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Special Issue "Metformin: Mechanism and Application"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 July 2018)

Special Issue Editor

Guest Editor
Dr. Jolanta Weaver

Newcastle University, United Kingdom, Institute of Cellular Medicine/Cardiovascular Research Centre, Newcastle, UK
Website | E-Mail
Interests: cardiovascular disease; diabetes mellitus; vascular stem cells; endothelial progenitor cells; repurposing metformin for CVD; risk factors for CVD; in vitro models of CVD; clinical trials

Special Issue Information

Dear Colleagues,

Although metformin has been available for almost a century, Europe only discovered it 60 years ago. However, it took a further 38 years for America to appreciate its virtues. Metformin has been shown to be the first cardioprotective drug in type 2 diabetes, as born by UKPDS trial, and others that followed. The scientific interest in metformin has recently increased with a variety of tissues being studied, and use of metformin in a wide range of patients outside licensed indications. The pleiotrophic actions of metformin stretch from improving insulin resistance, membrane-related effects to cardioprotective mechanism via CD34+ umbilical cord blood stem cells and the reduction of myocardial infarct size. This Special Issue of the International Journal of Molecular Sciences has the aspiration of addressing (nonexclusively) the mechanisms of metformin action in different tissues from endothelial cells, hepatocytes, myocytes, cancer cells to clinical studies of translational design supported by laboratory investigations. The purpose of this issue is to focus on fundamental differences distinguishing tissue-specific effects and common themes related to metformin therapy in different patient groups. The appraisal of previous and current research on this compound is likely to benefit the future discoveries of novel applications of metformin.

Dr. Jolanta Weaver
Guest Editor

Manuscript Submission Information

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Keywords

  • metformin
  • energy metabolism
  • AMPK
  • hepatocytes
  • adipocytes
  • endothelial cells
  • angiogenesis
  • VEGFR
  • eNOS
  • cardiovascular disease
  • diabetes

Published Papers (11 papers)

