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Emerging Microbes & Infections Dec 2022Increased evidence shows that gut microbiota acts as the primary regulator of the liver; however, its role in sepsis-related liver injury (SLI) in the elderly is...
Increased evidence shows that gut microbiota acts as the primary regulator of the liver; however, its role in sepsis-related liver injury (SLI) in the elderly is unclear. This study assessed whether metformin could attenuate SLI by modulating gut microbiota in septic-aged rats. Cecal ligation and puncture (CLP) was used to induce SLI in aged rats. Fecal microbiota transplantation (FMT) was used to validate the roles of gut microbiota in these pathologies. The composition of gut microbiota was analysed by 16S rRNA sequencing. Moreover, the liver and colon tissues were analysed by histopathology, immunofluorescence, immunohistochemistry, and reverse transcription polymerase chain reaction (RT-PCR). Metformin improved liver damage, colon barrier dysfunction in aged SLI rats. Moreover, metformin improved sepsis-induced liver inflammation and damage under gut microbiota. Importantly, FMT assay showed that rats gavaged with faeces from metformin-treated SLI rats displayed less severe liver damage and colon barrier dysfunctions than those gavaged with faeces from SLI rats. The gut microbiota composition among the sham-operated, CLP-operated and metformin-treated SLI rats was different. In particular, the proportion of and was higher in SLI rats than sham-operated and metformin-treated SLI rats; while metformin could increase the proportion of , , and in aged SLI rats. Additionally, and correlated positively with the inflammatory factors in the liver. Our findings suggest that metformin may improve liver injury by regulating the gut microbiota and alleviating colon barrier dysfunction in septic-aged rats, which may be an effective therapy for SLI.
Topics: Animals; Gastrointestinal Microbiome; Liver; Metformin; RNA, Ribosomal, 16S; Rats; Sepsis
PubMed: 35191819
DOI: 10.1080/22221751.2022.2045876 -
American Journal of Physiology. Cell... May 2021The biguanide metformin is the most commonly used antidiabetic drug. Recent studies show that metformin not only improves chronic inflammation by improving metabolic... (Review)
Review
The biguanide metformin is the most commonly used antidiabetic drug. Recent studies show that metformin not only improves chronic inflammation by improving metabolic parameters but also has a direct anti-inflammatory effect. In light of these findings, it is essential to identify the inflammatory pathways targeted by metformin to develop a comprehensive understanding of the mechanisms of action of this drug. Commonly accepted mechanisms of metformin action include AMPK activation and inhibition of mTOR pathways, which are evaluated in multiple diseases. Additionally, metformin's action on mitochondrial function and cellular homeostasis processes such as autophagy is of particular interest because of the importance of these mechanisms in maintaining cellular health. Both dysregulated mitochondria and failure of the autophagy pathways, the latter of which impair clearance of dysfunctional, damaged, or excess organelles, affect cellular health drastically and can trigger the onset of metabolic and age-related diseases. Immune cells are the fundamental cell types that govern the health of an organism. Thus, dysregulation of autophagy or mitochondrial function in immune cells has a remarkable effect on susceptibility to infections, response to vaccination, tumor onset, and the development of inflammatory and autoimmune conditions. In this study, we summarize the latest research on metformin's regulation of immune cell mitochondrial function and autophagy as evidence that new clinical trials on metformin with primary outcomes related to the immune system should be considered to treat immune-mediated diseases over the near term.
Topics: Animals; Anti-Inflammatory Agents; Autophagy-Related Proteins; Humans; Inflammation; Inflammation Mediators; Metformin; Mitochondria; Mitophagy; Signal Transduction
PubMed: 33689478
DOI: 10.1152/ajpcell.00604.2020 -
International Journal of Molecular... Jan 2022Metformin is the most commonly used treatment to increase insulin sensitivity in insulin-resistant (IR) conditions such as diabetes, prediabetes, polycystic ovary... (Review)
Review
Metformin is the most commonly used treatment to increase insulin sensitivity in insulin-resistant (IR) conditions such as diabetes, prediabetes, polycystic ovary syndrome, and obesity. There is a well-documented correlation between glucose transporter 4 (GLUT4) expression and the level of IR. Therefore, the observed increase in peripheral glucose utilization after metformin treatment most likely comes from the induction of GLUT4 expression and its increased translocation to the plasma membrane. However, the mechanisms behind this effect and the critical metformin targets are still largely undefined. The present review explores the evidence for the crucial role of changes in the expression and activation of insulin signaling pathway mediators, AMPK, several GLUT4 translocation mediators, and the effect of posttranscriptional modifications based on previously published preclinical and clinical models of metformin's mode of action in animal and human studies. Our aim is to provide a comprehensive review of the studies in this field in order to shed some light on the complex interactions between metformin action, GLUT4 expression, GLUT4 translocation, and the observed increase in peripheral insulin sensitivity.
