Projects per year
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.
Original language | English |
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Pages (from-to) | 652-665 |
Number of pages | 14 |
Journal | Circulation Research |
Volume | 119 |
Issue number | 5 |
Early online date | 14 Jul 2016 |
DOIs | |
Publication status | Published - 19 Aug 2016 |
Keywords
- metformin
- NF-κB
- diabetes mellitus
- heart failure
- metabolism
- inflammation
- pharmacology
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Dive into the research topics of 'Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status'. Together they form a unique fingerprint.Projects
- 3 Finished
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Moving Towards a New Personalised Medicine Approach to Primary Prevention in Diabetes: The First Steps
Dow, E. (Investigator), Lang, C. (Investigator), McCrimmon, R. (Investigator) & Struthers, A. (Investigator)
5/08/15 → 4/09/17
Project: Research
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MetfoRmin and its Effects on Myocardial Dimension and Left Ventricular Hypertrophy in Normotensive Patients with Coronary Artery Disease (MET-REMODEL Trial)
George, J. (Investigator), Houston, G. (Investigator), Lang, C. (Investigator) & Struthers, A. (Investigator)
1/10/14 → 31/12/17
Project: Research
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Investigation of the Target of Metformin
Prescott, A. (Investigator) & Rena, G. (Investigator)
1/05/13 → 30/04/16
Project: Research
Press/Media
Profiles
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Rena, Graham
- Diabetes Endocrinology and Reproductive Biology - Professor (Teaching and Research) of CARDIOVASCULAR AND METABOLIC MEDICINE
Person: Academic