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Metformin: Mechanism and Application 2022
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Metformin: Mechanism and Application 2022

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 111735

Special Issue Editor

Dr. Agnieszka Sliwinska

E-Mail Website
Guest Editor
Zakład Biochemii Kwasów Nukleinowych, Uniwersytet Medyczny w Łodzi, Pomorska 251, 92-213 Łódź, Poland
Interests: hypoglycemic drugs; insulin resistance; type 2 diabetes; obesity; cancer; oxidative stress; vitamin D; DNA damage and repair
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Metformin, a mainstay in type 2 diabetes treatment according to EASD and ADA expert guidelines, represents an impressive example of an effective and safe drug that still inspires further research. Metformin has been proven to prevent the conversion of prediabetes to type 2 diabetes. In addition, evidence has been recognized that metformin acts against aging, metabolic syndrome, obesity, cardiovascular diseases, cancers, infertility in women with polycystic ovary syndrome (PCOS), and neurodegenerative disorders. New evidence has been accumulated suggesting that metformin exerts beneficial effects on bone and mineral metabolism, gut microbiota, and the immune system. Although metformin has been available on the pharmaceutical market since the 1960s, a great amount of research into its molecular mechanisms of action is ongoing. In an attempt to explain the pleiotropic effects of metformin, a number of biological targets involved in metabolic homeostasis, cell cycle, autophagy, apoptosis, oxidative stress, inflammation, and epigenetic regulation have been discovered. Authors are invited to submit original and review articles of metformin to be published in this Special Issue of Pharmaceuticals.

Dr. Agnieszka Sliwinska
Guest Editor

Manuscript Submission Information

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Keywords

  • metformin
  • hypoglycemic action
  • antioxidant properties
  • improvement of insulin sensitivity
  • cardioprotection
  • lifespan extension
  • anticancer action
  • anti-inflammatory properties
  • polycystic ovary syndrome
  • neuroprotection
  • bone and mineral protection
  • microbiota composition

Published Papers (20 papers)

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Research

Jump to: Review

25 pages, 2642 KiB  
Article
Metformin Induces Apoptosis in Human Pancreatic Cancer (PC) Cells Accompanied by Changes in the Levels of Histone Acetyltransferases (Particularly, p300/CBP-Associated Factor (PCAF) Protein Levels)
by Izabela Szymczak-Pajor, Józef Drzewoski, Ewa Świderska, Justyna Strycharz, Anna Gabryanczyk, Jacek Kasznicki, Marta Bogdańska and Agnieszka Śliwińska
Pharmaceuticals 2023, 16(1), 115; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16010115 - 12 Jan 2023
Cited by 4 | Viewed by 3181
Abstract
Accumulating evidence (mainly from experimental research) suggests that metformin possesses anticancer properties through the induction of apoptosis and inhibition of the growth and proliferation of cancer cells. However, its effect on the enzymes responsible for histone acetylation status, which plays a key role [...] Read more.
Accumulating evidence (mainly from experimental research) suggests that metformin possesses anticancer properties through the induction of apoptosis and inhibition of the growth and proliferation of cancer cells. However, its effect on the enzymes responsible for histone acetylation status, which plays a key role in carcinogenesis, remains unclear. Therefore, the aim of our study was to evaluate the impact of metformin on histone acetyltransferases (HATs) (i.e., p300/CBP-associated factor (PCAF), p300, and CBP) and on histone deacetylases (HDACs) (i.e., SIRT-1 in human pancreatic cancer (PC) cell lines, 1.2B4, and PANC-1). The cells were exposed to metformin, an HAT inhibitor (HATi), or a combination of an HATi with metformin for 24, 48, or 72 h. Cell viability was determined using an MTT assay, and the percentage of early apoptotic cells was determined with an Annexin V-Cy3 Apoptosis Detection Assay Kit. Caspase-9 activity was also assessed. SIRT-1, PCAF, p300, and CBP expression were determined at the mRNA and protein levels using RT-PCR and Western blotting methods, respectively. Our results reveal an increase in caspase-9 in response to the metformin, indicating that it induced the apoptotic death of both 1.2B4 and PANC-1 cells. The number of cells in early apoptosis and the activity of caspase-9 decreased when treated with an HATi alone or a combination of an HATi with metformin, as compared to metformin alone. Moreover, metformin, an HATi, and a combination of an HATi with metformin also modified the mRNA expression of SIRT-1, PCAF, CBP, and p300. However, metformin did not change the expression of the studied genes in 1.2B4 cells. The results of the Western blot analysis showed that metformin diminished the protein expression of PCAF in both the 1.2B4 and PANC-1 cells. Hence, it appears possible that PCAF may be involved in the metformin-mediated apoptosis of PC cells. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application 2022)
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22 pages, 3567 KiB  
Article
Pharmacogenetics of Metformin Transporters Suggests No Association with Therapeutic Inefficacy among Diabetes Type 2 Mexican Patients
by Adiel Ortega-Ayala, Nidia Samara Rodríguez-Rivera, Fernando de Andrés, Adrián LLerena, Eliseo Pérez-Silva, Adriana Guadalupe Espinosa-Sánchez and Juan Arcadio Molina-Guarneros
Pharmaceuticals 2022, 15(7), 774; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15070774 - 22 Jun 2022
Cited by 4 | Viewed by 2270
Abstract
Mexico has been under official epidemiological alert due to diabetes since 2016. This study presents new information on the frequency and variants of metformin transporters OCT1, OCT2, OCT3, ABCB1, and CYP2C9 variants as well. It also reports the association with HbA1c control [...] Read more.
