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Nature Reviews. Endocrinology Aug 2023Currently, metformin is the first-line medication to treat type 2 diabetes mellitus (T2DM) in most guidelines and is used daily by >200 million patients. Surprisingly,... (Review)
Review
Currently, metformin is the first-line medication to treat type 2 diabetes mellitus (T2DM) in most guidelines and is used daily by >200 million patients. Surprisingly, the mechanisms underlying its therapeutic action are complex and are still not fully understood. Early evidence highlighted the liver as the major organ involved in the effect of metformin on reducing blood levels of glucose. However, increasing evidence points towards other sites of action that might also have an important role, including the gastrointestinal tract, the gut microbial communities and the tissue-resident immune cells. At the molecular level, it seems that the mechanisms of action vary depending on the dose of metformin used and duration of treatment. Initial studies have shown that metformin targets hepatic mitochondria; however, the identification of a novel target at low concentrations of metformin at the lysosome surface might reveal a new mechanism of action. Based on the efficacy and safety records in T2DM, attention has been given to the repurposing of metformin as part of adjunct therapy for the treatment of cancer, age-related diseases, inflammatory diseases and COVID-19. In this Review, we highlight the latest advances in our understanding of the mechanisms of action of metformin and discuss potential emerging novel therapeutic uses.
Topics: Humans; Metformin; Diabetes Mellitus, Type 2; Hypoglycemic Agents; COVID-19; Glucose
PubMed: 37130947
DOI: 10.1038/s41574-023-00833-4 -
Drug Design, Development and Therapy 2023Metformin has been designated as one of the most crucial first-line therapeutic agents in the management of type 2 diabetes mellitus. Primarily being an... (Review)
Review
Metformin has been designated as one of the most crucial first-line therapeutic agents in the management of type 2 diabetes mellitus. Primarily being an antihyperglycemic agent, metformin also has a plethora of pleiotropic effects on various systems and processes. It acts majorly by activating AMPK (Adenosine Monophosphate-Activated Protein Kinase) in the cells and reducing glucose output from the liver. It also decreases advanced glycation end products and reactive oxygen species production in the endothelium apart from regulating the glucose and lipid metabolism in the cardiomyocytes, hence minimizing the cardiovascular risks. Its anticancer, antiproliferative and apoptosis-inducing effects on malignant cells might prove instrumental in the malignancy of organs like the breast, kidney, brain, ovary, lung, and endometrium. Preclinical studies have also shown some evidence of metformin's neuroprotective role in Parkinson's disease, Alzheimer's disease, multiple sclerosis and Huntington's disease. Metformin exerts its pleiotropic effects through varied pathways of intracellular signalling and exact mechanism in the majority of them remains yet to be clearly defined. This article has extensively reviewed the therapeutic benefits of metformin and the details of its mechanism for a molecule of boon in various conditions like diabetes, prediabetes, obesity, polycystic ovarian disease, metabolic derangement in HIV, various cancers and aging.
Topics: Female; Humans; Metformin; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Neoplasms; Glucose; AMP-Activated Protein Kinases
PubMed: 37397787
DOI: 10.2147/DDDT.S409373 -
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 -
International Dental Journal Nov 2023This narrative review describes the oral microbiome, and its role in oral health and disease, before considering the impact of commonly used over-the-counter (OTC)... (Review)
Review
This narrative review describes the oral microbiome, and its role in oral health and disease, before considering the impact of commonly used over-the-counter (OTC) mouthwashes on oral bacteria, viruses, bacteriophages, and fungi that make up these microbial communities in different niches of the mouth. Whilst certain mouthwashes have proven antimicrobial actions and clinical effectiveness supported by robust evidence, this review reports more recent metagenomics evidence, suggesting that mouthwashes such as chlorhexidine may cause "dysbiosis," whereby certain species of bacteria are killed, leaving others, sometimes unwanted, to predominate. There is little known about the effects of mouthwashes on fungi and viruses in the context of the oral microbiome (virome) in vivo, despite evidence that they "kill" certain viral pathogens ex vivo. Evidence for mouthwashes, much like antibiotics, is also emerging with regards to antimicrobial resistance, and this should further be considered in the context of their widespread use by clinicians and patients. Therefore, considering the potential of currently available OTC mouthwashes to alter the oral microbiome, this article finally proposes that the ideal mouthwash, whilst combatting oral disease, should "balance" antimicrobial communities, especially those associated with health. Which antimicrobial mouthwash best fits this ideal remains uncertain.
