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Ageing Research Reviews Nov 2021The present paper demonstrates that metformin (MF) induced a broad spectrum of hormetic biphasic dose responses in a wide range of experimental studies, affecting... (Review)
Review
The present paper demonstrates that metformin (MF) induced a broad spectrum of hormetic biphasic dose responses in a wide range of experimental studies, affecting multiple organ systems, cell types, and endpoints enhancing resilience to chemical stresses in preconditioning and co-current exposure protocols. Detailed mechanistic evaluations indicate that MF-induced hormetic-adaptive responses are mediated often via the activation of adenosine monophosphate-activated kinase (AMPK) protein and its subsequent upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2). Hormesis-induced protective responses by MF are largely mediated via a vast and highly integrated anti-inflammatory molecular network that enhances longevity and delays the onset and slows the progression of neurodegenerative and other chronic diseases.
Topics: Hormesis; Longevity; Metformin
PubMed: 34365027
DOI: 10.1016/j.arr.2021.101418 -
Regulatory Toxicology and Pharmacology... Feb 2018This review investigates the different biological effect of Metformin (MET) in different conditions. MET is an oral antidiabetic drug used for the treatment of type 2... (Review)
Review
This review investigates the different biological effect of Metformin (MET) in different conditions. MET is an oral antidiabetic drug used for the treatment of type 2 diabetes mellitus (T2DM) particularly in overweight people. The main mechanism of action of the MET is inhibition of hepatic glucose production and reduction of insulin resistance. In addition to its antidiabetic effects, MET is also found to be related with the risk for development of several human solid cancers types such as colorectal, breast and pancreas cancer in the diabetic patients. Nowadays according to some researches, MET is believed to decrease or prevent aging and mortality. Moreover, clinical and experimental evidence has shown that MET has beneficial effects in patient with obesity, polycystic ovarian syndrome and Alzheimer's disease. Recent studies have shown that activation of adenosine monophosphate-activated protein kinase (AMPK) by MET can explain its beneficial metabolic effects. In this manuscript, a reevaluation of mechanisms as well as pharmacokinetic properties, genetic variants of transporters, drug-drug interactions, side effects and potential clinical benefits of MET have been reviewed.
Topics: Animals; Diabetes Mellitus, Type 2; Drug Interactions; Humans; Hypoglycemic Agents; Metformin
PubMed: 29291990
DOI: 10.1016/j.yrtph.2017.12.023 -
Annual Review of Pharmacology and... Jan 2022Metformin has been extensively used for the treatment of type 2 diabetes, and it may also promote healthy aging. Despite its widespread use and versatility, metformin's...
Metformin has been extensively used for the treatment of type 2 diabetes, and it may also promote healthy aging. Despite its widespread use and versatility, metformin's mechanisms of action remain elusive. The gut typically harbors thousands of bacterial species, and as the concentration of metformin is much higher in the gut as compared to plasma, it is plausible that microbiome-drug-host interactions may influence the functions of metformin. Detrimental perturbations in the aging gut microbiome lead to the activation of the innate immune response concomitant with chronic low-grade inflammation. With the effectiveness of metformin in diabetes and antiaging varying among individuals, there is reason to believe that the gut microbiome plays a role in the efficacy of metformin. Metformin has been implicated in the promotion and maintenance of a healthy gut microbiome and reduces many age-related degenerative pathologies. Mechanistic understanding of metformin in the promotion of a healthy gut microbiome and aging will require a systems-level approach.
Topics: Aging; Diabetes Mellitus, Type 2; Gastrointestinal Microbiome; Humans; Hypoglycemic Agents; Metformin
PubMed: 34449247
DOI: 10.1146/annurev-pharmtox-051920-093829 -
International Journal of Molecular... Jan 2023Metformin has been a long-standing prescribed drug for treatment of type 2 diabetes (T2D) and its beneficial effects on virus infection, autoimmune diseases, aging and... (Review)
Review
Metformin has been a long-standing prescribed drug for treatment of type 2 diabetes (T2D) and its beneficial effects on virus infection, autoimmune diseases, aging and cancers are also recognized. Metformin modulates the differentiation and activation of various immune-mediated cells such as CD4+ and CD+8 T cells. The activation of adenosine 5'-monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1) pathway may be involved in this process. Recent studies using Extracellular Flux Analyzer demonstrated that metformin alters the activities of glycolysis, oxidative phosphorylation (OXPHOS), lipid oxidation, and glutaminolysis, which tightly link to the modulation of cytokine production in CD4+ and CD+8 T cells in various disease states, such as virus infection, autoimmune diseases, aging and cancers.
