
and Biocentrum Helsinki. M.F. acknowledges funding from the Région Ile de France-CORDDIM and
by the Société Francophone du Diabète. C.C.L. acknowledges support from the British Heart
Foundation (grant number PG/06/143/21897 and PG/14/4/30539). A.K.F.W acknowledges support
from the British Heart Foundation (grant number PG/06/143/21897). M.P.M. acknowledges fellowship support from the British Heart Foundation (grant number PG/14/4/30539). V.M. was supported by the Ella and Georg Ehrnrooth foundation and D.J.K.B. acknowledges funding from Alzheimer’s Research UK, grant number ART-EXT-2010-2. C.B. is an RD Lawrence Fellow (Diabetes UK grant number: 13/00004647). | en_GB |
dc.identifier.citation | Published online before print July 14, 2016 | en_GB |
dc.identifier.doi | 10.1161/CIRCRESAHA.116.308445 | |
dc.identifier.uri | http://hdl.handle.net/10871/22788 | |
dc.language.iso | en | en_GB |
dc.publisher | American Heart Association | en_GB |
dc.relation.url | http://www.ncbi.nlm.nih.gov/pubmed/27418629 | en_GB |
dc.rights | This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited. | en_GB |
dc.subject | NF-kB | en_GB |
dc.subject | diabetes mellitus | en_GB |
dc.subject | heart failure | en_GB |
dc.subject | inflammation | en_GB |
dc.subject | metabolism | en_GB |
dc.subject | metformin | en_GB |
dc.subject | pharmacology | en_GB |
dc.title | Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2016-07-29T09:28:24Z | |
dc.description | Final version of the article available from American Heart Association via the DOI in this record. | en_GB |
dc.identifier.journal | Circulation Research | en_GB |