Metformin Inhibits Proinflammatory Responses and Nuclear Factor-κB in Human Vascular Wall Cells

Isoda, Kikuo; Young, James L.; Zirlik, Andreas; MacFarlane, Lindsey A.; Tsuboi, Naotake; Gerdes, Norbert; Schönbeck, Uwe; Libby, Peter

doi:10.1161/01.atv.0000201938.78044.75

Cited by 445 publications

(373 citation statements)

References 48 publications

(47 reference statements)

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“…Studies indicate that metformin may exert direct effects on arterial cells. Thus, metformin appears to reduce the release of some proinflammatory cytokines through nuclear factor-kB (39), and, moreover, in vitro experiments on human aortic smooth muscle cells demonstrated that metformin inhibits leptin-induced nuclear factor-kB activation (40). Our findings fit well with the notion that metformin may exert direct beneficial effects in the arterial wall and expand this idea by pointing toward metformininduced alterations in the metabolism of the ECM molecule fibulin-1.…”

Section: Discussionsupporting

confidence: 85%

Metformin, but Not Rosiglitazone, Attenuates the Increasing Plasma Levels of a New Cardiovascular Marker, Fibulin-1, in Patients With Type 2 Diabetes

et al. 2014

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OBJECTIVEThe extracellular matrix protein fibulin-1 is upregulated in the arterial wall in type 2 diabetes (T2D) and circulates in increased concentrations in diabetes. Metformin is an antidiabetic drug with beneficial cardiovascular disease effects in diabetes. We hypothesized that metformin would influence the increased level of plasma fibulin-1 in diabetes. RESEARCH DESIGN AND METHODSAfter a 4-week run-in period, 371 eligible patients with T2D were randomized to treatment groups in a factorial design including insulin alone (control), +metfor-min, +rosiglitazone, or +both metformin and rosiglitazone. Plasma fibulin-1 was analyzed at the beginning of the study and after 18 and 24 months. RESULTSPlasma fibulin-1 increased in all groups throughout the 2-year period; however, the increase was strongly attenuated among patients treated with metformin. A highly significant difference was observed when the mean change in plasma fibulin-1 was compared between metformin-and non-metformin-treated individuals both at 18 and 24 months of treatment, but rosiglitazone had no effect. Metformin and rosiglitazone alone reduced the HbA 1c levels to comparable levels and in combination even further. CONCLUSIONSMetformin attenuates the increase in plasma fibulin-1 concentrations in T2D, independently of glycemic effects. Changes in fibulin-1 may reflect an important element in diabetic arteriopathy that can be influenced by metformin. Increased mortality and morbidity owing to a higher incidence of cardiovascular diseases (CVDs) is a major clinical challenge in type 2 diabetes (T2D) (1,2). Several studies have demonstrated that management of hypertension, LDL cholesterol, and other major CVD risk factors have reduced micro-and macrovascular complications in patients with T2D; however, optimal risk reduction is still not achieved when these important risk factors are controlled, indicating that further attempts are needed to control the CVD risk burden (3-5). One assumption is that improvement

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Section: Discussionsupporting

confidence: 85%

Metformin, but Not Rosiglitazone, Attenuates the Increasing Plasma Levels of a New Cardiovascular Marker, Fibulin-1, in Patients With Type 2 Diabetes

et al. 2014

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“…the AMPactivated kinase (AMPK). The activated AMPK, in turn, inhibits the TNF-a-induced activation of the nuclear transcription factor, NF-kB, and hereby the NF-kBinduced gene expression of sICAM-1, sVCAM and sE-selectin (53,54). Hence, the observed decrease in several CVD biomarkers, in the present study, may be explained by actions of metformin via the pathway of AMPK, TNF-a and NF-kB.…”

Section: Discussionsupporting

confidence: 58%

Impact of metformin versus repaglinide on non-glycaemic cardiovascular risk markers related to inflammation and endothelial dysfunction in non-obese patients with type 2 diabetes