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Research

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Open AccessArticle
Anti-Angiogenic miR-222, miR-195, and miR-21a Plasma Levels in T1DM Are Improved by Metformin Therapy, Thus Elucidating Its Cardioprotective Effect: The MERIT Study
Int. J. Mol. Sci. 2018, 19(10), 3242; https://doi.org/10.3390/ijms19103242
Received: 27 July 2018 / Revised: 4 September 2018 / Accepted: 6 September 2018 / Published: 19 October 2018
Cited by 2 | PDF Full-text (1417 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Type 1 diabetes (T1DM) is associated with increased cardiovascular disease (CVD) and reduced life expectancy. We thus hypothesized that anti-angiogenic miRs are increased in T1DM, and the cardioprotective effect of metformin is mediated via reducing those miRs. In an open label, case-controlled study, [...] Read more.
Type 1 diabetes (T1DM) is associated with increased cardiovascular disease (CVD) and reduced life expectancy. We thus hypothesized that anti-angiogenic miRs are increased in T1DM, and the cardioprotective effect of metformin is mediated via reducing those miRs. In an open label, case-controlled study, 23 T1DM patients without CVD were treated with metformin for eight weeks (TG), matched with nine T1DM patients on standard treatment (SG) and 23 controls (CG). Plasma miR-222, miR-195, miR-21a and miR-126 were assayed by real-time RT-qPCR. The results were correlated with: endothelial function (RHI), circulating endothelial progenitor cells (cEPCs) (vascular repair marker, CD45dimCD34+VEGFR2+ cells) and circulating endothelial cells (cECs) (vascular injury marker, CD45dimCD34+CD133-CD144+ cells). miR-222, miR-195 and miR-21a were higher in T1DM than CG; p = 0.009, p < 0.0001, p = 0.0001, respectively. There was an inverse correlation between logmiR-222 and logRHI (p < 0.05) and a direct correlation between logmiR-222 and logCD34+ (p < 0.05) in TG. Metformin reduced miR-222, miR-195 and miR-21a levels in TG; p = 0.007, p = 0.002 p = 0.0012, respectively. miRs remained unchanged in SG. miR-126 was similar in all groups. There was a positive association between changes in logmiR-222 and logcECs after metformin in TG (p < 0.05). Anti-angiogenic miRs are increased in T1DM. Metformin has cardioprotective effects through downregulating miR-222, miR-195 and miR-21a, beyond improving glycemic control. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application)
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Open AccessArticle
Hyperglycemia-Associated Dysregulation of O-GlcNAcylation and HIF1A Reduces Anticancer Action of Metformin in Ovarian Cancer Cells (SKOV-3)
Int. J. Mol. Sci. 2018, 19(9), 2750; https://doi.org/10.3390/ijms19092750
Received: 13 July 2018 / Revised: 5 September 2018 / Accepted: 11 September 2018 / Published: 13 September 2018
Cited by 1 | PDF Full-text (22498 KB) | HTML Full-text | XML Full-text
Abstract
Although cancer cells need more glucose than normal cells to maintain energy demand, chronic hyperglycemia induces metabolic alteration that may dysregulate signaling pathways, including the O-GlcNAcylation and HIF1A (Hypoxia-inducible factor 1-alpha) pathways. Metformin was demonstrated to evoke metabolic stress and induce cancer cell [...] Read more.
Although cancer cells need more glucose than normal cells to maintain energy demand, chronic hyperglycemia induces metabolic alteration that may dysregulate signaling pathways, including the O-GlcNAcylation and HIF1A (Hypoxia-inducible factor 1-alpha) pathways. Metformin was demonstrated to evoke metabolic stress and induce cancer cell death. The aim of this study was to determine the cytotoxic efficiency of metformin on SKOV-3 cells cultured in hyperglycemia and normoglycemia. To identify the potential mechanism, we assessed the expression of O-linked β-N-acetlyglucosamine transferase (OGT) and glycoside hydrolase O-GlcNAcase (OGA), as well as hypoxia-inducible factor 1-alpha (HIF1A) and glucose transporters (GLUT1, GLUT3). SKOV-3 cells were cultured in normoglycaemia (NG, 5 mM) and hyperglycemia (HG, 25 mM) with and without 10 mM metformin for 24, 48, and 72 h. The proliferation rate, apoptotic and necrotic SKOV-3 cell death were evaluated. Real-Time qPCR was employed to determine mRNA expression of OGT, OGA, GLUT1, GLUT3, and HIF1A. Metformin significantly reduced the proliferation of SKOV-3 cells under normal glucose conditions. Whereas, the efficacy of metformin to induce SKOV-3 cell death was reduced in hyperglycemia. Both hyperglycemia and metformin induced changes in the expression of genes involved in the O-GlcNAcylation status and HIF1A pathway. The obtained results suggest that dysregulation of O-GlcNAcylation, and the related HIF1A pathway, via hyperglycemia, is responsible for the decreased cytotoxic efficiency of metformin in human ovarian cancer cells. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application)
