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Metformin: Mechanism and Application 2023

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

Deadline for manuscript submissions: closed (25 April 2024) | Viewed by 35355

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Dr. Agnieszka Sliwinska

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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
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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 found 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 that suggests 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 regarding metformin to be published in this Special Issue of Pharmaceuticals.

Dr. Agnieszka Sliwinska
Guest Editor

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Research

Jump to: Review

18 pages, 1997 KiB

Open AccessArticle

Metformin-Associated Gastrointestinal Adverse Events Are Reduced by Probiotics: A Meta-Analysis

by Izabela Szymczak-Pajor, Józef Drzewoski, Sylwia Wenclewska and Agnieszka Śliwińska

Pharmaceuticals 2024, 17(7), 898; https://doi.org/10.3390/ph17070898 - 5 Jul 2024

Viewed by 1317

Abstract

Metformin, one of the most frequently used oral glucose-lowering drugs (GLDs), is associated with the occurrence of gastrointestinal (GI) adverse events in approximately 20% of users. These unwanted actions result in non-compliance or even discontinuation of metformin therapy. The aim of the presented meta-analysis was to determine whether adding a drug from the group of sulfonylureas, glitazones, DPP-IV inhibitors, or probiotics to metformin monotherapy may affect the risk of GI side effects. The material for this meta-analysis comprised data from 26 randomized controlled clinical trials (RCTs) published in English. This meta-analysis included 41,048 patients. The PubMed, Cochrane Library, and Clinical Trials databases were thoroughly searched to find relevant RCTs. The Population, Intervention, Comparison, Outcomes, and Study Type (PICOT) structure was used to formulate study selection criteria and the research question. Cochrane Review Manager Software 5.4 was used to carry out analysis of collected data. The results were presented as relative risk (RR) and 95% confidence interval (95% CI) for each group, and p < 0.05 was considered as statistically significant. As expected from clinical practice, metformin was associated with a markedly increased risk of abdominal pain, nausea, and vomiting compared to placebo. In comparison to other GLDs, taking metformin was related to an elevated risk of diarrhea and abdominal pain and to a lowered risk of vomiting and bloating. In turn, adding other GLDs to metformin treatment was associated with an elevated risk of nausea and vomiting than treatment with metformin in monotherapy. However, adding probiotics to metformin therapy was related to a decreased risk of diarrhea, bloating, and constipation. The obtained results demonstrate that the combination of metformin with other GLDs may elevate the risk of nausea and vomiting, whereas combination with probiotics decreases the risk of diarrhea, bloating, and constipation. Thus, the results of our meta-analysis suggest that probiotics may reduce the risk of some GI side effects in people with type 2 diabetes mellitus (T2DM) who started treatment with metformin. Full article

(This article belongs to the Special Issue Metformin: Mechanism and Application 2023)

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20 pages, 3505 KiB

Open AccessArticle

Lipidomics Profiling of Metformin-Induced Changes in Obesity and Type 2 Diabetes Mellitus: Insights and Biomarker Potential

by Muhammad Mujammami, Shereen M. Aleidi, Adriana Zardini Buzatto, Awad Alshahrani, Reem H. AlMalki, Hicham Benabdelkamel, Mohammed Al Dubayee, Liang Li, Ahmad Aljada and Anas M. Abdel Rahman

Pharmaceuticals 2023, 16(12), 1717; https://doi.org/10.3390/ph16121717 - 11 Dec 2023

