title: Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status.
abstract: BACKGROUND
  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.
  
  
  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).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Name of the trial registry: TAYSIDE trial (Metformin in Insulin Resistant Left Ventricular [LV] Dysfunction). URL: https://www.clinicaltrials.gov. Unique identifier: NCT00473876.
authors.affiliation: 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.).
authors.forename: Amy R
authors.initials: AR
authors.lastname: Cameron
authors.affiliation: 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.).
authors.forename: Vicky L
authors.initials: VL
authors.lastname: Morrison
authors.affiliation: 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.).
authors.forename: Daniel
authors.initials: D
authors.lastname: Levin
authors.affiliation: 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.).
authors.forename: Mohapradeep
authors.initials: M
authors.lastname: Mohan
authors.affiliation: 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.).
authors.forename: Calum
authors.initials: C
authors.lastname: Forteath
authors.affiliation: 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.).
authors.forename: Craig
authors.initials: C
authors.lastname: Beall
authors.affiliation: 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.).
authors.forename: Alison D
authors.initials: AD
authors.lastname: McNeilly
authors.affiliation: 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.).
authors.forename: David J K
authors.initials: DJ
authors.lastname: Balfour
authors.affiliation: 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.).
authors.forename: Terhi
authors.initials: T
authors.lastname: Savinko
authors.affiliation: 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.).
authors.forename: Aaron K F
authors.initials: AK
authors.lastname: Wong
authors.affiliation: 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.).
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.affiliation: 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.).
authors.forename: Kei
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: 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.).
authors.forename: Susanna C
authors.initials: SC
authors.lastname: Fagerholm
authors.affiliation: 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.).
authors.forename: Marc
authors.initials: M
authors.lastname: Foretz
authors.affiliation: 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.). c.c.lang@dundee.ac.uk g.rena@dundee.ac.uk.
authors.forename: Chim C
authors.initials: CC
authors.lastname: Lang
authors.affiliation: 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.). c.c.lang@dundee.ac.uk g.rena@dundee.ac.uk.
authors.forename: Graham
authors.initials: G
authors.lastname: Rena
mesh_terms: D000368:Aged; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D015331:Cohort Studies; D003920:Diabetes Mellitus / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010880:Piperidines / Q000494:pharmacology; D012189:Retrospective Studies; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; C556457:BI605906; D007004:Hypoglycemic Agents; D010880:Piperidines; D013449:Sulfonamides; D008687:Metformin
keywords: NF-kappa B; cardiovascular diseases; diabetes mellitus; heart failure; inflammation; metabolism; metformin