Metformin is a plant-based drug belonging to the class of biguanides and is known to treat type-2 diabetes mellitus (T2DM). The drug, combined with controlling blood glucose levels, improves the body's response to insulin. In addition, trials have identified the cardioprotective potential of metformin in the diabetic population receiving the drug. Activation of 5' AMP-activated protein kinase (AMPK) is the major pathway for these potential beneficial effects of metformin. Historically, much emphasis has been placed on the potential indications of metformin beyond its anti-diabetic use. This review aims to appraise other potential uses of metformin primarily mediated by the activation of AMPK. We also discuss various mechanisms, other than AMPK activation, by which metformin could produce beneficial effects for different conditions. Databases including PubMed/MEDLINE and Embase were searched for literature relevant to the review's objective. Reports from both research and review articles were considered. We found that metformin has diverse effects on the human body systems. It has been shown to exert anti-inflammatory, antioxidant, cardioprotective, metabolic, neuroprotective, anti-cancer, and antimicrobial effects and has now even been identified as effective against SARS-CoV-2. Above all, the AMPK pathway has been recognized as responsible for metformin's efficiency and effectiveness. Owing to its extensive potential, it has the capability to become a part of treatment regimens for diseases apart from T2DM.

• Klíčová slova
• anticancer, cardioprotective, hyperglycemia, metformin, oxidative stress,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Metformin is widely prescribed as a first-choice antihyperglycemic drug for treatment of type 2 diabetes mellitus, and recent epidemiological studies showed its utility also in cancer therapy. Although it is in use since the 1970s, its molecular target, either for antihyperglycemic or antineoplastic action, remains elusive. However, the body of the research on metformin effect oscillates around mitochondrial metabolism, including the function of oxidative phosphorylation (OXPHOS) apparatus. In this study, we focused on direct inhibitory mechanism of biguanides (metformin and phenformin) on OXPHOS complexes and its functional impact, using the model of isolated brown adipose tissue mitochondria. We demonstrate that biguanides nonspecifically target the activities of all respiratory chain dehydrogenases (mitochondrial NADH, succinate, and glycerophosphate dehydrogenases), but only at very high concentrations (10-2-10-1 M) that highly exceed cellular concentrations observed during the treatment. In addition, these concentrations of biguanides also trigger burst of reactive oxygen species production which, in combination with pleiotropic OXPHOS inhibition, can be toxic for the organism. We conclude that the beneficial effect of biguanides should probably be associated with subtler mechanism, different from the generalized inhibition of the respiratory chain.

• MeSH
• biguanidy farmakologie   MeSH
• fenformin farmakologie   MeSH
• glycerolfosfátdehydrogenasa metabolismus   MeSH
• hnědá tuková tkáň cytologie   MeSH
• hypoglykemika farmakologie   MeSH
• krysa rodu Rattus MeSH
• kyselina jantarová metabolismus   MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• metformin farmakologie   MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• oxidace-redukce účinky léků   MeSH
• peroxid vodíku farmakologie   MeSH
• potkani Wistar MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• biguanidy MeSH
• fenformin MeSH
• glycerolfosfátdehydrogenasa MeSH
• hypoglykemika MeSH
• kyselina jantarová MeSH
• metformin MeSH
• peroxid vodíku MeSH
• reaktivní formy kyslíku MeSH

Metformin is widely used in the treatment of type-2 diabetes. The pleotropic effects of metformin on glucose and lipid metabolism have been proposed to be mediated by the activation of AMP-activated protein kinase (AMPK) and the subsequent up-regulation of small heterodimer partner (SHP). SHP suppresses the functions of several nuclear receptors involved in the regulation of hepatic metabolism, including pregnane X receptor (PXR), which is referred to as a "master regulator" of drug/xenobiotic metabolism. In this study, we hypothesize that metformin suppresses the expression of CYP3A4, a main detoxification enzyme and a target gene of PXR, due to SHP up-regulation. We employed various gene reporter assays in cell lines and qRT-PCR in human hepatocytes and in Pxr(-/-) mice. We show that metformin dramatically suppresses PXR-mediated expression of CYP3A4 in hepatocytes. Consistently, metformin significantly suppressed the up-regulation of Cyp3a11 mRNA in the liver and intestine of wild-type mice, but not in Pxr(-/-) mice. A mechanistic investigation of the phenomenon showed that metformin does not significantly up-regulate SHP in human hepatocytes. We further demonstrate that AMPK activation is not involved in this process. We show that metformin disrupts PXR's interaction with steroid receptor coactivator-1 (SRC1) in a two-hybrid assay independently of the PXR ligand binding pocket. Metformin also inhibited vitamin D receptor-, glucocorticoid receptor- and constitutive androstane receptor (CAR)-mediated induction of CYP3A4 mRNA in human hepatocytes. We show, therefore, a suppressive effect of metformin on PXR and other ligand-activated nuclear receptors in transactivation of the main detoxification enzyme CYP3A4 in human hepatocytes.

• MeSH
• aktivace transkripce MeSH
• cytochrom P-450 CYP3A genetika   metabolismus   MeSH
• hepatocyty účinky léků   metabolismus   MeSH
• hypoglykemika farmakologie   MeSH
• koaktivátory jaderných receptorů metabolismus   MeSH
• konstitutivní androstanový receptor MeSH
• kultivované buňky MeSH
• lidé MeSH
• membránové proteiny genetika   metabolismus   MeSH
• messenger RNA metabolismus   MeSH
• metformin farmakologie   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• polohový reflex účinky léků   MeSH
• pregnanový X receptor MeSH
• proteinkinasy aktivované AMP fyziologie   MeSH
• receptory cytoplazmatické a nukleární metabolismus   fyziologie   MeSH
• receptory glukokortikoidů fyziologie   MeSH
• receptory kalcitriolu fyziologie   MeSH
• reportérové geny MeSH
• signální transdukce MeSH
• steroidní receptory genetika   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• Cyp3a11 protein, mouse MeSH Prohlížeč
• cytochrom P-450 CYP3A MeSH
• hypoglykemika MeSH
• koaktivátory jaderných receptorů MeSH
• konstitutivní androstanový receptor MeSH
• membránové proteiny MeSH
• messenger RNA MeSH
• metformin MeSH
• nuclear receptor subfamily 0, group B, member 2 MeSH Prohlížeč
• pregnanový X receptor MeSH
• proteinkinasy aktivované AMP MeSH
• receptory cytoplazmatické a nukleární MeSH
• receptory glukokortikoidů MeSH
• receptory kalcitriolu MeSH
• steroidní receptory MeSH