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Open AccessArticle
Combined Modulation of Tumor Metabolism by Metformin and Diclofenac in Glioma
Int. J. Mol. Sci. 2018, 19(9), 2586; https://doi.org/10.3390/ijms19092586
Received: 15 July 2018 / Revised: 24 August 2018 / Accepted: 28 August 2018 / Published: 31 August 2018
Cited by 3 | PDF Full-text (1920 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Glioblastoma remains a fatal diagnosis. Previous research has shown that metformin, which is an inhibitor of complex I of the respiratory chain, may inhibit some brain tumor initiating cells (BTICs), albeit at dosages that are too high for clinical use. Here, we explored [...] Read more.
Glioblastoma remains a fatal diagnosis. Previous research has shown that metformin, which is an inhibitor of complex I of the respiratory chain, may inhibit some brain tumor initiating cells (BTICs), albeit at dosages that are too high for clinical use. Here, we explored whether a combined treatment of metformin and diclofenac, which is a non-steroidal anti-inflammatory drug (NSAID) shown to inhibit glycolysis by interfering with lactate efflux, may lead to additive or even synergistic effects on BTICs (BTIC-8, -11, -13 and -18) and tumor cell lines (TCs, U87, and HTZ349). Therefore, we investigated the functional effects, including proliferation and migration, metabolic effects including oxygen consumption and extracellular lactate levels, and effects on the protein level, including signaling pathways. Functional investigation revealed synergistic anti-migratory and anti-proliferative effects of the combined treatment with metformin and diclofenac on BTICs and TCs. Signaling pathways did not sufficiently explain synergistic effects. However, we observed that metformin inhibited cellular oxygen consumption and increased extracellular lactate levels, indicating glycolytic rescue mechanisms. Combined treatment inhibited metformin-induced lactate increase. The combination of metformin and diclofenac may represent a promising new strategy in the treatment of glioblastoma. Combined treatment may reduce the effective doses of the single agents and prevent metabolic rescue mechanisms. Further studies are needed in order to determine possible side effects in humans. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application)
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Open AccessArticle
Metformin Induces Apoptosis and Alters Cellular Responses to Oxidative Stress in Ht29 Colon Cancer Cells: Preliminary Findings
Int. J. Mol. Sci. 2018, 19(5), 1478; https://doi.org/10.3390/ijms19051478
Received: 20 March 2018 / Revised: 25 April 2018 / Accepted: 10 May 2018 / Published: 16 May 2018
Cited by 6 | PDF Full-text (3559 KB) | HTML Full-text | XML Full-text
Abstract
Accumulating evidence suggests that metformin, used as an antidiabetic drug, possesses anti-cancer properties. Metformin reduced the incidence and growth of experimental tumors in vivo. In a randomized clinical trial among nondiabetic patients, metformin treatment significantly decreased the number of aberrant crypt foci compared [...] Read more.
Accumulating evidence suggests that metformin, used as an antidiabetic drug, possesses anti-cancer properties. Metformin reduced the incidence and growth of experimental tumors in vivo. In a randomized clinical trial among nondiabetic patients, metformin treatment significantly decreased the number of aberrant crypt foci compared to the untreated group with a follow-up of 1 month. In our study, HT29 cells were treated with graded concentrations of metformin, 10 mM/25 mM/50 mM for 24/48 h. We performed immunofluorescence experiments by means of confocal microscopy and western blot analysis to evaluate a panel of factors involved in apoptotic/autophagic processes and oxidative stress response. Moreover, HT29 cells treated with metformin were analyzed by a flow cytometry assay to detect the cell apoptotic rate. The results demonstrate that metformin exerts growth inhibitory effects on cultured HT29 cells by increasing both apoptosis and autophagy; moreover, it affects the survival of cultured cells inhibiting the transcriptional activation of Nuclear factor E2-related factor 2 (NRF-2) and nuclear factor-kappa B (NF-κB). The effects of metformin on HT29 cells were dose- and time-dependent. These results are very intriguing since metformin is emerging as a multi-faceted drug: It has a good safety profile and is associated with low cost and might be a promising candidate for the prevention or the treatment of colorectal cancer. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application)