Mexico has been under official epidemiological alert due to diabetes since 2016. This study presents new information on the frequency and variants of metformin transporters OCT1, OCT2, OCT3, ABCB1, and CYP2C9 variants as well. It also reports the association with HbA1c control on 103 DMT2 patients. They were genotyped through real-time PCR (TaqMan assays) and grouped according to treatment: metformin and metformin + glibenclamide. Metformin plasmatic levels were determined through mass spectrometry. The analysis of HbA1c showed statistical significance across genotypes in polymorphisms rs72552763 (p = 0.022), rs622342 (p = 0.009), rs1128503 (p = 0.021), and rs2032582 (p = 0.009) within the monotherapy group. Bivariate analysis found no association between any polymorphism and HbA1c control. Two logistic regression models accounted for two diplotypes in OCT1 and ABCB1, including statistically significant covariates. The first model yielded significance in age (p = 0.026), treatment period [p = 0.001], BMI ≥ 25 kg/m2 (p = 0.043), and combined therapy (p < 0.001). There was no association with GAT/GAT of rs72552763 or A/A rs622342 in OCT1. The second model yielded significance in age (p = 0.017), treatment period (p = 0.001), BMI ≥ 25 kg/m2 (p = 0.042), and combined therapy (p < 0.001), finding no association with C/C of rs1128503 or G/G of rs2032582 in ABCB1. Our multinomial logistic regression results may benefit future predictive analyses in diabetic populations. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application 2022)
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15 pages, 5183 KiB  
Article
Metformin Modifies the Gut Microbiota of Mice Infected with Helicobacter pylori
by Marine Jauvain, Sarah Courtois, Philippe Lehours and Emilie Bessède
Pharmaceuticals 2021, 14(4), 329; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14040329 - 03 Apr 2021
Cited by 3 | Viewed by 3248
Abstract
Metformin is widely prescribed to treat type 2 diabetes. Diabetes patients treated with metformin have a decreased risk of cancers, including gastric cancer. Among the factors influencing digestive carcinogenesis, gut microbiota interactions have been intensively studied. Metformin exhibits direct antimicrobial activity toward Helicobacter [...] Read more.
Metformin is widely prescribed to treat type 2 diabetes. Diabetes patients treated with metformin have a decreased risk of cancers, including gastric cancer. Among the factors influencing digestive carcinogenesis, gut microbiota interactions have been intensively studied. Metformin exhibits direct antimicrobial activity toward Helicobacterpylori, which plays a crucial role in gastric carcinogenesis. Mice were infected with H. pylori and treated for 12 days with either metformin or phosphate-buffered saline (PBS) as a control. At the end of the treatment period, the mice were euthanized and cecal and intestinal contents and stool were collected. The gut microbiota of the three different digestive sites (stool, cecal, and intestinal contents) were characterized through 16S RNA gene sequencing. In mice infected with H. pylori, metformin significantly decreased alpha diversity indices and led to significant variation in the relative abundance of some bacterial taxa including Clostridium and Lactobacillus, which were directly inhibited by metformin in vitro. PICRUSt analysis suggested that metformin modifies functional pathway expression, including a decrease in nitrate reducing bacteria in the intestine. Metformin significantly changed the composition and predicted function of the gut microbiota of mice infected with H. pylori; these modifications could be implicated in digestive cancer prevention. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application 2022)
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16 pages, 8369 KiB  
Article
Evaluation of the Effectiveness of Post-Stroke Metformin Treatment Using Permanent Middle Cerebral Artery Occlusion in Rats
by Gintare Zemgulyte, Shigeru Tanaka, Izumi Hide, Norio Sakai, Katryna Pampuscenko, Vilmante Borutaite and Daiva Rastenyte
Pharmaceuticals 2021, 14(4), 312; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14040312 - 01 Apr 2021
Cited by 18 | Viewed by 2648
Abstract
Stroke is the second leading cause of death worldwide. Treatment options for ischemic stroke are limited, and the development of new therapeutic agents or combined therapies is imperative. Growing evidence suggests that metformin treatment, due to its anti-inflammatory action, exerts a neuroprotective effect [...] Read more.
