Anti-inflammatory effects of metformin irrespective of diabetes status

Cameron, A. E. et al. (2016) Anti-inflammatory effects of metformin irrespective of diabetes status. Circulation Research, 119(5), pp. 652-665. (doi:10.1161/CIRCRESAHA.116.308445) (PMID:27418629) (PMCID:PMC4990459)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Morrison, Dr Vicky
Authors: Cameron, A. E., Morrison, V., Levin, D., Mohan, M., Forteath, C., Beall, C., McNeilly, A. D., Balfour, D. J.K., Savinko, T., Wong, A. K.F., Viollet, B., Sakamoto, K., Fagerholm, S. C., Foretz, M., Lang, C. C., and Rena, G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Circulation Research
Publisher:Wolters Kluwer
ISSN:0009-7330
ISSN (Online):1524-4571
Published Online:14 July 2016
Copyright Holders:Copyright © 2016 American Heart Association Inc.
First Published:First published in Circulation Research 119(5): 652-665
Publisher Policy:Reproduced under a Creative Commons License

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