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Open AccessArticle
Prenatal Metformin Therapy Attenuates Hypertension of Developmental Origin in Male Adult Offspring Exposed to Maternal High-Fructose and Post-Weaning High-Fat Diets
Int. J. Mol. Sci. 2018, 19(4), 1066; https://doi.org/10.3390/ijms19041066
Received: 17 February 2018 / Revised: 19 March 2018 / Accepted: 1 April 2018 / Published: 3 April 2018
Cited by 2 | PDF Full-text (7119 KB) | HTML Full-text | XML Full-text
Abstract
Widespread consumption of a Western diet, comprised of highly refined carbohydrates and fat, may play a role in the epidemic of hypertension. Hypertension can take origin from early life. Metformin is the preferred treatment for type 2 diabetes. We examined whether prenatal metformin [...] Read more.
Widespread consumption of a Western diet, comprised of highly refined carbohydrates and fat, may play a role in the epidemic of hypertension. Hypertension can take origin from early life. Metformin is the preferred treatment for type 2 diabetes. We examined whether prenatal metformin therapy can prevent maternal high-fructose plus post-weaning high-fat diets-induced hypertension of developmental origins via regulation of nutrient sensing signals, uric acid, oxidative stress, and the nitric oxide (NO) pathway. Gestating Sprague–Dawley rats received regular chow (ND) or chow supplemented with 60% fructose diet (HFR) throughout pregnancy and lactation. Male offspring were onto either the ND or high-fat diet (HFA) from weaning to 12 weeks of age. A total of 40 male offspring were assigned to five groups (n = 8/group): ND/ND, HFR/ND, ND/HFA, HFR/HFA, and HFR/HFA+metformin. Metformin (500 mg/kg/day) was administered via gastric gavage for three weeks during the pregnancy period. Combined maternal HFR plus post-weaning HFA induced hypertension in male adult offspring, which prenatal metformin therapy prevented. The protective effects of prenatal metformin therapy on HFR/HFA-induced hypertension, including downregulation of the renin-angiotensin system, decrease in uric acid level, and reduction of oxidative stress. Our results highlighted that the programming effects of metformin administered prenatally might be different from those reported in adults, and that deserves further elucidation. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application)
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Open AccessArticle
Proangiogenic Effect of Metformin in Endothelial Cells Is via Upregulation of VEGFR1/2 and Their Signaling under Hyperglycemia-Hypoxia
Int. J. Mol. Sci. 2018, 19(1), 293; https://doi.org/10.3390/ijms19010293
Received: 10 December 2017 / Revised: 12 January 2018 / Accepted: 17 January 2018 / Published: 19 January 2018
Cited by 9 | PDF Full-text (2577 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Cardiovascular disease is the leading cause of morbidity/mortality worldwide. Metformin is the first therapy offering cardioprotection in type 2 diabetes and non-diabetic animals with unknown mechanism. We have shown that metformin improves angiogenesis via affecting expression of growth factors/angiogenic inhibitors in CD34+ [...] Read more.
Cardiovascular disease is the leading cause of morbidity/mortality worldwide. Metformin is the first therapy offering cardioprotection in type 2 diabetes and non-diabetic animals with unknown mechanism. We have shown that metformin improves angiogenesis via affecting expression of growth factors/angiogenic inhibitors in CD34+ cells under hyperglycemia-hypoxia. Now we studied the direct effect of physiological dose of metformin on human umbilical vein endothelial cells (HUVEC) under conditions mimicking hypoxia-hyperglycemia. HUVEC migration and apoptosis were studied after induction with euglycemia or hyperglycemia and/or CoCl2 induced hypoxia in the presence or absence of metformin. HUVEC mRNA was assayed by whole transcript microarrays. Genes were confirmed by qRT-PCR, proteins by western blot, ELISA or flow cytometry. Metformin promoted HUVEC migration and inhibited apoptosis via upregulation of vascular endothelial growth factor (VEGF) receptors (VEGFR1/R2), fatty acid binding protein 4 (FABP4), ERK/mitogen-activated protein kinase signaling, chemokine ligand 8, lymphocyte antigen 96, Rho kinase 1 (ROCK1), matrix metalloproteinase 16 (MMP16) and tissue factor inhibitor-2 under hyperglycemia-chemical hypoxia. Therefore, metformin’s dual effect in hyperglycemia-chemical hypoxia is mediated by direct effect on VEGFR1/R2 leading to activation of cell migration through MMP16 and ROCK1 upregulation, and inhibition of apoptosis by increase in phospho-ERK1/2 and FABP4, components of VEGF signaling cascades. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application)
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Review