Stroke is the second leading cause of death worldwide. Treatment options for ischemic stroke are limited, and the development of new therapeutic agents or combined therapies is imperative. Growing evidence suggests that metformin treatment, due to its anti-inflammatory action, exerts a neuroprotective effect against ischemia/reperfusion-induced brain damage. Experimental assessment has typically been performed in models of cerebral transient ischemia followed by long-term reperfusion. The aim of this study was to evaluate the neuroprotective effect of metformin treatment after permanent middle cerebral artery occlusion (pMCAO) without reperfusion in rats. Neurological deficits were assessed using the Longa scale, which offers a graded scale on body movement following pMCAO. Both infarct size and brain oedema area were measured by staining with 2,3,5-triphenyltetrazolium chloride. The number of neurons and total and activated microglia, as well as interleukin 10 (IL-10) production, in brain sections were evaluated by immunohistochemical staining. Our results show that metformin treatment improves the neurological state and reduces infarct size after 120 h of pMCAO. Metformin also prevents neuronal loss in the ischemic cortex but not in the striatum after 48 h of pMCAO. Moreover, post-stroke treatment with metformin significantly decreases the number of total and activated microglia at 48 h. The anti-inflammatory effect of metformin is associated with increased IL-10 production at 48 h after pMCAO. The results of the present study suggest that post-stroke treatment with metformin exerts anti-inflammatory and neuroprotective effects in a pMCAO model. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application 2022)
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16 pages, 4021 KiB  
Article
Metformin Increases Survival in Hypopharyngeal Cancer Patients with Diabetes Mellitus: Retrospective Cohort Study and Cell-Based Analysis
by Yung-An Tsou, Wei-Chao Chang, Chia-Der Lin, Ro-Lin Chang, Ming-Hsui Tsai, Liang-Chun Shih, Theresa Staniczek, Tsu-Fang Wu, Hui-Ying Hsu, Wen-Dien Chang, Chih-Ho Lai and Chuan-Mu Chen
Pharmaceuticals 2021, 14(3), 191; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14030191 - 26 Feb 2021
Cited by 9 | Viewed by 2497
Abstract
Hypopharyngeal squamous cell carcinoma (HSCC) is usually diagnosed at an advanced stage, leading to a poor prognosis. Even after improvement of surgical techniques, chemotherapy, and radiation technology, the survival rate of HSCC remains poor. Metformin, which is commonly used for type 2 diabetes [...] Read more.
Hypopharyngeal squamous cell carcinoma (HSCC) is usually diagnosed at an advanced stage, leading to a poor prognosis. Even after improvement of surgical techniques, chemotherapy, and radiation technology, the survival rate of HSCC remains poor. Metformin, which is commonly used for type 2 diabetes mellitus (DM), has been suggested to reduce the risk of various cancer types. However, only a few clinical studies mentioned the relationship between metformin use and HSCC. Hence, the aim of this study was to elucidate the specific effect and mechanism of action of metformin in hypopharyngeal cancer. We first assessed whether metformin use has an effect on hypopharyngeal cancer patients with DM by conducting a retrospective cohort study. Our results showed that DM hypopharyngeal cancer patients who used metformin exhibited significantly better overall survival rates than that without metformin treatment. The cell-based analysis further indicated that metformin treatment regulated p38/JNK pathway to reduce Cyclin D1 and Bcl-2 expressions. In addition, metformin activated the pathways of AMPKα and MEK/ERK to phosphorylate p27(Thr198) and reduce mTOR phosphorylation in cells. These actions direct cells toward G1 cell cycle arrest, apoptosis, and autophagy. Our results, through combining a clinical cohort analysis with an in vitro study, demonstrate that metformin can be used for drug repositioning in the treatment of DM patients with hypopharyngeal cancer. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application 2022)
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11 pages, 1096 KiB  
Article
The Effects of Maternal Metformin Treatment on Late Prenatal and Early Postnatal Development of the Offspring Are Modulated by Sex
by Consolacion Garcia-Contreras, Marta Vazquez-Gomez, José Luis Pesantez-Pacheco, Ana Heras-Molina, Teresa Encinas, Susana Astiz and Antonio Gonzalez-Bulnes
Pharmaceuticals 2020, 13(11), 363; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13110363 - 04 Nov 2020
Cited by 7 | Viewed by 2067
Abstract
Metformin is currently used to improve pregnancy outcome in women affected by polycystic ovary syndrome (PCOS) or diabetes. However, metformin may also be useful in pregnancies at risk of intrauterine growth restriction (IUGR) since it improves placental efficiency and the fetuses’ developmental competence. [...] Read more.