Cited by 2 | Viewed by 1962

Abstract

Metformin is the first-line oral medication for treating type 2 diabetes mellitus (T2DM). In the current study, an untargeted lipidomic analytical approach was used to investigate the alterations in the serum lipidome of a cohort of 89 participants, including healthy lean controls and obese diabetic patients, and to examine the alterations associated with metformin administration. A total of 115 lipid molecules were significantly dysregulated (64 up-regulated and 51 down-regulated) in the obese compared to lean controls. However, the levels of 224 lipid molecules were significantly dysregulated (125 up-regulated and 99 down-regulated) in obese diabetic patients compared to the obese group. Metformin administration in obese diabetic patients was associated with significant dysregulation of 54 lipid molecule levels (20 up-regulated and 34 down-regulated). Levels of six molecules belonging to five lipid subclasses were simultaneously dysregulated by the effects of obesity, T2DM, and metformin. These include two putatively annotated triacylglycerols (TGs), one plasmenyl phosphatidylcholine (PC), one phosphatidylglycerol (PGs), one sterol lipid (ST), and one Mannosyl-phosphoinositol ceramide (MIPC). This study provides new insights into our understanding of the lipidomics alterations associated with obesity, T2DM, and metformin and offers a new platform for potential biomarkers for the progression of diabetes and treatment response in obese patients. Full article

(This article belongs to the Special Issue Metformin: Mechanism and Application 2023)

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12 pages, 2666 KiB

Open AccessArticle

The Impact of Metformin on the Development of Hypothyroidism and Cardiotoxicity Induced by Cyclophosphamide, Methotrexate, and Fluorouracil in Rats

by Ahmad H. Alhowail and Maha A. Aldubayan

Pharmaceuticals 2023, 16(9), 1312; https://doi.org/10.3390/ph16091312 - 16 Sep 2023

Cited by 1 | Viewed by 1452

Abstract

Cyclophosphamide (CYP), methotrexate (MTX), and 5-fluorouracil (5-FU) are extensively utilized in the therapeutic management of various malignancies. It is noteworthy, however, that potential chemotherapy-related complications include the occurrence of hypothyroidism and cardiotoxicity. Metformin (MET) is a pharmacological agent for managing type 2 diabetes. It has been reported to mitigate certain toxic manifestations associated with chemotherapy. This study’s primary objective is to investigate MET’s protective effects against hypothyroidism and cardiotoxicity induced by CMF treatment. A total of forty male rats were allocated into four distinct groups, each consisting of ten rats per group. These groups were categorized as follows: saline, MET, CMF, and CMF + MET. The experimental group of rats were administered CMF via intraperitoneal injection, receiving two doses of CMF, and fed MET in their daily drinking water, with a 2.5 mg/mL concentration. Blood samples were collected into EDTA tubes for assessment of TSH, free and total (T4 and T3), troponin I, CK, and CK-MB levels utilizing Electrochemiluminescence Immunoassays (ECI). The saline and MET groups did not exhibit significant alterations in thyroid hormones or cardiotoxic biomarkers. In contrast, in the CMF group, there was a notable reduction in T4, FT4, T3, and FT3 levels but no significant changes in TSH levels; however, troponin I, CK, and CK-MB levels were notably elevated. MET co-treatment with CMF did not ameliorate these effects caused by CMF. In conclusion, CMF treatment induced hypothyroidism and cardiotoxicity in rats, but MET co-treatment did not rescue the reduction of thyroid hormones or the elevation of cardiotoxic biomarkers. Full article

(This article belongs to the Special Issue Metformin: Mechanism and Application 2023)

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13 pages, 296 KiB

Open AccessArticle

Impaired Gonadotropin-Lowering Effects of Metformin in Postmenopausal Women with Autoimmune Thyroiditis: A Pilot Study

by Robert Krysiak, Marcin Basiak, Grzegorz Machnik and Bogusław Okopień

Pharmaceuticals 2023, 16(7), 922; https://doi.org/10.3390/ph16070922 - 24 Jun 2023