Topics: Animals; Female; Gene Expression; Glucose; Glucose Transport Proteins, Facilitative; Glucose Transporter Type 4; Humans; Insulin; Insulin Resistance; Male; Metformin; Obesity; Polycystic Ovary Syndrome
PubMed: 35163187
DOI: 10.3390/ijms23031264 -
JAMA Oct 2023Gestational diabetes is a common complication of pregnancy and the optimal management is uncertain. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Gestational diabetes is a common complication of pregnancy and the optimal management is uncertain.
OBJECTIVE
To test whether early initiation of metformin reduces insulin initiation or improves fasting hyperglycemia at gestation weeks 32 or 38.
DESIGN, SETTING, AND PARTICIPANTS
Double-blind, placebo-controlled trial conducted in 2 centers in Ireland (one tertiary hospital and one smaller regional hospital). Participants were enrolled from June 2017 through September 2022 and followed up until 12 weeks' postpartum. Participants comprised 510 individuals (535 pregnancies) diagnosed with gestational diabetes based on World Health Organization 2013 criteria.
INTERVENTIONS
Randomized 1:1 to either placebo or metformin (maximum dose, 2500 mg) in addition to usual care.
MAIN OUTCOMES AND MEASURES
The primary outcome was a composite of insulin initiation or a fasting glucose level of 5.1 mmol/L or greater at gestation weeks 32 or 38.
RESULTS
Among 510 participants (mean age, 34.3 years), 535 pregnancies were randomized. The primary composite outcome was not significantly different between groups and occurred in 150 pregnancies (56.8%) in the metformin group and 167 pregnancies (63.7%) in the placebo group (between-group difference, -6.9% [95% CI, -15.1% to 1.4%]; relative risk, 0.89 [95% CI, 0.78-1.02]; P = .13). Of 6 prespecified secondary maternal outcomes, 3 favored the metformin group, including time to insulin initiation, self-reported capillary glycemic control, and gestational weight gain. Secondary neonatal outcomes differed by group, with smaller neonates (lower mean birth weights, a lower proportion weighing >4 kg, a lower proportion in the >90% percentile, and smaller crown-heel length) in the metformin group without differences in neonatal intensive care needs, respiratory distress requiring respiratory support, jaundice requiring phototherapy, major congenital anomalies, neonatal hypoglycemia, or proportion with 5-minute Apgar scores less than 7.
CONCLUSION AND RELEVANCE
Early treatment with metformin was not superior to placebo for the composite primary outcome. Prespecified secondary outcome data support further investigation of metformin in larger clinical trials.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02980276; EudraCT: 2016-001644-19.
Topics: Adult; Female; Humans; Infant, Newborn; Pregnancy; Birth Weight; Diabetes, Gestational; Hypoglycemic Agents; Insulin; Metformin; Double-Blind Method
PubMed: 37786390
DOI: 10.1001/jama.2023.19869 -
Acta Dermatovenerologica Alpina,... Dec 2023The objective of anti-aging medicine is to decelerate the aging process and mitigate its associated effects, such as susceptibility to cancer, diabetes, and... (Review)
Review
The objective of anti-aging medicine is to decelerate the aging process and mitigate its associated effects, such as susceptibility to cancer, diabetes, and cardiovascular and neurodegenerative diseases. This review provides an overview of the latest advancements in this field, considering both pharmaceutical and non-pharmaceutical approaches. Electronic literature search involved three databases: MEDLINE, Cochrane, and Google Scholar, supplemented by other available literature. Strategies for delaying aging and related diseases comprise pharmaceutical interventions and lifestyle choices. It is crucial for these strategies to be substantiated by research-based evidence. Lifestyle options include fasting, fasting-mimicking, and ketogenic diets. Anti-aging drugs and supplements operate through diverse mechanisms. Calorie restriction mimetics include the activator of AMP-activated protein kinase (metformin) and inhibitor of mTOR (rapamycin), alongside rilmenidine, exhibiting both effects. Rosmarinic acid, a natural product, functions through its anti-glycation properties. Age-related protein crosslinks are acknowledged as a causative factor in age-related diseases. Anti-aging medicine is an evolving field with a multitude of drugs and strategies, necessitating further clinical studies and long-term follow-up based on clinical experience and insights gained from delayed adverse events.