Metformin is currently used to improve pregnancy outcome in women affected by polycystic ovary syndrome (PCOS) or diabetes. However, metformin may also be useful in pregnancies at risk of intrauterine growth restriction (IUGR) since it improves placental efficiency and the fetuses’ developmental competence. There is no data on the duration of the effect of this treatment from the prenatal up to the postnatal stages. Therefore, the present trial aimed at determining the impact of metformin treatment on the offspring neonatal traits and early postnatal development (i.e., during lactation) using an in vivo swine model. The results support that maternal metformin treatment during pregnancy induces protective changes in body shape and composition of the progeny (i.e., larger head size and body length at birth and higher total viscera weight at weaning). However, there were also major effects of the offspring sex (smaller corpulence in females and lower relative weight of main viscerae in males), which should be considered for further preclinical studies and when even the current clinical application in women affected by PCOS or diabetes is implemented. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application 2022)
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20 pages, 3303 KiB  
Communication
Metformin Reduces NGF-Induced Tumour Promoter Effects in Epithelial Ovarian Cancer Cells
by Maritza P. Garrido, Renato Salvatierra, Manuel Valenzuela-Valderrama, Christopher Vallejos, Nicole Bruneau, Andrea Hernández, Margarita Vega, Alberto Selman, Andrew F. G. Quest and Carmen Romero
Pharmaceuticals 2020, 13(10), 315; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13100315 - 16 Oct 2020
Cited by 12 | Viewed by 3458
Abstract
Epithelial ovarian cancer (EOC) is a lethal gynaecological neoplasm characterized by rapid growth and angiogenesis. Nerve growth factor (NGF) and its high affinity receptor tropomyosin receptor kinase A (TRKA) contribute to EOC progression by increasing the expression of c-MYC, survivin and vascular endothelial [...] Read more.
Epithelial ovarian cancer (EOC) is a lethal gynaecological neoplasm characterized by rapid growth and angiogenesis. Nerve growth factor (NGF) and its high affinity receptor tropomyosin receptor kinase A (TRKA) contribute to EOC progression by increasing the expression of c-MYC, survivin and vascular endothelial growth factor (VEGF) along with a decrease in microRNAs (miR) 23b and 145. We previously reported that metformin prevents NGF-induced proliferation and angiogenic potential of EOC cells. In this study, we sought to obtain a better understanding of the mechanism(s) by which metformin blocks these NGF-induced effects in EOC cells. Human ovarian surface epithelial (HOSE) and EOC (A2780/SKOV3) cells were stimulated with NGF and/or metformin to assess the expression of c-MYC, β-catenin, survivin and VEGF and the abundance of the tumor suppressor miRs 23b and 145. Metformin decreased the NGF-induced transcriptional activity of MYC and β-catenin/T-cell factor/lymphoid enhancer-binding factor (TCF-Lef), as well as the expression of c-MYC, survivin and VEGF in EOC cells, while it increased miR-23b and miR-145 levels. The preliminary analysis of ovarian biopsies from women users or non-users of metformin was consistent with these in vitro results. Our observations shed light on the mechanisms by which metformin may suppress tumour growth in EOC and suggest that metformin should be considered as a possible complementary therapy in EOC treatment. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application 2022)
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15 pages, 2533 KiB  
Article
Metformin Derivative HL156A Reverses Multidrug Resistance by Inhibiting HOXC6/ERK1/2 Signaling in Multidrug-Resistant Human Cancer Cells
by Yun Soo Jeong, Thuy Giang Lam, Seho Jeong and Sang-Gun Ahn
Pharmaceuticals 2020, 13(9), 218; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13090218 - 28 Aug 2020
Cited by 6 | Viewed by 2904
Abstract
Multidrug resistance is a significant clinical crisis in cancer treatment and has been linked to the cellular expression of multidrug efflux transporters. The aim of this study was to examine the effects and mechanisms of the metformin derivative HL156A on human multidrug resistance [...] Read more.
Multidrug resistance is a significant clinical crisis in cancer treatment and has been linked to the cellular expression of multidrug efflux transporters. The aim of this study was to examine the effects and mechanisms of the metformin derivative HL156A on human multidrug resistance (MDR) cancer cells. Here, HL156A significantly suppressed cell growth and colony formation through G2/M phase cell cycle arrest in MDR cancer cells. HL156A also reduced the wound closure rate and cell migration and induced caspase-3-dependent apoptosis. We found that HL156A inhibited the expression of MDR1 by inhibiting the HOXC6-mediated ERK1/2 signaling pathway and increased the sensitivity to paclitaxel or doxorubicin in MDR cells. Furthermore, HL156A significantly inhibited angiogenesis in a chicken chorioallantoic membrane (CAM) assay. These results suggest the potential of the metformin derivative HL156A as a candidate therapeutic modality for the treatment of human multidrug-resistant cancers. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application 2022)
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16 pages, 16127 KiB  
Article
Metformin Restores the Drug Sensitivity of MCF-7 Cells Resistant Derivates via the Cooperative Modulation of Growth and Apoptotic-Related Pathways
by Danila Sorokin, Yuri Shchegolev, Alexander Scherbakov, Oxana Ryabaya, Margarita Gudkova, Lev Berstein and Mikhail Krasil’nikov
Pharmaceuticals 2020, 13(9), 206; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13090206 - 21 Aug 2020
Cited by 8 | Viewed by 3875
Abstract
The phenomenon of the primary or acquired resistance of cancer cells to antitumor drugs is among the key problems of oncology. For breast cancer, the phenomenon of the resistance to hormonal or target therapy may be based on the numerous mechanisms including the [...] Read more.