Topics: Humans; Metformin; Diabetes Mellitus, Type 2; Protein Kinases; Mechanistic Target of Rapamycin Complex 1; Neoplasms; AMP-Activated Protein Kinases
PubMed: 36614197
DOI: 10.3390/ijms24010755 -
Oral Oncology Nov 2022
Topics: Humans; Hypoglycemic Agents; Metformin; Mouth Neoplasms
PubMed: 36108523
DOI: 10.1016/j.oraloncology.2022.106125 -
Molecular Metabolism Nov 2023The gut microbiota is increasingly recognized as a crucial factor in human health and disease. Metformin, a commonly prescribed medication for type 2 diabetes, has been... (Review)
Review
BACKGROUND
The gut microbiota is increasingly recognized as a crucial factor in human health and disease. Metformin, a commonly prescribed medication for type 2 diabetes, has been studied for its potential impact on the gut microbiota in preclinical models. However, the effects of metformin on the gut microbiota in humans remain uncertain.
SCOPE OF REVIEW
We conducted a systematic review of clinical trials and observational studies to assess the existing knowledge on the impact of metformin on the gut microbiota in humans. The review focused on changes in bacterial composition and diversity following metformin treatment.
MAJOR CONCLUSIONS
Thirteen studies were included in the analysis. The results revealed alterations in the abundance of bacterial genera from various phyla, suggesting that metformin may selectively influence certain groups of bacteria in the gut microbiota. However, the effects on gut microbiota diversity were inconsistent across populations, with conflicting findings on changes in alpha and beta diversity measures. Overall, the use of metformin was associated with changes in the abundance of specific bacterial genera within the gut microbiota of human populations. However, the effects on gut microbiota diversity were not consistent, highlighting the need for further research to understand the underlying mechanisms and clinical significance of these changes.
Topics: Humans; Metformin; Diabetes Mellitus, Type 2; Gastrointestinal Microbiome; Bacteria
PubMed: 37696355
DOI: 10.1016/j.molmet.2023.101805 -
Current Diabetes Reports Jan 2017Metformin has been widely used for over 5 decades. New preparations have been developed for possible enhancement of efficiency, tolerability, and pleiotropic nonglycemic... (Review)
Review
Metformin has been widely used for over 5 decades. New preparations have been developed for possible enhancement of efficiency, tolerability, and pleiotropic nonglycemic effects. Extended-release metformin has contributed to adherence and improved gastrointestinal tolerability. Delayed-release metformin acts in the lower gastrointestinal tract and exerts glucose-lowering effects at lower plasma metformin levels, which might suggest use of this biguanide in patients with chronic kidney disease. Metformin is also known to have numerous nonglycemic effects. Results of the UK Prospective Diabetes Study indicate improvements in cardiovascular outcome and reduced total mortality independent of glycemic control. Anticancer effects of metformin have been discussed and many clinical trials are on-going. Metformin is noted for its beneficial effects on lifespan extension and on disorders due to increased insulin resistance. Further investigations, including randomized control trials in nondiabetic individuals, are required to demonstrate the nonglycemic effects of metformin.