Lund

Tarnow

Stehouwer

et al. 2008

European Journal of Endocrinology

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Objective: In patients with type 2 diabetes mellitus (T2DM), biomarkers reflecting inflammation and endothelial dysfunction have been linked to cardiovascular disease (CVD biomarkers) and metabolic regulation. In T2DM patients, metformin and insulin secretagogues have demonstrated equal antihyperglycaemic potency. Here, we report the effect of metformin versus an insulin secretagogue, repaglinide, on CVD biomarkers in non-obese T2DM patients. Design and methods: Single-centre, double-masked, double-dummy, crossover study during 2!4 months involving 96 non-obese (body mass index%27 kg/m 2 ) insulin-naïve T2DM patients. At enrolment, previous oral hypoglycaemic agents were stopped and the patients entered a 1-month runin on diet-only treatment. Hereafter, patients were randomized to either 2 mg repaglinide thrice daily followed by 1 g metformin twice daily or vice versa each during 4 months with a 1-month washout between interventions. Results: Levels of tumour necrosis factor-a, plasminogen activator inhibitor-1 antigen, tissue-type plasminogen activator antigen, von Willebrand factor, soluble intercellular adhesion molecule-1 and soluble E-selectin were significantly lower during metformin versus repaglinide treatments. In contrast, Amadori albumin and heart rate were higher during metformin versus repaglinide. Levels of interleukin-6, fibrinogen, soluble vascular cell adhesion molecule-1, asymmetric dimethylarginine and advanced glycation end products as well as glycaemic levels (previously reported) and 24-h blood pressure were similar between treatments. Adjustment for known macrovascular disease did not affect the between-treatment effects. Conclusions: In non-obese T2DM patients, metformin was more effective in reducing selected biomarkers reflecting inflammation and endothelial dysfunction compared with repaglinide despite similar glycaemic levels between treatments.European Journal of Endocrinology 158 631-641

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“…Treatment with metformin increased insulin-induced Akt phosphorylation in cultured HepG2 cells [52] and HGL5 cells [53], as well as in vivo in rat heart [54]. In contrast, metformin reduced Akt phosphorylation stimulated by interleukin-1b or by high glucose [55], whereas Akt phosphorylation was unaltered by metformin treatment in H4IIE cells [56] and in vivo in diabetic muscle [57][58][59]. These mixed results with metformin indicate that context (i.e., cell type and stimulus) as well as possible multiple targets of metformin cause this diversity of effects on Akt phosphorylation.…”

Section: Discussionmentioning

confidence: 96%

AMP-activated protein kinase (AMPK) activating agents cause dephosphorylation of Akt and glycogen synthase kinase-3

King

Lee

Jope

2006

Biochemical Pharmacology

120

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AMP-activated protein kinase (AMPK) is a key cellular sensor of reduced energy supply that is activated by increases in the cellular ratio of AMP/ATP. Phenformin and 5-aminoimida-zole-4-carboxamide riboside (AICAR) are two drugs widely used to activate AMPK experimentally. In both differentiated hippocampal neurons and neuroblastoma SH-SY5Y cells we found that these two agents not only activated AMPK, but conversely greatly reduced the activating Ser/Thr phosphorylation of Akt. This blockade of Akt activity consequently lowered the inhibitory serinephosphorylation of its substrates, glycogen synthase kinase-3a/b (GSK3a/b). An inhibitor of AMPK (Compound C) did not block dephosphorylation of Akt and GSK3. Thus, both drugs widely used to activate AMPK also caused dephosphorylation of Akt and of GSK3. The mechanism for Akt dephosphorylation caused by phenformin, but not AICAR, was due to inhibition of growth factorinduced signaling that leads to Akt phosphorylation. Stimulation of muscarinic receptors with carbachol in SH-SY5Y cells also activated AMPK and transiently caused dephosphorylation of Akt. These findings show that Akt dephosphorylation often occurs concomitantly with AMPK activation when cells are treated with phenformin or AICAR, indicating that these drugs do not only affect AMPK but also cause a coordinated inverse regulation of AMPK and Akt.

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Metformin Inhibits Proinflammatory Responses and Nuclear Factor-κB in Human Vascular Wall Cells

Cited by 445 publications

References 48 publications

Metformin, but Not Rosiglitazone, Attenuates the Increasing Plasma Levels of a New Cardiovascular Marker, Fibulin-1, in Patients With Type 2 Diabetes

Metformin, but Not Rosiglitazone, Attenuates the Increasing Plasma Levels of a New Cardiovascular Marker, Fibulin-1, in Patients With Type 2 Diabetes

Impact of metformin versus repaglinide on non-glycaemic cardiovascular risk markers related to inflammation and endothelial dysfunction in non-obese patients with type 2 diabetes

AMP-activated protein kinase (AMPK) activating agents cause dephosphorylation of Akt and glycogen synthase kinase-3

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