The phenomenon of the primary or acquired resistance of cancer cells to antitumor drugs is among the key problems of oncology. For breast cancer, the phenomenon of the resistance to hormonal or target therapy may be based on the numerous mechanisms including the loss or mutation of estrogen receptor, alterations of antiapoptotic pathways, overexpression of growth-related signaling proteins, etc. The perspective approaches for overcoming the resistance may be based on the usage of compounds such as inhibitors of the cell energetic metabolism. Among the latter, the antidiabetic drug metformin exerts antitumor activity via the activation of AMPK and the subsequent inhibition of mTOR signaling. The experiments were performed on the ERα-positive MCF-7 breast cancer cells, the MCF-7 sublines resistant to tamoxifen (MCF-7/T) and rapamycin (MCF-7/Rap), and on triple-negative MDA-MB-231 breast cancer cells. We have demonstrated metformin’s ability to enhance the cytostatic activity of the tamoxifen and rapamycin on both parent MCF-7 cells and MCF-7-resistant derivates mediated via the suppression of mTOR signaling and growth-related transcriptional factors. The cooperative effect of metformin and tested drugs was realized in an estrogen-independent manner, and, in the case of tamoxifen, was associated with the activation of apoptotic cell death. Similarly, the stimulation of apoptosis under metformin/tamoxifen co-treatment was shown to occur in the MCF-7 cells after steroid depletion as well as in the ERα-negative MDA-MB-231 cells. We conclude that metformin co-treatment may be used for the increase and partial restoration of the cancer cell sensitivity to hormonal and target drugs. Moreover, the combination of metformin with tamoxifen induces the apoptotic death in the ERα-negative breast cancer cells opening the additional perspectives in the treatment of estrogen-independent breast tumors. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application 2022)
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8 pages, 577 KiB  
Communication
Metformin Alleviates Obesity and Systemic Oxidative Stress in Obese Young Swine
by Susana Astiz, Antonio Gonzalez-Bulnes, Isabel Astiz, Alicia Barbero, Jose Luis Pesantez-Pacheco, Consolacion Garcia-Contreras, Marta Vazquez-Gomez and Ana Heras-Molina
Pharmaceuticals 2020, 13(7), 142; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13070142 - 06 Jul 2020
Cited by 4 | Viewed by 2378
Abstract
The present study assessed the relationship between obesity induced by lifestyle and systemic oxidative stress and possible modulations by oral metformin treatments in young individuals, by using a translational swine model of obesity and associated cardiometabolic disorders (Iberian pig). The results indicate the [...] Read more.
The present study assessed the relationship between obesity induced by lifestyle and systemic oxidative stress and possible modulations by oral metformin treatments in young individuals, by using a translational swine model of obesity and associated cardiometabolic disorders (Iberian pig). The results indicate the existence of an age-related increase in both adiposity and systemic oxidative stress (using hydrogen peroxide as a marker), which is higher in individuals with obesogenic lifestyle and increased weight and obesity. Such effect was not found in individuals treated with metformin. The translation of these results suggests that childhood obesity increases production of reactive oxygen species (ROS), and therefore systemic oxidative stress. Treatment with metformin would improve such oxidative status. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application 2022)
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Review

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20 pages, 2393 KiB  
Review
Metabolic Action of Metformin
by Izabela Szymczak-Pajor, Sylwia Wenclewska and Agnieszka Śliwińska
Pharmaceuticals 2022, 15(7), 810; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15070810 - 30 Jun 2022
Cited by 24 | Viewed by 10106
Abstract
Metformin, a cheap and safe biguanide derivative, due to its ability to influence metabolism, is widely used as a first-line drug for type 2 diabetes (T2DM) treatment. Therefore, the aim of this review was to present the updated biochemical and molecular effects exerted [...] Read more.
Metformin, a cheap and safe biguanide derivative, due to its ability to influence metabolism, is widely used as a first-line drug for type 2 diabetes (T2DM) treatment. Therefore, the aim of this review was to present the updated biochemical and molecular effects exerted by the drug. It has been well explored that metformin suppresses hepatic glucose production in both AMPK-independent and AMPK-dependent manners. Substantial scientific evidence also revealed that its action is related to decreased secretion of lipids from intestinal epithelial cells, as well as strengthened oxidation of fatty acids in adipose tissue and muscles. It was recognized that metformin’s supra-therapeutic doses suppress mitochondrial respiration in intestinal epithelial cells, whereas its therapeutic doses elevate cellular respiration in the liver. The drug is also suggested to improve systemic insulin sensitivity as a result of alteration in gut microbiota composition, maintenance of intestinal barrier integrity, and alleviation of low-grade inflammation. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application 2022)
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29 pages, 1314 KiB  
Review
Metformin and Cancer, an Ambiguanidous Relationship
by Sarah J. Skuli, Safwan Alomari, Hallie Gaitsch, A’ishah Bakayoko, Nicolas Skuli and Betty M. Tyler
Pharmaceuticals 2022, 15(5), 626; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15050626 - 19 May 2022
Cited by 24 | Viewed by 7601
Abstract
The deregulation of energetic and cellular metabolism is a signature of cancer cells. Thus, drugs targeting cancer cell metabolism may have promising therapeutic potential. Previous reports demonstrate that the widely used normoglycemic agent, metformin, can decrease the risk of cancer in type 2 [...] Read more.