Topics: Humans; Mouthwashes; Chlorhexidine; Mouth; Anti-Infective Agents; Bacteria; Microbiota
PubMed: 37867065
DOI: 10.1016/j.identj.2023.08.010 -
Nature Communications Nov 2023Acute inflammation can either resolve through immunosuppression or persist, leading to chronic inflammation. These transitions are driven by distinct molecular and...
Acute inflammation can either resolve through immunosuppression or persist, leading to chronic inflammation. These transitions are driven by distinct molecular and metabolic reprogramming of immune cells. The anti-diabetic drug Metformin inhibits acute and chronic inflammation through mechanisms still not fully understood. Here, we report that the anti-inflammatory and reactive-oxygen-species-inhibiting effects of Metformin depend on the expression of the plasticity factor ZEB1 in macrophages. Using mice lacking Zeb1 in their myeloid cells and human patient samples, we show that ZEB1 plays a dual role, being essential in both initiating and resolving inflammation by inducing macrophages to transition into an immunosuppressed state. ZEB1 mediates these diverging effects in inflammation and immunosuppression by modulating mitochondrial content through activation of autophagy and inhibition of mitochondrial protein translation. During the transition from inflammation to immunosuppression, Metformin mimics the metabolic reprogramming of myeloid cells induced by ZEB1. Mechanistically, in immunosuppression, ZEB1 inhibits amino acid uptake, leading to downregulation of mTORC1 signalling and a decrease in mitochondrial translation in macrophages. These results identify ZEB1 as a driver of myeloid cell metabolic plasticity, suggesting that targeting its expression and function could serve as a strategy to modulate dysregulated inflammation and immunosuppression.
Topics: Humans; Animals; Mice; Macrophages; Myeloid Cells; Inflammation; Metformin; Immunosuppression Therapy
PubMed: 37978290
DOI: 10.1038/s41467-023-42277-4 -
JAMA Oncology Jul 2023Evidence-based approaches for the prevention of acute radiation dermatitis (ARD) are limited, and additional strategies are necessary to optimize care. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Evidence-based approaches for the prevention of acute radiation dermatitis (ARD) are limited, and additional strategies are necessary to optimize care.
OBJECTIVE
To determine the efficacy of bacterial decolonization (BD) to reduce ARD severity compared with standard of care.
DESIGN, SETTING, AND PARTICIPANTS
This phase 2/3 randomized clinical trial was conducted from June 2019 to August 2021 with investigator blinding at an urban academic cancer center and enrolled patients with breast cancer or head and neck cancer receiving radiation therapy (RT) with curative intent. Analysis was performed on January 7, 2022.
INTERVENTIONS
Intranasal mupirocin ointment twice daily and chlorhexidine body cleanser once daily for 5 days prior to RT and repeated for 5 days every 2 weeks through RT.
MAIN OUTCOMES AND MEASURES
The primary outcome as planned prior to data collection was the development of grade 2 or higher ARD. Based on wide clinical variability of grade 2 ARD, this was refined to grade 2 ARD with moist desquamation (grade 2-MD).
RESULTS
Of 123 patients assessed for eligibility via convenience sampling, 3 were excluded, and 40 refused to participate, with 80 patients in our final volunteer sample. Of 77 patients with cancer (75 patients with breast cancer [97.4%] and 2 patients with head and neck cancer [2.6%]) who completed RT, 39 were randomly assigned BC, and 38 were randomly assigned standard of care; the mean (SD) age of the patients was 59.9 (11.9) years, and 75 (97.4%) were female. Most patients were Black (33.7% [n = 26]) or Hispanic (32.5% [n = 25]). Among patients with breast cancer and patients with head and neck cancer (N = 77), none of the 39 patients treated with BD and 9 of the 38 patients (23.7%) treated with standard of care developed ARD grade 2-MD or higher (P = .001). Similar results were observed among the 75 patients with breast cancer (ie, none treated with BD and 8 [21.6%] receiving standard of care developed ARD grade ≥2-MD; P = .002). The mean (SD) ARD grade was significantly lower for patients treated with BD (1.2 [0.7]) compared with patients receiving standard of care (1.6 [0.8]) (P = .02). Of the 39 patients randomly assigned to BD, 27 (69.2%) reported regimen adherence, and only 1 patient (2.5%) experienced an adverse event related to BD (ie, itch).