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Open AccessReview
Metformin: A Candidate Drug for Renal Diseases
Int. J. Mol. Sci. 2019, 20(1), 42; https://doi.org/10.3390/ijms20010042
Received: 27 October 2018 / Revised: 12 December 2018 / Accepted: 20 December 2018 / Published: 21 December 2018
Cited by 1 | PDF Full-text (1403 KB) | HTML Full-text | XML Full-text
Abstract
Over the past decades metformin has been the optimal first-line treatment for type 2 diabetes mellitus (T2DM). Only in the last few years, it has become increasingly clear that metformin exerts benign pleiotropic actions beyond its prescribed use and ongoing investigations focus on [...] Read more.
Over the past decades metformin has been the optimal first-line treatment for type 2 diabetes mellitus (T2DM). Only in the last few years, it has become increasingly clear that metformin exerts benign pleiotropic actions beyond its prescribed use and ongoing investigations focus on a putative beneficial impact of metformin on the kidney. Both acute kidney injury (AKI) and chronic kidney disease (CKD), two major renal health issues, often result in the need for renal replacement therapy (dialysis or transplantation) with a high socio-economic impact for the patients. Unfortunately, to date, effective treatment directly targeting the kidney is lacking. Metformin has been shown to exert beneficial effects on the kidney in various clinical trials and experimental studies performed in divergent rodent models representing different types of renal diseases going from AKI to CKD. Despite growing evidence on metformin as a candidate drug for renal diseases, in-depth research is imperative to unravel the molecular signaling pathways responsible for metformin’s renoprotective actions. This review will discuss the current state-of-the-art literature on clinical and preclinical data, and put forward potential cellular mechanisms and molecular pathways by which metformin ameliorates AKI/CKD. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application)
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Open AccessReview
Metabolic Effects of Metformin in the Failing Heart
Int. J. Mol. Sci. 2018, 19(10), 2869; https://doi.org/10.3390/ijms19102869
Received: 14 August 2018 / Revised: 11 September 2018 / Accepted: 17 September 2018 / Published: 21 September 2018
PDF Full-text (3115 KB) | HTML Full-text | XML Full-text
Abstract
Accumulating evidence shows that metformin is an insulin-sensitizing antidiabetic drug widely used in the treatment of type 2 diabetes mellitus (T2DM), which can exert favorable effects on cardiovascular risk and may be safely used in patients with heart failure (HF), and even able [...] Read more.
Accumulating evidence shows that metformin is an insulin-sensitizing antidiabetic drug widely used in the treatment of type 2 diabetes mellitus (T2DM), which can exert favorable effects on cardiovascular risk and may be safely used in patients with heart failure (HF), and even able to reduce the incidence of HF and to reduce HF mortality. In failing hearts, metformin improves myocardial energy metabolic status through the activation of AMP (adenosine monophosphate)-activated protein kinase (AMPK) and the regulation of lipid and glucose metabolism. By increasing nitric oxide (NO) bioavailability, limiting interstitial fibrosis, reducing the deposition of advanced glycation end-products (AGEs), and inhibiting myocardial cell apoptosis metformin reduces cardiac remodeling and hypertrophy, and thereby preserves left ventricular systolic and diastolic functions. While a lot of preclinical and clinical studies showed the cardiovascular safety of metformin therapy in diabetic patients and HF, to confirm observed benefits, the specific large-scale trials configured for HF development in diabetic patients as a primary endpoints are necessary. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application)
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Open AccessReview
Metformin: An Old Drug with New Applications
Int. J. Mol. Sci. 2018, 19(10), 2863; https://doi.org/10.3390/ijms19102863
Received: 27 July 2018 / Revised: 11 September 2018 / Accepted: 17 September 2018 / Published: 21 September 2018
Cited by 5 | PDF Full-text (1610 KB) | HTML Full-text | XML Full-text
Abstract
Metformin is a biguanide drug that has been used to treat type 2 diabetes mellitus for more than 60 years. The United Kingdom Prospective Diabetic Study (UKPDS) has shown metformin to improve mortality rates in diabetes patients, and recent studies suggest metformin has [...] Read more.
