Metformin: From Mechanisms of Action to Therapies

Foretz, Marc; Guigas, Bruno; Bertrand, Luc; Pollak, Michael; Viollet, Benoı̂t

doi:10.1016/j.cmet.2014.09.018

Cited by 1,050 publications

(882 citation statements)

References 122 publications

(163 reference statements)

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“…The mechanisms of action of metformin have been reviewed extensively [2][3][4][5]. At the molecular level, many targets have been studied (for examples, [6,7]) but most studies have focused on respiratory complex I of the electron transport chain [8,9].…”

Section: Molecular Targetsmentioning

confidence: 99%

The effects of metformin on gut microbiota and the immune system as research frontiers

Pollak

2017

Diabetologia

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Recent studies have revealed that metformin influences gut microbiota and the immune system although neither is a classic target of the drug. This research has revealed complexity not previously appreciated, and opened new research directions. The extent to which immunomodulatory effects and actions on the microbiota are related to each other and account for effects on host energy metabolism remains to be determined. These sites of action may be relevant not only to the efficacy of metformin for its established use in type 2 diabetes, but also to proposed novel indications in oncology and other diseases.

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Section: Molecular Targetsmentioning

confidence: 99%

The effects of metformin on gut microbiota and the immune system as research frontiers

Pollak

2017

Diabetologia

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“…Activation of AMPK, in turn, leads to a plethora of signaling cascades that regulate energy homeostasis and metabolism (Hardie et al ., 2012). However, AMPK‐independent pathways activated by metformin have also been described (Pollak, 2012; Foretz et al ., 2014) and recent data also suggest that systemic effects of metformin may have different mechanisms of action in different tissues (Duca et al ., 2015). Gaps in our knowledge about the mechanisms that underlie its therapeutic effects persist.…”

Section: Introductionmentioning

confidence: 99%

“…Metformin enhances insulin sensitivity and lowers blood glucose levels by inhibiting gluconeogenesis in the liver. Metformin elicits these effects by inhibiting the mitochondrial respiratory‐chain complex I and glycerophosphate dehydrogenase (mGPD) and also by activating adenosine monophosphate‐activated protein kinase (AMPK) (Foretz et al ., 2014; Madiraju et al ., 2014). Activation of AMPK, in turn, leads to a plethora of signaling cascades that regulate energy homeostasis and metabolism (Hardie et al ., 2012).…”

Section: Introductionmentioning

confidence: 99%

“…These retrospective epidemiologic studies have led to intensive focus on the potential use of metformin as an anticancer therapeutic agent. Although many studies have focused on uncovering how metformin elicits anticancer effects, the exact mechanism of tumor inhibition remains unknown (Foretz et al ., 2014). Studies using cancer cells in culture and murine tumor xenografts have found that metformin inhibits tumorigenesis by upregulating DICER1 (Blandino et al ., 2012), a key enzyme that processes microRNAs (miRNAs).…”

Section: Introductionmentioning

confidence: 99%

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Metformin‐mediated increase in DICER1 regulates microRNA expression and cellular senescence

et al. 2016

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SummaryMetformin, an oral hypoglycemic agent, has been used for decades to treat type 2 diabetes mellitus. Recent studies indicate that mice treated with metformin live longer and have fewer manifestations of age‐related chronic disease. However, the molecular mechanisms underlying this phenotype are unknown. Here, we show that metformin treatment increases the levels of the microRNA‐processing protein DICER1 in mice and in humans with diabetes mellitus. Our results indicate that metformin upregulates DICER1 through a post‐transcriptional mechanism involving the RNA‐binding protein AUF1. Treatment with metformin altered the subcellular localization of AUF1, disrupting its interaction with DICER1 mRNA and rendering DICER1 mRNA stable, allowing DICER1 to accumulate. Consistent with the role of DICER1 in the biogenesis of microRNAs, we found differential patterns of microRNA expression in mice treated with metformin or caloric restriction, two proven life‐extending interventions. Interestingly, several microRNAs previously associated with senescence and aging, including miR‐20a, miR‐34a, miR‐130a, miR‐106b, miR‐125, and let‐7c, were found elevated. In agreement with these findings, treatment with metformin decreased cellular senescence in several senescence models in a DICER1‐dependent manner. Metformin lowered p16 and p21 protein levels and the abundance of inflammatory cytokines and oncogenes that are hallmarks of the senescence‐associated secretory phenotype (SASP). These data lead us to hypothesize that changes in DICER1 levels may be important for organismal aging and to propose that interventions that upregulate DICER1 expression (e.g., metformin) may offer new pharmacotherapeutic approaches for age‐related disease.

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“…• Les premiers éléments de preuve ont été apportés, en 1998, avec les résultats positifs du bras metformine dans l'étude UKPDS [5], même si la metformine ne peut pas être considérée comme un médicament insulino-sensibilisateur stricto sensu [6]. Peu après ont été commercialisées les thiazolidinediones (glitazones), médicaments ayant une action plus spécifique et plus puissante sur l'insulinorésistance, et sur lesquels de grands espoirs avaient été placés [7].…”

Section: Introductionunclassified

Insulinosensibilisateurs (metformine/glitazones) : niveau de preuve et controverse

Scheen

2015

Médecine des Maladies Métaboliques

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A.-J. Scheen RésuméAu vu du rôle délétère de l'insulinorésistance, un médicament insulino-sensibilisateur devrait normalement réduire l'incidence des complications cardiovasculaires du diabète de type 2. Dans l'étude UKPDS, la metformine a réduit le risque d'infarctus du myocarde et la mortalité cardiovasculaire chez des ptients récemment diagnostiqués et à faible risque, résultats qui mériteraient d'être confirmés chez des patients à haut risque cardiovasculaire. Les glitazones (des agents insulinosensibilisateurs plus spécifiques) avaient suscité beaucoup d'espoirs. Cependant la rosiglitazone est tombée de son piédestal après la suspicion d'une augmentation du risque coronarien (non réellement prouvé). Dans PROactive, conduite chez des patients à haut risque cardiovasculaire, la pioglitazone a donné des résultats discutables : la signification statistique n'était pas atteinte pour le principal critère d'évaluation composite étendu, mais bien pour le critère secondaire principal restreint pré-spécifié ou dans des analyses post-hoc. Ainsi, si les données disponibles apparaissent plutôt favorables concernant les insulino-sensibilisateurs, les preuves sont fragiles, d'où la controverse récurrente. Mots-clés :

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Metformin: From Mechanisms of Action to Therapies

Cited by 1,050 publications

References 122 publications

The effects of metformin on gut microbiota and the immune system as research frontiers

The effects of metformin on gut microbiota and the immune system as research frontiers

Metformin‐mediated increase in DICER1 regulates microRNA expression and cellular senescence

Insulinosensibilisateurs (metformine/glitazones) : niveau de preuve et controverse

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