Cited by 3 | Viewed by 1604

Abstract

Metformin has been found to reduce elevated gonadotropin levels. Hashimoto’s thyroiditis is the most common thyroid disorder in iodine-sufficient areas, and it often develops in postmenopausal women. The aim of this study was to investigate whether autoimmune thyroiditis determines the impact of metformin on gonadotrope secretory function. Two matched groups of postmenopausal women were studied: 35 with euthyroid Hashimoto’s thyroiditis (group A) and 35 without thyroid disorders (group B). Throughout the study, all participants received oral metformin (2.55–3 g daily). Plasma glucose, insulin, gonadotropins, estradiol, progesterone, thyrotropin, free thyroid hormones, prolactin, adrenocorticotropic hormone, insulin-like growth factor-1, hsCRP, thyroid peroxidase, and thyroglobulin antibody titers were measured at the beginning of the study and six months later. At entry, both groups differed in thyroid peroxidase antibody titers, thyroglobulin antibody titers, and hsCRP levels. In group A, baseline antibody titers correlated positively with hsCRP and negatively with insulin sensitivity. Although metformin improved glucose homeostasis and reduced hsCRP levels in both study groups, these effects were more pronounced in group B than in group A. Only in group B did metformin decrease FSH levels and tend to reduce LH levels. Thyroid antibody titers and the levels of the remaining hormones did not change throughout the study. The impact of metformin on gonadotropin levels correlated with their baseline values and the degree of improvement in insulin sensitivity, as well as with the baseline and treatment-induced reduction in hsCRP. Moreover, the impact on gonadotropins and insulin sensitivity in group A depended on baseline antibody titers. The obtained results indicate that coexisting autoimmune thyroiditis impairs the gonadotropin-lowering effects of metformin in postmenopausal women. Full article

(This article belongs to the Special Issue Metformin: Mechanism and Application 2023)

14 pages, 2378 KiB

Open AccessCommunication

Metformin Therapy Changes Gut Microbiota Alpha-Diversity in COVID-19 Patients with Type 2 Diabetes: The Role of SARS-CoV-2 Variants and Antibiotic Treatment

by Pavlo Petakh, Iryna Kamyshna, Valentyn Oksenych, Denis Kainov and Aleksandr Kamyshnyi

Pharmaceuticals 2023, 16(6), 904; https://doi.org/10.3390/ph16060904 - 20 Jun 2023

Cited by 12 | Viewed by 2726

Abstract

The gut microbiota play a crucial role in maintaining host health and have a significant impact on human health and disease. In this study, we investigated the alpha diversity of gut microbiota in COVID-19 patients and analyzed the impact of COVID-19 variants, antibiotic treatment, type 2 diabetes (T2D), and metformin therapy on gut microbiota composition and diversity. We used a culture-based method to analyze the gut microbiota and calculated alpha-diversity using the Shannon H′ and Simpson 1/D indices. We collected clinical data, such as the length of hospital stay (LoS), C-reactive protein (CRP) levels, and neutrophil-to-lymphocyte ratio. We found that patients with T2D had significantly lower alpha-diversity than those without T2D. Antibiotic use was associated with a reduction in alpha-diversity, while metformin therapy was associated with an increase. We did not find significant differences in alpha-diversity between the Delta and Omicron groups. The length of hospital stay, CRP levels, and NLR showed weak to moderate correlations with alpha diversity. Our findings suggest that maintaining a diverse gut microbiota may benefit COVID-19 patients with T2D. Interventions to preserve or restore gut microbiota diversity, such as avoiding unnecessary antibiotic use, promoting metformin therapy, and incorporating probiotics, may improve patient outcomes. Full article

(This article belongs to the Special Issue Metformin: Mechanism and Application 2023)

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Review

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25 pages, 1912 KiB

Open AccessReview

View on Metformin: Antidiabetic and Pleiotropic Effects, Pharmacokinetics, Side Effects, and Sex-Related Differences

by Guglielmina Froldi

Pharmaceuticals 2024, 17(4), 478; https://doi.org/10.3390/ph17040478 - 8 Apr 2024