Topics: Humans; Aging; Caloric Restriction; Metformin; Sirolimus
PubMed: 38126098
DOI: No ID Found -
Biomedicine & Pharmacotherapy =... May 2021Metformin is the first-line option for treating newly diagnosed diabetic patients and also involved in other pharmacological actions, including antitumor effect,... (Review)
Review
Metformin is the first-line option for treating newly diagnosed diabetic patients and also involved in other pharmacological actions, including antitumor effect, anti-aging effect, polycystic ovarian syndrome prevention, cardiovascular action, and neuroprotective effect, etc. However, the mechanisms of metformin actions were not fully illuminated. Recently, increasing researches showed that autophagy is a vital medium of metformin playing pharmacological actions. Nevertheless, results on the effects of metformin on autophagy were inconsistent. Apart from few clinical evidences, more data focused on kinds of no-clinical models. First, many studies showed that metformin could induce autophagy via a number of signaling pathways, including AMPK-related signaling pathways (e.g. AMPK/mTOR, AMPK/CEBPD, MiTF/TFE, AMPK/ULK1, and AMPK/miR-221), Redd1/mTOR, STAT, SIRT, Na/H exchangers, MAPK/ERK, PK2/PKR/AKT/ GSK3β, and TRIB3. Secondly, some signaling pathways were involved in the process of metformin inhibiting autophagy, such as AMPK-related signaling pathways (AMPK/NF-κB and other undetermined AMPK-related signaling pathways), Hedgehog, miR-570-3p, miR-142-3p, and MiR-3127-5p. Thirdly, two types of signaling pathways including PI3K/AKT/mTOR and endoplasmic reticulum (ER) stress could bidirectionally impact the effectiveness of metformin on autophagy. Finally, multiple signal pathways were reviewed collectively in terms of affecting the effectiveness of metformin on autophagy. The pharmacological effects of metformin combining its actions on autophagy were also discussed. It would help better apply metformin to treat diseases in term of mediating autophagy.
Topics: Animals; Autophagy; Autophagy-Related Proteins; Humans; Hypoglycemic Agents; Metformin; Signal Transduction
PubMed: 33524789
DOI: 10.1016/j.biopha.2021.111286 -
Journal of Advanced Research Nov 2022Vascular smooth muscle cell (VSMC) senescence in the vasculature results in vascular aging as well as age-related diseases, while metformin improves the inflamm-aging...
INTRODUCTION
Vascular smooth muscle cell (VSMC) senescence in the vasculature results in vascular aging as well as age-related diseases, while metformin improves the inflamm-aging profile by enhancing autophagy. However, metformin's impact on VSMC senescence is largely undefined.
OBJECTIVES
To test the hypothesis that metformin exerts an anti-senescence role by restoring autophagic activity in VSMCs and vascular tissues.
METHODS
Animal models established by angiotensin II (Ang II) induction and physiological aging and senescent primary VSMCs from the aortas of elderly patients were treated with metformin. Cellular and vascular senescence were assessed by measuring the amounts of senescence-associated β-galactosidase and senescence markers, including p21 and p53. Autophagy levels were assessed by autophagy-related protein expression, transmission electron microscope, and autolysosome staining. In order to explore the underlying mechanism of the anti-senescence effects of metformin, 4D label-free quantitative proteomics and bioinformatic analyses were conducted, with subsequent experiments validating these findings.
RESULTS
Ang II-dependent senescence was suppressed by metformin in VSMCs and vascular tissues. Metformin also significantly improved arterial stiffness and alleviated structural changes in aged arteries, reduced senescence-associated secretory phenotype (SASP), and improved proliferation and migration of senescent VSMCs. Mechanistically, the proteomic analysis indicated that autophagy might contribute to metformin's anti-senescence effects. Reduced autophagic flux was observed in Ang II-induced cellular and vascular senescence; this reduction was reversed by metformin. Specifically, metformin enhanced the autophagic flux at the autophagosome-lysosome fusion level, whereas blockade of autophagosome-lysosome fusion inhibited the anti-senescence effects of metformin.
CONCLUSIONS
Metformin prevents VSMC and vascular senescence by promoting autolysosome formation.