The deregulation of energetic and cellular metabolism is a signature of cancer cells. Thus, drugs targeting cancer cell metabolism may have promising therapeutic potential. Previous reports demonstrate that the widely used normoglycemic agent, metformin, can decrease the risk of cancer in type 2 diabetics and inhibit cell growth in various cancers, including pancreatic, colon, prostate, ovarian, and breast cancer. While metformin is a known adenosine monophosphate-activated protein kinase (AMPK) agonist and an inhibitor of the electron transport chain complex I, its mechanism of action in cancer cells as well as its effect on cancer metabolism is not clearly established. In this review, we will give an update on the role of metformin as an antitumoral agent and detail relevant evidence on the potential use and mechanisms of action of metformin in cancer. Analyzing antitumoral, signaling, and metabolic impacts of metformin on cancer cells may provide promising new therapeutic strategies in oncology. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application 2022)
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69 pages, 17931 KiB  
Review
Biological Properties of Transition Metal Complexes with Metformin and Its Analogues
by Daniil A. Rusanov, Jiaying Zou and Maria V. Babak
Pharmaceuticals 2022, 15(4), 453; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15040453 - 06 Apr 2022
Cited by 17 | Viewed by 4764
Abstract
Metformin is a widely prescribed medication for the treatment and management of type 2 diabetes. It belongs to a class of biguanides, which are characterized by a wide range of diverse biological properties, including anticancer, antimicrobial, antimalarial, cardioprotective and other activities. It is [...] Read more.
Metformin is a widely prescribed medication for the treatment and management of type 2 diabetes. It belongs to a class of biguanides, which are characterized by a wide range of diverse biological properties, including anticancer, antimicrobial, antimalarial, cardioprotective and other activities. It is known that biguanides serve as excellent N-donor bidentate ligands and readily form complexes with virtually all transition metals. Recent evidence suggests that the mechanism of action of metformin and its analogues is linked to their metal-binding properties. These findings prompted us to summarize the existing data on the synthetic strategies and biological properties of various metal complexes with metformin and its analogues. We demonstrated that coordination of biologically active biguanides to various metal centers often resulted in an improved pharmacological profile, including reduced drug resistance as well as a wider spectrum of activity. In addition, coordination to the redox-active metal centers, such as Au(III), allowed for various activatable strategies, leading to the selective activation of the prodrugs and reduced off-target toxicity. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application 2022)
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20 pages, 532 KiB  
Review
Metformin: A Narrative Review of Its Potential Benefits for Cardiovascular Disease, Cancer and Dementia
by Wiebe M. C. Top, Adriaan Kooy and Coen D. A. Stehouwer
Pharmaceuticals 2022, 15(3), 312; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15030312 - 04 Mar 2022
Cited by 19 | Viewed by 7195
Abstract
The biguanide metformin has been used as first-line therapy in type 2 diabetes mellitus (T2DM) treatment for several decades. In addition to its glucose-lowering properties and its prevention of weight gain, the landmark UK Prospective Diabetes Study (UKPDS) demonstrated cardioprotective properties in obese [...] Read more.
The biguanide metformin has been used as first-line therapy in type 2 diabetes mellitus (T2DM) treatment for several decades. In addition to its glucose-lowering properties and its prevention of weight gain, the landmark UK Prospective Diabetes Study (UKPDS) demonstrated cardioprotective properties in obese T2DM patients. Coupled with a favorable side effect profile and low cost, metformin has become the cornerstone in the treatment of T2DM worldwide. In addition, metformin is increasingly being investigated for its potential anticancer and neuroprotective properties both in T2DM patients and non-diabetic individuals. In the meantime, new drugs with powerful cardioprotective properties have been introduced and compete with metformin for its place in the treatment of T2DM. In this review we will discuss actual insights in the various working mechanisms of metformin and the evidence for its beneficial effects on (the prevention of) cardiovascular disease, cancer and dementia. In addition to observational evidence, emphasis is placed on randomized trials and recent meta-analyses to obtain an up-to-date overview of the use of metformin in clinical practice. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application 2022)
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33 pages, 1094 KiB  
Review
The Current and Potential Therapeutic Use of Metformin—The Good Old Drug
by Józef Drzewoski and Markolf Hanefeld
Pharmaceuticals 2021, 14(2), 122; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14020122 - 05 Feb 2021
Cited by 54 | Viewed by 12511
Abstract
Metformin, one of the oldest oral antidiabetic agents and still recommended by almost all current guidelines as the first-line treatment for type 2 diabetes mellitus (T2DM), has become the medication with steadily increasing potential therapeutic indications. A broad spectrum of experimental and clinical [...] Read more.
