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Anti-inflammatory effects of metformin irrespective of diabetes status

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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. and Rena, Graham (2016) Anti-inflammatory effects of metformin irrespective of diabetes status. Circulation research, 119 (5). pp. 652-65. doi:10.1161/CIRCRESAHA.116.308445 ISSN 1524-4571.

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Official URL: https://doi.org/10.1161/CIRCRESAHA.116.308445

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Abstract

Rationale:
The diabetes mellitus 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 antihyperglycemic properties.

Methods and Results:
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).

Conclusion:
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.

Item Type: Journal Article
Subjects: Q Science > QP Physiology
R Medicine > RB Pathology
R Medicine > RC Internal medicine
Divisions: Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Health Sciences
Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Health Sciences > Mental Health and Wellbeing
Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH): Metformin, Cardiovascular system -- Diseases , Diabetes , Heart failure, Inflammation, Metabolism, NF-kappa B (DNA-binding protein)
Journal or Publication Title: Circulation research
Publisher: Lippincott Williams & Wilkins
ISSN: 1524-4571
Official Date: 19 August 2016
Dates:
DateEvent
19 August 2016Published
13 July 2016Accepted
Volume: 119
Number: 5
Page Range: pp. 652-65
DOI: 10.1161/CIRCRESAHA.116.308445
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access (Creative Commons)
Date of first compliant deposit: 17 June 2019
Date of first compliant Open Access: 20 June 2019
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
MR/K012924/1[MRC] Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
12/0004625Diabetes UKhttp://dx.doi.org/10.13039/501100000361
UNSPECIFIEDSuomen Akatemiahttp://viaf.org/viaf/150026070
UNSPECIFIEDBiocentre (Viikki)http://viaf.org/viaf/149795314
CORDDIMÎle-de-France (France)http://viaf.org/viaf/137807822
UNSPECIFIEDSociété Francophone du Diabètehttp://dx.doi.org/10.13039/501100008966
PG/06/143/21897British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
PG/14/4/30539British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
UNSPECIFIEDElla ja Georg Ehrnroothin Säätiöhttp://dx.doi.org/10.13039/501100003502
ART-EXT-2010–2Alzheimer's Disease Research Foundationhttp://dx.doi.org/10.13039/100001449
13/00004647Diabetes UKhttp://dx.doi.org/10.13039/501100000361

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