Topics: Animals; Muscle, Smooth, Vascular; Cellular Senescence; Metformin; Proteomics; Tumor Suppressor Protein p53; Oxidative Stress; Angiotensin II; Autophagy
PubMed: 36328749
DOI: 10.1016/j.jare.2021.12.009 -
Journal of Translational Medicine Jun 2023Metformin is a well-known anti-diabetic drug that has been repurposed for several emerging applications, including as an anti-cancer agent. It boasts the distinct... (Review)
Review
Metformin is a well-known anti-diabetic drug that has been repurposed for several emerging applications, including as an anti-cancer agent. It boasts the distinct advantages of an excellent safety and tolerability profile and high cost-effectiveness at less than one US dollar per daily dose. Epidemiological evidence reveals that metformin reduces the risk of cancer and decreases cancer-related mortality in patients with diabetes; however, the exact mechanisms are not well understood. Energy metabolism may be central to the mechanism of action. Based on altering whole-body energy metabolism or cellular state, metformin's modes of action can be divided into two broad, non-mutually exclusive categories: "direct effects", which induce a direct effect on cancer cells, independent of blood glucose and insulin levels, and "indirect effects" that arise from systemic metabolic changes depending on blood glucose and insulin levels. In this review, we summarize an updated account of the current knowledge on metformin antitumor action, elaborate on the underlying mechanisms in terms of the hallmarks of cancer, and propose potential applications for repurposing metformin for cancer therapeutics.
Topics: Humans; Metformin; Blood Glucose; Drug Repositioning; Neoplasms; Insulins; Hypoglycemic Agents; Diabetes Mellitus, Type 2
PubMed: 37344841
DOI: 10.1186/s12967-023-04263-8 -
Frontiers in Endocrinology 2023PCOS is a common metabolic disorder in women of reproductive age, which pathogenesis is very complex. The role of ferroptosis in PCOS is a novel finding, and the...
BACKGROUND AND OBJECTIVE
PCOS is a common metabolic disorder in women of reproductive age, which pathogenesis is very complex. The role of ferroptosis in PCOS is a novel finding, and the mechanistic studies are not clear. Metformin is a commonly used drug of PCOS but few studies on whether metformin can improve the follicle development and ovarian function in PCOS. We aims to use PCOS mouse model to study the effect of metformin on PCOS based on the ovarian function and explored the regulation of metformin in PCOS mice by intervening in ferroptosis pathway.
MATERIALS AND METHODS
C57 BL/6J female mice aged 4-5 weeks were purchased and gavaged with letrozole (1 mg/kg/day) combined with high-fat diet for 21days to establish PCOS model, and control group was set up. After modeling, the mice were divided into PCOS model group and metformin treatment group (Met) (n=6).The Met group were gavaged metformin (200 mg/kg/day) for 28 days. The body weight, estrous cycle, glucose tolerance test (OGTT)and insulin resistance test (ITT) were monitored. Then, The mice were euthanized to collect serum and ovaries. Elisa was used to detect changes in related serum hormones (E2, LH, FSH, TP). Ovaries used for molecular biology experiments to detect changes in GPX4, SIRT3, AMPK/p-AMPK, and mTOR/p-mTOR by Western blot and qPCR.
RESULTS
Compared with the model group mice, body weight was significantly reduced, and their estrous cycle was restored in Met group. The results of OGTT and ITT showed an improvment of glucose tolerance and insulin resistance. Morphological results showed that after metformin treatment, polycystic lesions in ovaries were reduced, the ovarian function was restored, and the expressions of SIRT3 and GPX4 were elevated. WB results demonstrated that the expressions of p-mTOR and p-AMPK in ovaries were significantly reduced in Model group, but reversed in MET group.
CONCLUSION
Our study confirmed metformin could not only improve body weight and metabolism disorders, but also improve ovarian dysfunction in PCOS mice.In addition, we explored metformin could regulate ferroptosis to improve PCOS the SIRT3/AMPK/mTOR pathway. Our study complements the mechanisms by which metformin improves PCOS.
Topics: Humans; Female; Mice; Animals; Polycystic Ovary Syndrome; Metformin; Insulin Resistance; AMP-Activated Protein Kinases; Ferroptosis; Sirtuin 3; Body Weight; TOR Serine-Threonine Kinases
PubMed: 36755918
DOI: 10.3389/fendo.2023.1070264 -
Acta Dermato-venereologica Dec 2023Metformin is a widely used drug for treatment of diabetes mellitus, due to its safety and efficacy. In addition to its role as an antidiabetic drug, numerous beneficial... (Review)
Review
Metformin is a widely used drug for treatment of diabetes mellitus, due to its safety and efficacy. In addition to its role as an antidiabetic drug, numerous beneficial effects of metformin have enabled its use in various diseases. Considering the anti-androgenic, anti-angiogenic, anti-fibrotic and antioxidant properties of metformin, it may have the potential to improve chronic inflammatory skin diseases. However, further evidence is needed to confirm the efficacy of metformin in dermatological conditions, This review focuses on exploring the therapeutic targets of metformin in acne vulgaris, hidradenitis suppurativa and rosacea, by studying their pathogeneses.
Topics: Humans; Hidradenitis Suppurativa; Metformin; Acne Vulgaris; Rosacea; Skin
PubMed: 38078688
DOI: 10.2340/actadv.v103.18392