Metformin, one of the oldest oral antidiabetic agents and still recommended by almost all current guidelines as the first-line treatment for type 2 diabetes mellitus (T2DM), has become the medication with steadily increasing potential therapeutic indications. A broad spectrum of experimental and clinical studies showed that metformin has a pleiotropic activity and favorable effect in different pathological conditions, including prediabetes, type 1 diabetes mellitus (T1DM) and gestational diabetes mellitus (GDM). Moreover, there are numerous studies, meta-analyses and population studies indicating that metformin is safe and well tolerated and may be associated with cardioprotective and nephroprotective effect. Recently, it has also been reported in some studies, but not all, that metformin, besides improvement of glucose homeostasis, may possibly reduce the risk of cancer development, inhibit the incidence of neurodegenerative disease and prolong the lifespan. This paper presents some arguments supporting the initiation of metformin in patients with newly diagnosed T2DM, especially those without cardiovascular risk factors or without established cardiovascular disease or advanced kidney insufficiency at the time of new guidelines favoring new drugs with pleotropic effects complimentary to glucose control. Moreover, it focuses on the potential beneficial effects of metformin in patients with T2DM and coexisting chronic diseases. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application 2022)
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45 pages, 1929 KiB  
Review
Improvement Effect of Metformin on Female and Male Reproduction in Endocrine Pathologies and Its Mechanisms
by Alexander O. Shpakov
Pharmaceuticals 2021, 14(1), 42; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010042 - 08 Jan 2021
Cited by 30 | Viewed by 8230
Abstract
Metformin (MF), a first-line drug to treat type 2 diabetes mellitus (T2DM), alone and in combination with other drugs, restores the ovarian function in women with polycystic ovary syndrome (PCOS) and improves fetal development, pregnancy outcomes and offspring health in gestational diabetes mellitus [...] Read more.
Metformin (MF), a first-line drug to treat type 2 diabetes mellitus (T2DM), alone and in combination with other drugs, restores the ovarian function in women with polycystic ovary syndrome (PCOS) and improves fetal development, pregnancy outcomes and offspring health in gestational diabetes mellitus (GDM) and T2DM. MF treatment is demonstrated to improve the efficiency of in vitro fertilization and is considered a supplementary drug in assisted reproductive technologies. MF administration shows positive effect on steroidogenesis and spermatogenesis in men with metabolic disorders, thus MF treatment indicates prospective use for improvement of male reproductive functions and fertility. MF lacks teratogenic effects and has positive health effect in newborns. The review is focused on use of MF therapy for restoration of female and male reproductive functions and improvement of pregnancy outcomes in metabolic and endocrine disorders. The mechanisms of MF action are discussed, including normalization of metabolic and hormonal status in PCOS, GDM, T2DM and metabolic syndrome and restoration of functional activity and hormonal regulation of the gonadal axis. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application 2022)
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26 pages, 2435 KiB  
Review
Metformin Protects against Podocyte Injury in Diabetic Kidney Disease
by Sanna Lehtonen
Pharmaceuticals 2020, 13(12), 452; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13120452 - 10 Dec 2020
Cited by 11 | Viewed by 10488
Abstract
Metformin is the most commonly prescribed drug for treating type 2 diabetes mellitus (T2D). Its mechanisms of action have been under extensive investigation, revealing that it has multiple cellular targets, either direct or indirect ones, via which it regulates numerous cellular pathways. Diabetic [...] Read more.
Metformin is the most commonly prescribed drug for treating type 2 diabetes mellitus (T2D). Its mechanisms of action have been under extensive investigation, revealing that it has multiple cellular targets, either direct or indirect ones, via which it regulates numerous cellular pathways. Diabetic kidney disease (DKD), the serious complication of T2D, develops in up to 50% of the individuals with T2D. Various mechanisms contribute to the development of DKD, including hyperglycaemia, dyslipidemia, oxidative stress, chronic low-grade inflammation, altered autophagic activity and insulin resistance, among others. Metformin has been shown to affect these pathways, and thus, it could slow down or prevent the progression of DKD. Despite several animal studies demonstrating the renoprotective effects of metformin, there is no concrete evidence in clinical settings. This review summarizes the renoprotective effects of metformin in experimental settings. Special emphasis is on the effects of metformin on podocytes, the glomerular epithelial cells that are central in maintaining the glomerular ultrafiltration function. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application 2022)
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25 pages, 618 KiB  
Review
Where Does Metformin Stand in Modern Day Management of Type 2 Diabetes?
by Ehtasham Ahmad, Jack A. Sargeant, Francesco Zaccardi, Kamlesh Khunti, David R. Webb and Melanie J. Davies
Pharmaceuticals 2020, 13(12), 427; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13120427 - 27 Nov 2020
Cited by 14 | Viewed by 5497
Abstract
Metformin is the most commonly used glucose-lowering therapy (GLT) worldwide and remains the first-line therapy for newly diagnosed individuals with type 2 diabetes (T2D) in management algorithms and guidelines after the UK Prospective Diabetes Study (UKPDS) showed cardiovascular mortality benefits in the overweight [...] Read more.
