TY - JOUR
T1 - Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status
AU - Cameron, A. R.
AU - Morrison, V. L.
AU - Levin, D.
AU - Mohan, M.
AU - Forteath, C.
AU - Beall, C.
AU - McNeilly, A. D.
AU - Balfour, D. J.
AU - Savinko, T.
AU - Wong, A. K.
AU - Viollet, B.
AU - Sakamoto, K.
AU - Fagerholm, S. C.
AU - Foretz, M.
AU - Lang, C. C.
AU - Rena, G.
N1 - 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 Rena, Graham 2016/7/16
PY - 2016
Y1 - 2016
N2 - The diabetes mellitus drug metformin is under investigation in cardiovascular disease, but the molecular mechanisms underlying possible benefits are poorly understood.|Here, we have studied anti-inflammatory effects of the drug and their relationship to antihyperglycemic properties.|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).|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.|Name of the trial registry: TAYSIDE trial (Metformin in Insulin Resistant Left Ventricular [LV] Dysfunction). URL: https://www.clinicaltrials.gov. Unique identifier: NCT00473876.
AB - The diabetes mellitus drug metformin is under investigation in cardiovascular disease, but the molecular mechanisms underlying possible benefits are poorly understood.|Here, we have studied anti-inflammatory effects of the drug and their relationship to antihyperglycemic properties.|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).|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.|Name of the trial registry: TAYSIDE trial (Metformin in Insulin Resistant Left Ventricular [LV] Dysfunction). URL: https://www.clinicaltrials.gov. Unique identifier: NCT00473876.
KW - Aged Animals Anti-Inflammatory Agents Cells, Cultured Cohort Studies Diabetes Mellitus Double-Blind Method Female Hepatocytes Humans Hypoglycemic Agents Male Metformin Mice Mice, Inbred C57BL Middle Aged Piperidines Retrospective Studies Sulfonamides NF-k
U2 - 10.1161/CIRCRESAHA.116.308445
DO - 10.1161/CIRCRESAHA.116.308445
M3 - Article
SN - 1524-4571
VL - 119
SP - 652
EP - 665
JO - Circulation Research
JF - Circulation Research
IS - 5
ER -
