Special Issue "Metformin: Mechanism and Application 2020"

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

Deadline for manuscript submissions: closed (31 January 2021).

Special Issue Editor

Dr. Agnieszka Sliwinska
E-Mail
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 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

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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 (14 papers)

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Research

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Open AccessArticle
Metformin Modifies the Gut Microbiota of Mice Infected with Helicobacter pylori
Pharmaceuticals 2021, 14(4), 329; https://doi.org/10.3390/ph14040329 - 03 Apr 2021
Viewed by 562
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 2020)
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Open AccessArticle
Evaluation of the Effectiveness of Post-Stroke Metformin Treatment Using Permanent Middle Cerebral Artery Occlusion in Rats
Pharmaceuticals 2021, 14(4), 312; https://doi.org/10.3390/ph14040312 - 01 Apr 2021
Viewed by 321
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 2020)
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Open AccessArticle
Metformin Increases Survival in Hypopharyngeal Cancer Patients with Diabetes Mellitus: Retrospective Cohort Study and Cell-Based Analysis
Pharmaceuticals 2021, 14(3), 191; https://doi.org/10.3390/ph14030191 - 26 Feb 2021
Viewed by 490
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 2020)
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Open AccessFeature PaperArticle
The Effects of Maternal Metformin Treatment on Late Prenatal and Early Postnatal Development of the Offspring Are Modulated by Sex
Pharmaceuticals 2020, 13(11), 363; https://doi.org/10.3390/ph13110363 - 04 Nov 2020
Viewed by 598
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 2020)
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Open AccessCommunication
Metformin Reduces NGF-Induced Tumour Promoter Effects in Epithelial Ovarian Cancer Cells
Pharmaceuticals 2020, 13(10), 315; https://doi.org/10.3390/ph13100315 - 16 Oct 2020
Cited by 2 | Viewed by 980
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 2020)
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Open AccessArticle
Metformin Derivative HL156A Reverses Multidrug Resistance by Inhibiting HOXC6/ERK1/2 Signaling in Multidrug-Resistant Human Cancer Cells
Pharmaceuticals 2020, 13(9), 218; https://doi.org/10.3390/ph13090218 - 28 Aug 2020
Viewed by 702
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 2020)
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Open AccessArticle
Metformin Restores the Drug Sensitivity of MCF-7 Cells Resistant Derivates via the Cooperative Modulation of Growth and Apoptotic-Related Pathways
Pharmaceuticals 2020, 13(9), 206; https://doi.org/10.3390/ph13090206 - 21 Aug 2020
Cited by 1 | Viewed by 966
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 2020)
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Open AccessCommunication
Metformin Alleviates Obesity and Systemic Oxidative Stress in Obese Young Swine
Pharmaceuticals 2020, 13(7), 142; https://doi.org/10.3390/ph13070142 - 06 Jul 2020
Viewed by 716
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 2020)
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Review

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Open AccessReview
The Current and Potential Therapeutic Use of Metformin—The Good Old Drug
Pharmaceuticals 2021, 14(2), 122; https://doi.org/10.3390/ph14020122 - 05 Feb 2021
Cited by 1 | Viewed by 989
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 2020)
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Open AccessReview
Improvement Effect of Metformin on Female and Male Reproduction in Endocrine Pathologies and Its Mechanisms
Pharmaceuticals 2021, 14(1), 42; https://doi.org/10.3390/ph14010042 - 08 Jan 2021
Cited by 1 | Viewed by 874
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 2020)
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Open AccessReview
Metformin Protects against Podocyte Injury in Diabetic Kidney Disease
Pharmaceuticals 2020, 13(12), 452; https://doi.org/10.3390/ph13120452 - 10 Dec 2020
Viewed by 864
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 2020)
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Open AccessReview
Where Does Metformin Stand in Modern Day Management of Type 2 Diabetes?
Pharmaceuticals 2020, 13(12), 427; https://doi.org/10.3390/ph13120427 - 27 Nov 2020
Cited by 1 | Viewed by 806
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 2020)
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Open AccessFeature PaperReview
Gastrointestinal Mechanisms Underlying the Cardiovascular Effect of Metformin
Pharmaceuticals 2020, 13(11), 410; https://doi.org/10.3390/ph13110410 - 22 Nov 2020
Viewed by 746
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 2020)
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Open AccessReview
Metformin: A Potential Therapeutic Tool for Rheumatologists
Pharmaceuticals 2020, 13(9), 234; https://doi.org/10.3390/ph13090234 - 04 Sep 2020
Cited by 5 | Viewed by 1114
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 2020)
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