Cited by 6 | Viewed by 4122

Abstract

Metformin is a synthetic biguanide used as an antidiabetic drug in type 2 diabetes mellitus, achieved by studying the bioactive metabolites of Galega officinalis L. It is also used off-label for various other diseases, such as subclinical diabetes, obesity, polycystic ovary syndrome, etc. In addition, metformin is proposed as an add-on therapy for several conditions, including autoimmune diseases, neurodegenerative diseases, and cancer. Although metformin has been used for many decades, it is still the subject of many pharmacodynamic and pharmacokinetic studies in light of its extensive use. Metformin acts at the mitochondrial level by inhibiting the respiratory chain, thus increasing the AMP/ATP ratio and, subsequently, activating the AMP-activated protein kinase. However, several other mechanisms have been proposed, including binding to presenilin enhancer 2, increasing GLP1 release, and modification of microRNA expression. Regarding its pharmacokinetics, after oral administration, metformin is absorbed, distributed, and eliminated, mainly through the renal route, using transporters for cationic solutes, since it exists as an ionic molecule at physiological pH. In this review, particular consideration has been paid to literature data from the last 10 years, deepening the study of clinical trials inherent to new uses of metformin, the differences in effectiveness and safety observed between the sexes, and the unwanted side effects. For this last objective, metformin safety was also evaluated using both VigiBase and EudraVigilance, respectively, the WHO and European databases of the reported adverse drug reactions, to assess the extent of metformin side effects in real-life use. Full article

(This article belongs to the Special Issue Metformin: Mechanism and Application 2023)

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36 pages, 1970 KiB

Open AccessReview

Metformin and Breast Cancer: Current Findings and Future Perspectives from Preclinical and Clinical Studies

by Karen A. Corleto, Jenna L. Strandmo and Erin D. Giles

Pharmaceuticals 2024, 17(3), 396; https://doi.org/10.3390/ph17030396 - 19 Mar 2024

Cited by 2 | Viewed by 5449

Abstract

Over the last several decades, a growing body of research has investigated the potential to repurpose the anti-diabetic drug metformin for breast cancer prevention and/or treatment. Observational studies in the early 2000s demonstrated that patients with diabetes taking metformin had decreased cancer risk, providing the first evidence supporting the potential role of metformin as an anti-cancer agent. Despite substantial efforts, two decades later, the exact mechanisms and clinical efficacy of metformin for breast cancer remain ambiguous. Here, we have summarized key findings from studies examining the effect of metformin on breast cancer across the translational spectrum including in vitro, in vivo, and human studies. Importantly, we discuss critical factors that may help explain the significant heterogeneity in study outcomes, highlighting how metformin dose, underlying metabolic health, menopausal status, tumor subtype, membrane transporter expression, diet, and other factors may play a role in modulating metformin’s anti-cancer effects. We hope that these insights will help with interpreting data from completed studies, improve the design of future studies, and aid in the identification of patient subsets with breast cancer or at high risk for the disease who are most likely to benefit from metformin treatment. Full article

(This article belongs to the Special Issue Metformin: Mechanism and Application 2023)

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36 pages, 2464 KiB

Open AccessReview

Metformin: The Winding Path from Understanding Its Molecular Mechanisms to Proving Therapeutic Benefits in Neurodegenerative Disorders

by Laura Mihaela Isop, Andrea Elena Neculau, Radu Dan Necula, Cristian Kakucs, Marius Alexandru Moga and Lorena Dima

Pharmaceuticals 2023, 16(12), 1714; https://doi.org/10.3390/ph16121714 - 11 Dec 2023

Cited by 4 | Viewed by 4104

Abstract

Metformin, a widely prescribed medication for type 2 diabetes, has garnered increasing attention for its potential neuroprotective properties due to the growing demand for treatments for Alzheimer’s, Parkinson’s, and motor neuron diseases. This review synthesizes experimental and clinical studies on metformin’s mechanisms of action and potential therapeutic benefits for neurodegenerative disorders. A comprehensive search of electronic databases, including PubMed, MEDLINE, Embase, and Cochrane library, focused on key phrases such as “metformin”, “neuroprotection”, and “neurodegenerative diseases”, with data up to September 2023. Recent research on metformin’s glucoregulatory mechanisms reveals new molecular targets, including the activation of the LKB1–AMPK signaling pathway, which is crucial for chronic administration of metformin. The pleiotropic impact may involve other stress kinases that are acutely activated. The precise role of respiratory chain complexes (I and IV), of the mitochondrial targets, or of the lysosomes in metformin effects remains to be established by further research. Research on extrahepatic targets like the gut and microbiota, as well as its antioxidant and immunomodulatory properties, is crucial for understanding neurodegenerative disorders. Experimental data on animal models shows promising results, but clinical studies are inconclusive. Understanding the molecular targets and mechanisms of its effects could help design clinical trials to explore and, hopefully, prove its therapeutic effects in neurodegenerative conditions. Full article

