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Bioorganic & Medicinal Chemistry Letters Apr 2023Metformin is the most widely known anti-hyperglycemic, officially acquired by the USA government in 1995 and in 2001 it became the most prescribed treatment for type II... (Review)
Review
Metformin is the most widely known anti-hyperglycemic, officially acquired by the USA government in 1995 and in 2001 it became the most prescribed treatment for type II diabetes. But how did it become the must-use drug for this disease in such a short period of time? it all started with traditional medicine, by using a plant known as "goat's rue" for the reduction of blood glucose levels. Its use arose in 1918 and evolved to the metformin synthesis in laboratories a couple of years later, using very rudimentary methods which involved melting and strong heating. Thus, a first synthetic route that allowed the preparation of the initial metformin derivates was established. Some of these resulted toxics, and others outperformed the metformin, reducing the blood glucose levels in such efficient way. Nevertheless, the risk and documented cases of lactic acidosis increased with metformin derivatives like buformin and phenformin. Recently, metformin has been widely studied, and it has been associated and tested in the treatment of type II diabetes, cancer, polycystic ovarian syndrome, cell differentiation to oligodendrocytes, reduction of oxidative stress in cells, weight reduction, as anti-inflammatory and even in the recent COVID-19 disease. Herein we briefly review and analyze the history, synthesis, and biological applications of metformin and its derivates.
Topics: Humans; Metformin; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Blood Glucose; COVID-19
PubMed: 36933671
DOI: 10.1016/j.bmcl.2023.129241 -
Biochemical Pharmacology Sep 2023Metformin has been used for ages to treat diabetes mellitus due to its safety profile and low cost. However, metformin has variable pharmacokinetics in patients, and due... (Review)
Review
Metformin has been used for ages to treat diabetes mellitus due to its safety profile and low cost. However, metformin has variable pharmacokinetics in patients, and due to its poor oral absorption, the therapeutic doses are relatively high, causing unpleasant gastrointestinal adverse effects. Therefore, novel derivatives of metformin have been synthesized during the past decades. Particularly, after the mid-2000 s, when organic cation transporters were identified as the main metformin carriers, metformin derivatives have been under intensive investigation. Nevertheless, due to the biguanide structure, derivatives of metformin have been challenging to synthesize. Moreover, the mechanisms of metformin's action are not fully understood to date, and since it has multifunctional properties, the interests have switched to re-purposing for other diseases. Indeed, metformin derivatives have been demonstrated in many cases to be more effective than metformin itself and have the potential to be used in different diseases, including several types of cancers and neurodegenerative diseases. On the other hand, the pleiotropic nature of metformin and its derivatives can also create challenges. Not all properties are fit for all diseases. In this review, the history of the development of metformin-like compounds is summarized, and insights into their potential for future drug discovery are discussed.
Topics: Humans; Metformin; Drug Discovery; Drug-Related Side Effects and Adverse Reactions
PubMed: 37591450
DOI: 10.1016/j.bcp.2023.115743 -
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 -
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 -
Drug Delivery Oct 2016Metformin hydrochloride is a biguanide derivative widely used for the treatment of type 2 diabetes, prescribed nearly to 120 million people worldwide. Metformin has a... (Review)
Review
CONTEXT
Metformin hydrochloride is a biguanide derivative widely used for the treatment of type 2 diabetes, prescribed nearly to 120 million people worldwide. Metformin has a relatively low oral bioavailability (about 50-60%). Although the major effect of metformin is to decrease hepatic glucose output as an antihyperglycemic agent, its inhibitory effects on the proliferation of some cancer cells (e.g. prostate, breast, glioma cells) have been demonstrated in the cell culture studies. Development of novel formulation (e.g. microparticles, nanoparticles) strategies for metformin might be useful to improve its bioavailability, to reduce the dosing frequency, to decrease gastrointestinal side effects and toxicity and to be helpful for effective use of metformin in cancer treatment.
OBJECTIVE
The main aim of this review is to summarize metformin HCl-loaded micro- and nanoparticulate drug delivery systems.
METHOD
The literature was rewieved with regard to the physicochemical, pharmacological properties of metformin, and also its mechanism of action in type 2 diabetes and cancer. In addition, micro- and nanoparticulate drug delivery systems developed for metformin were gathered from the literature and the results were discussed.
CONCLUSION
Metformin is an oral antihyperglycemic agent and also has potential antitumorigenic effects. The repeated applications of high doses of metformin (as immediate release formulations) are needed for an effective treatment due to its low oral bioavailability and short biological half-life. Drug delivery systems are very useful systems to overcome the difficulties associated with conventional dosage forms of metformin and also for its effective use in cancer treatment.
Topics: Chemistry, Pharmaceutical; Diabetes Mellitus, Type 2; Drug Delivery Systems; Humans; Hypoglycemic Agents; Metformin; Nanoparticles
PubMed: 26394019
DOI: 10.3109/10717544.2015.1089957 -
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 -
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