Topics: Blood Glucose; Cardiovascular Diseases; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Longevity; Metformin; Neoplasms
PubMed: 28116648
DOI: 10.1007/s11892-017-0829-8 -
Archives of Pharmacal Research May 2023Metformin has been used clinically for more than 60 years. As time goes by, more and more miraculous effects of metformin beyond the clinic have been discovered and... (Review)
Review
Metformin has been used clinically for more than 60 years. As time goes by, more and more miraculous effects of metformin beyond the clinic have been discovered and discussed. In addition to the clinically approved hypoglycemic effect, it also has a positive metabolic regulation effect on the human body that cannot be ignored. Such as anti-cancer, anti-aging, brain repair, cardiovascular protection, gastrointestinal regulation, hair growth and inhibition of thyroid nodules, and other nonclinical effects. Metformin affects almost the entire body in the situation taking it over a long period, and the preventive effects of metformin in addition to treating diabetes are also beginning to be recommended in some guidelines. This review is mainly composed of four parts: the development history of metformin, the progress of clinical efficacy, the nonclinical efficacy of metformin, and the consideration and prospect of its application.
Topics: Humans; Metformin; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Neoplasms; Aging
PubMed: 36964307
DOI: 10.1007/s12272-023-01445-2 -
Ageing Research Reviews Dec 2023Here we propose that SGLT2 inhibitors (SGLT2i), a class of drugs primarily used to treat type 2 diabetes, could also be repositioned as anti-aging senomorphic drugs...
Here we propose that SGLT2 inhibitors (SGLT2i), a class of drugs primarily used to treat type 2 diabetes, could also be repositioned as anti-aging senomorphic drugs (agents that prevent the extrinsic harmful effects of senescent cells). As observed for metformin, another anti-diabetic drug with established anti-aging potential, increasing evidence suggests that SGLT2i can modulate some relevant pathways associated with the aging process, such as free radical production, cellular energy regulation through AMP-activated protein kinase (AMPK), autophagy, and the activation of nuclear factor (NF)-kB/inflammasome. Some interesting pro-healthy effects were also observed on human microbiota. All these mechanisms converge on fueling a systemic proinflammatory condition called inflammaging, now recognized as the main risk factor for accelerated aging and increased risk of age-related disease development and progression. Inflammaging can be worsened by cellular senescence and immunosenescence, which contributes to the increased burden of senescent cells during aging, perpetuating the proinflammatory condition. Interestingly, increasing evidence suggested the direct effects of SGLT-2i against senescent cells, chronic activation of immune cells, and metabolic alterations induced by overnutrition (meta-inflammation). In this framework, we analyzed and discussed the multifaceted impact of SGLT2i, compared with metformin effects, as a potential anti-aging drug beyond diabetes management. Despite promising results in experimental studies, rigorous investigations with well-designed cellular and clinical investigations will need to validate SGLT2 inhibitors' anti-aging effects.
Topics: Humans; Aging; Cellular Senescence; Diabetes Mellitus, Type 2; Metformin; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 37984626
DOI: 10.1016/j.arr.2023.102131 -
Diabetes Research and Clinical Practice Jan 2020Metformin is the most widely used glucose lowering drug worldwide in the treatment of patients with type 2 diabetes, since we have experience with this drug for more... (Review)
Review
Metformin is the most widely used glucose lowering drug worldwide in the treatment of patients with type 2 diabetes, since we have experience with this drug for more than 60 years about the efficacy and safety. Metformin is very effective in HbA1c lowering associated with some weight loss, but does not increase risk for hypoglycemia. At the moment all guidelines in the world recommend to use metformin in monotherapy in patients with newly diagnosed diabetes or in combination with other antidiabetic drugs with documented CV (and renal) benefit in cardiovascular outcome trials (CVOT). Although a randomized placebo controlled CVOT with metformin is lacking, many observational studies in patients with coronary heart disease, heart failure and chronic kidney disease have demonstrated consistent beneficial effects. A recent metanalysis of 26 observational studies including 815 839 patients showed that metformin use was associated with a significantly lower rate of all-cause mortality (HR: 0.74; 95% CI: 0.68-0.81). Whether this very consistent reduction of all-cause mortality is related to the incidence/outcome of several cancers has still to be investigated. In the future early combination therapy of metformin e.g. with SGLT-2 inhibitors should be more often used.
Topics: Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin; Middle Aged
PubMed: 31778746
DOI: 10.1016/j.diabres.2019.107946