Metformin is a biguanide drug that has been used to treat type 2 diabetes mellitus for more than 60 years. The United Kingdom Prospective Diabetic Study (UKPDS) has shown metformin to improve mortality rates in diabetes patients, and recent studies suggest metformin has additional effects in treating cancer, obesity, nonalcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), and metabolic syndrome. Metformin has also been shown to alleviate weight gain associated with antipsychotic medication. Metformin has recently been extensively studied and emerging evidence suggests metformin decreases hepatocyte triglyceride accumulation in NAFLD and prevents liver tumorigenesis. Interestingly, studies have also shown metformin reduces visceral fat, suppresses white-adipose-tissue (WAT) extracellular matrix remodeling, and inhibits obesity-induced inflammation. However, clinical evidence for using metformin to treat NAFLD, cancer, metabolic syndrome, or to prevent hepatocellular carcinoma in NAFLD patients is lacking. This review therefore addresses the potential beneficial effects of metformin on NAFLD, its role in protecting against cardiac ischemia–reperfusion (I/R) injury, atherosclerosis, glucotoxicity, and lipotoxicity induced oxidative and ER stress in pancreatic β-cell dysfunction, as well as its underlying molecular mechanisms of action. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application)
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Open AccessReview
Pleiotropic Effects of Metformin on Cancer
Int. J. Mol. Sci. 2018, 19(10), 2850; https://doi.org/10.3390/ijms19102850
Received: 20 July 2018 / Revised: 7 September 2018 / Accepted: 14 September 2018 / Published: 20 September 2018
Cited by 7 | PDF Full-text (570 KB) | HTML Full-text | XML Full-text
Abstract
Metformin (MTF) is a natural compound derived from the legume Galega officinalis. It is the first line antidiabetic drug for type 2 diabetes (T2D) treatment. One of its main antidiabetic effects results from the reduction of hepatic glucose release. First scientific evidence [...] Read more.
Metformin (MTF) is a natural compound derived from the legume Galega officinalis. It is the first line antidiabetic drug for type 2 diabetes (T2D) treatment. One of its main antidiabetic effects results from the reduction of hepatic glucose release. First scientific evidence for the anticancer effects of MTF was found in animal research, published in 2001, and some years later a retrospective observational study provided evidence that linked MTF to reduced cancer risk in T2D patients. Its pleiotropic anticancer effects were studied in numerous in vitro and in vivo studies at the molecular and cellular level. Although the majority of these studies demonstrated that MTF is associated with certain anticancer properties, clinical studies and trials provided a mixed view on its beneficial anticancer effects. This review emphasizes the pleiotropic effects of MTF and recent progress made in MTF applications in basic, preclinical, and clinical cancer research. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application)
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Open AccessReview
Metformin in Pregnancy: Mechanisms and Clinical Applications
Int. J. Mol. Sci. 2018, 19(7), 1954; https://doi.org/10.3390/ijms19071954
Received: 29 May 2018 / Revised: 12 June 2018 / Accepted: 29 June 2018 / Published: 4 July 2018
Cited by 2 | PDF Full-text (1959 KB) | HTML Full-text | XML Full-text
Abstract
Metformin use in pregnancy is increasing worldwide as randomised controlled trial (RCT) evidence is emerging demonstrating its safety and efficacy. The Metformin in Gestational Diabetes (MiG) RCT changed practice in many countries demonstrating that metformin had similar pregnancy outcomes to insulin therapy with [...] Read more.
Metformin use in pregnancy is increasing worldwide as randomised controlled trial (RCT) evidence is emerging demonstrating its safety and efficacy. The Metformin in Gestational Diabetes (MiG) RCT changed practice in many countries demonstrating that metformin had similar pregnancy outcomes to insulin therapy with less maternal weight gain and a high degree of patient acceptability. A multicentre RCT is currently assessing the addition of metformin to insulin in pregnant women with type 2 diabetes. RCT evidence is also available for the use of metformin in pregnancy for women with Polycystic Ovarian Syndrome and for nondiabetic women with obesity. No evidence of an increase in congenital malformations or miscarriages has been observed even when metformin is started before pregnancy and continued to term. Body composition and metabolic outcomes at two, seven, and nine years have now been reported for the offspring of mothers treated in the MiG study. In this review, we will briefly discuss the action of metformin and then consider the evidence from the key clinical trials. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application)
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