Metformin is the most commonly used glucose-lowering therapy (GLT) worldwide and remains the first-line therapy for newly diagnosed individuals with type 2 diabetes (T2D) in management algorithms and guidelines after the UK Prospective Diabetes Study (UKPDS) showed cardiovascular mortality benefits in the overweight population using metformin. However, the improved Major Adverse Cardiovascular Events (MACE) realised in some of the recent large cardiovascular outcomes trials (CVOTs) using sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have challenged metformin’s position as a first-line agent in the management of T2D. Many experts now advocate revising the existing treatment algorithms to target atherosclerotic cardiovascular disease (ASCVD) and improving glycaemic control as a secondary aim. In this review article, we will revisit the major cardiovascular outcome data for metformin and include a critique of the UKPDS data. We then review additional factors that might be pertinent to metformin’s status as a first-line agent and finally answer key questions when considering metformin’s role in the modern-day management of T2D. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application 2022)
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14 pages, 980 KiB  
Review
Gastrointestinal Mechanisms Underlying the Cardiovascular Effect of Metformin
by Malcolm J. Borg, Christopher K. Rayner, Karen L. Jones, Michael Horowitz, Cong Xie and Tongzhi Wu
Pharmaceuticals 2020, 13(11), 410; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13110410 - 22 Nov 2020
Cited by 4 | Viewed by 6767
Abstract
Metformin, the most widely prescribed drug therapy for type 2 diabetes, has pleiotropic benefits, in addition to its capacity to lower elevated blood glucose levels, including mitigation of cardiovascular risk. The mechanisms underlying the latter remain unclear. Mechanistic studies have, hitherto, focused on [...] Read more.
Metformin, the most widely prescribed drug therapy for type 2 diabetes, has pleiotropic benefits, in addition to its capacity to lower elevated blood glucose levels, including mitigation of cardiovascular risk. The mechanisms underlying the latter remain unclear. Mechanistic studies have, hitherto, focused on the direct effects of metformin on the heart and vasculature. It is now appreciated that effects in the gastrointestinal tract are important to glucose-lowering by metformin. Gastrointestinal actions of metformin also have major implications for cardiovascular function. This review summarizes the gastrointestinal mechanisms underlying the action of metformin and their potential relevance to cardiovascular benefits. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application 2022)
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16 pages, 1233 KiB  
Review
Metformin: A Potential Therapeutic Tool for Rheumatologists
by Teresa Salvatore, Pia Clara Pafundi, Raffaele Galiero, Klodian Gjeloshi, Francesco Masini, Carlo Acierno, Anna Di Martino, Gaetana Albanese, Maria Alfano, Luca Rinaldi and Ferdinando Carlo Sasso
Pharmaceuticals 2020, 13(9), 234; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13090234 - 04 Sep 2020
Cited by 33 | Viewed by 6978
Abstract
Metformin is an oral antihyperglycemic drug widely used to treat type 2 diabetes, acting via indirect activation of 5′ Adenosine Monophosphate-activated Protein Kinase (AMPK). Actually, evidence has accumulated of an intriguing anti-inflammatory activity, mainly mediated by AMPK through a variety of mechanisms such [...] Read more.
Metformin is an oral antihyperglycemic drug widely used to treat type 2 diabetes, acting via indirect activation of 5′ Adenosine Monophosphate-activated Protein Kinase (AMPK). Actually, evidence has accumulated of an intriguing anti-inflammatory activity, mainly mediated by AMPK through a variety of mechanisms such as the inhibition of cytokine-stimulated Nuclear Factor-κB (NF-κB) and the downregulation of the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathways. Moreover, AMPK plays an important role in the modulation of T lymphocytes and other pivotal cells of the innate immune system. The current understanding of these AMPK effects provides a strong rationale for metformin repurposing in the management of autoimmune and inflammatory conditions. Several studies demonstrated metformin’s beneficial effects on both animal and human rheumatologic diseases, especially on rheumatoid arthritis. Unfortunately, even though data are large and remarkable, they almost exclusively come from experimental investigations with only a few from clinical trials. The lack of support from prospective placebo-controlled trials does not allow metformin to enter the therapeutic repertoire of rheumatologists. However, a large proportion of rheumatologic patients can currently benefit from metformin, such as those with concomitant obesity and type 2 diabetes, two conditions strongly associated with rheumatoid arthritis, osteoarthritis, and gout, as well as those with diabetes secondary to steroid therapy. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application 2022)
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