CONCLUSIONS AND RELEVANCE
The results of this randomized clinical trial suggest that BD is effective for ARD prophylaxis, specifically for patients with breast cancer.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03883828.
Topics: Humans; Female; Middle Aged; Male; Radiodermatitis; Chlorhexidine; Mupirocin; Breast Neoplasms; Head and Neck Neoplasms
PubMed: 37140904
DOI: 10.1001/jamaoncol.2023.0444 -
The Lancet. Healthy Longevity Jul 2023Metformin, a first-line medication for type 2 diabetes, might also have a protective effect against ageing-related diseases, but so far little experimental evidence is...
BACKGROUND
Metformin, a first-line medication for type 2 diabetes, might also have a protective effect against ageing-related diseases, but so far little experimental evidence is available. We sought to assess the target-specific effect of metformin on biomarkers of ageing in the UK Biobank.
METHODS
In this drug target mendelian randomisation study, we assessed the target-specific effect of four putative targets of metformin (AMPK, ETFDH, GPD1, and PEN2), involving ten genes. Genetic variants with evidence of causation of gene expression, glycated haemoglobin A (HbA), and colocalisation were used as instruments mimicking the target-specific effect of metformin via HbA lowering. The biomarkers of ageing considered were phenotypic age (PhenoAge) and leukocyte telomere length. To triangulate the evidence, we also assessed the effect of HbA on the outcomes using a polygenic mendelian randomisation design and assessed the effect of metformin use on these outcomes using a cross-sectional observational design.
FINDINGS
GPD1-induced HbA lowering was associated with younger PhenoAge (β -5·26, 95% CI -6·69 to -3·83) and longer leukocyte telomere length (β 0·28, 0·03 to 0·53), and AMPKγ2 (PRKAG2)-induced HbA lowering was associated with younger PhenoAge (β -4·88, -7·14 to -2·62) but not with longer leukocyte telomere length. Genetically predicted HbA lowering was associated with younger PhenoAge (β -0·96 per SD lowering of HbA, 95% CI -1·19 to -0·74) but not associated with leukocyte telomere length. In the propensity score matched analysis, metformin use was associated with younger PhenoAge (β -0·36, 95% CI -0·59 to -0·13) but not with leukocyte telomere length.
INTERPRETATION
This study provides genetic validation evidence that metformin might promote healthy ageing via targets GPD1 and AMPKγ2 (PRKAG2), and the effect could be in part due to its glycaemic property. Our findings support further clinical research into metformin and longevity.
FUNDING
Healthy Longevity Catalyst Award, National Academy of Medicine, and Seed Fund for Basic Research, The University of Hong Kong.
Topics: Humans; Metformin; Diabetes Mellitus, Type 2; Biological Specimen Banks; Cross-Sectional Studies; Biomarkers; Hemoglobin A; Transcription Factors; Telomere; United Kingdom
PubMed: 37421961
DOI: 10.1016/S2666-7568(23)00085-5 -
Frontiers in Endocrinology 2023This study aimed to perform a network meta-analysis to objectively evaluate the efficacy and safety of 10 Glucagon-like peptide-1 receptor agonists (GLP-1RAs) in... (Comparative Study)
Comparative Study Meta-Analysis Review
PURPOSE
This study aimed to perform a network meta-analysis to objectively evaluate the efficacy and safety of 10 Glucagon-like peptide-1 receptor agonists (GLP-1RAs) in combination with metformin that is approved for use worldwide in patients with type 2 diabetes and to provide evidence-based support and reference for the selection of clinical treatment.