(This article belongs to the Special Issue Metformin: Mechanism and Application 2023)

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25 pages, 873 KiB

Open AccessReview

Metformin in Gestational Diabetes Mellitus: To Use or Not to Use, That Is the Question

by Vera Tocci, Maria Mirabelli, Alessandro Salatino, Luciana Sicilia, Stefania Giuliano, Francesco S. Brunetti, Eusebio Chiefari, Giovambattista De Sarro, Daniela P. Foti and Antonio Brunetti

Pharmaceuticals 2023, 16(9), 1318; https://doi.org/10.3390/ph16091318 - 18 Sep 2023

Cited by 7 | Viewed by 8399

Abstract

In recent years, there has been a dramatic increase in the number of pregnancies complicated by gestational diabetes mellitus (GDM). GDM occurs when maternal insulin resistance develops and/or progresses during gestation, and it is not compensated by a rise in maternal insulin secretion. If not properly managed, this condition can cause serious short-term and long-term problems for both mother and child. Lifestyle changes are the first line of treatment for GDM, but if ineffective, insulin injections are the recommended pharmacological treatment choice. Some guidance authorities and scientific societies have proposed the use of metformin as an alternative pharmacological option for treating GDM, but there is not yet a unanimous consensus on this. Although the use of metformin appears to be safe for the mother, concerns remain about its long-term metabolic effects on the child that is exposed in utero to the drug, given that metformin, contrary to insulin, crosses the placenta. This review article describes the existing lines of evidence about the use of metformin in pregnancies complicated by GDM, in order to clarify its potential benefits and limits, and to help clinicians make decisions about who could benefit most from this drug treatment. Full article

(This article belongs to the Special Issue Metformin: Mechanism and Application 2023)

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18 pages, 1034 KiB

Open AccessReview

Effects of Metformin on Ischemia/Reperfusion Injury: New Evidence and Mechanisms

by Estefanie Osorio-Llanes, Wendy Villamizar-Villamizar, María Clara Ospino Guerra, Luis Antonio Díaz-Ariza, Sara Camila Castiblanco-Arroyave, Luz Medrano, Daniela Mengual, Ricardo Belón, Jairo Castellar-López, Yanireth Sepúlveda, César Vásquez-Trincado, Aileen Y. Chang, Samir Bolívar and Evelyn Mendoza-Torres

Pharmaceuticals 2023, 16(8), 1121; https://doi.org/10.3390/ph16081121 - 9 Aug 2023

Cited by 4 | Viewed by 2542

Abstract

The search for new drugs with the potential to ensure therapeutic success in the treatment of cardiovascular diseases has become an essential pathway to follow for health organizations and committees around the world. In June 2021, the World Health Organization listed cardiovascular diseases as one of the main causes of death worldwide, representing 32% of them. The most common is coronary artery disease, which causes the death of cardiomyocytes, the cells responsible for cardiac contractility, through ischemia and subsequent reperfusion, which leads to heart failure in the medium and short term. Metformin is one of the most-used drugs for the control of diabetes, which has shown effects beyond the control of hyperglycemia. Some of these effects are mediated by the regulation of cellular energy metabolism, inhibiting apoptosis, reduction of cell death through regulation of autophagy and reduction of mitochondrial dysfunction with further reduction of oxidative stress. This suggests that metformin may attenuate left ventricular dysfunction induced by myocardial ischemia; preclinical and clinical trials have shown promising results, particularly in the setting of acute myocardial infarction. This is a review of the molecular and pharmacological mechanisms of the cardioprotective effects of metformin during myocardial ischemia-reperfusion injury. Full article

(This article belongs to the Special Issue Metformin: Mechanism and Application 2023)

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