METHODS
Three databases (PubMed, Embase, and Cochrane Library) were searched from their respective inception until September 30, 2022. Only randomized controlled trials comparing the efficacy and safety of GLP-1RAs for treating type 2 diabetes (T2D) were included. The 10 GLP-1RAs are exenatide (including exenatide twice daily and once weekly), liraglutide, lixisenatide, dulaglutide, PEX168, semaglutide (subcutaneous and oral semaglutide), tirzepatide and albiglutide.
RESULTS
34 RCTs with 10 GLP-1RAs and 12993 patients were included in the Network Meta-Analysis (NMA). According to the NMA, tirzepatide 15 mg, semaglutide 1.0 mg, PEX168-200μg, oral semaglutide 14 and dulaglutide 1.5 mg reduced HbA1c by -2.23%, -1.57%, -1.12%, -1.10%, -1.09% and body weight by -11.33 kg, -5.99 kg, +0.40 kg, -3.95 kg, -1.87 kg, respectively. There was no significant difference in the rate of adverse events for tirzepatide 15 mg, oral-semaglutide 14 mg, and semaglutide 1.0 mg. PEX168-200μg, tirzepatide 15mg, and oral semaglutide 14mg had Surface Under the Cumulative Ranking (SUCRA) values greater than placebo, and only tirzepatide 15mg and oral semaglutide 14mg were significantly different from placebo in the rate of serious adverse events. All GLP-1RA did not lead to increased incidence of hypoglycemia. Albiglutide 30mg and semaglutide 1.0mg significantly differed from placebo in Adverse Event (AE) withdrawal. Finally, the sensitivity analysis and publication bias analysis results indicate that the study results are reliable.
CONCLUSION
This study's results showed that GLP-1RAs were effective in lowering HbA1c and reducing body weight without increased incidence of hypoglycemic reactions. In addition, this study may provide reference and evidence-based medical evidence for clinicians to select GLP-1RAs in patients with T2D and high body mass index (BMI). Based on the NMA results, tirzepatide 15mg and semaglutide 1.0mg may be preferred.
Topics: Humans; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Metformin
PubMed: 37701904
DOI: 10.3389/fendo.2023.1244432 -
Drugs & Aging Aug 2023Sarcopenia, the age-related loss of muscle strength and mass or quality, is a common condition with major adverse consequences. Although the pathophysiology is... (Review)
Review
Sarcopenia, the age-related loss of muscle strength and mass or quality, is a common condition with major adverse consequences. Although the pathophysiology is incompletely understood, there are common mechanisms between sarcopenia and the phenomenon of accelerated ageing seen in diabetes mellitus. Drugs currently used to treat type 2 diabetes mellitus may have mechanisms of action that are relevant to the prevention and treatment of sarcopenia, for those with type 2 diabetes and those without diabetes. This review summarises shared pathophysiology between sarcopenia and diabetes mellitus, including the effects of advanced glycation end products, mitochondrial dysfunction, chronic inflammation and changes to the insulin signalling pathway. Cellular and animal models have generated intriguing, albeit mixed, evidence that supports possible beneficial effects on skeletal muscle function for some classes of drugs used to treat diabetes, including metformin and SGLT2 inhibitors. Most human observational and intervention evidence for the effects of these drugs has been derived from populations with type 2 diabetes mellitus, and there is a need for intervention studies for older people with, and at risk of, sarcopenia to further investigate the balance of benefit and risk in these target populations. Not all diabetes treatments will be safe to use in those without diabetes because of variable side effects across classes. However, some agents [including glucagon-like peptide (GLP)-1 receptor agonists and SGLT2 inhibitors] have already demonstrated benefits in populations without diabetes, and it is these agents, along with metformin, that hold out the most promise for further investigation in sarcopenia.
Topics: Animals; Humans; Aged; Diabetes Mellitus, Type 2; Sarcopenia; Sodium-Glucose Transporter 2 Inhibitors; Drug Repositioning; Metformin; Hypoglycemic Agents
PubMed: 37486575
DOI: 10.1007/s40266-023-01042-4 -
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