-
Endocrine Reviews Jan 2021Metformin is a first-line therapy for the treatment of type 2 diabetes, due to its robust glucose-lowering effects, well-established safety profile, and relatively low... (Review)
Review
Metformin is a first-line therapy for the treatment of type 2 diabetes, due to its robust glucose-lowering effects, well-established safety profile, and relatively low cost. While metformin has been shown to have pleotropic effects on glucose metabolism, there is a general consensus that the major glucose-lowering effect in patients with type 2 diabetes is mostly mediated through inhibition of hepatic gluconeogenesis. However, despite decades of research, the mechanism by which metformin inhibits this process is still highly debated. A key reason for these discrepant effects is likely due to the inconsistency in dosage of metformin across studies. Widely studied mechanisms of action, such as complex I inhibition leading to AMPK activation, have only been observed in the context of supra-pharmacological (>1 mM) metformin concentrations, which do not occur in the clinical setting. Thus, these mechanisms have been challenged in recent years and new mechanisms have been proposed. Based on the observation that metformin alters cellular redox balance, a redox-dependent mechanism of action has been described by several groups. Recent studies have shown that clinically relevant (50-100 μM) concentrations of metformin inhibit hepatic gluconeogenesis in a substrate-selective manner both in vitro and in vivo, supporting a redox-dependent mechanism of metformin action. Here, we review the current literature regarding metformin's cellular and molecular mechanisms of action.
Topics: Animals; Diabetes Mellitus, Type 2; Gluconeogenesis; Glucose; Humans; Hypoglycemic Agents; Metformin
PubMed: 32897388
DOI: 10.1210/endrev/bnaa023 -
Cell Metabolism Dec 2014Metformin is currently the first-line drug treatment for type 2 diabetes. Besides its glucose-lowering effect, there is interest in actions of the drug of potential... (Review)
Review
Metformin is currently the first-line drug treatment for type 2 diabetes. Besides its glucose-lowering effect, there is interest in actions of the drug of potential relevance to cardiovascular diseases and cancer. However, the underlying mechanisms of action remain elusive. Convincing data place energy metabolism at the center of metformin's mechanism of action in diabetes and may also be of importance in cardiovascular diseases and cancer. Metformin-induced activation of the energy-sensor AMPK is well documented, but may not account for all actions of the drug. Here, we summarize current knowledge about the different AMPK-dependent and AMPK-independent mechanisms underlying metformin action.
Topics: AMP-Activated Protein Kinases; Animals; Diabetes Mellitus, Type 2; Energy Metabolism; Humans; Hypoglycemic Agents; Metformin; Oxidative Phosphorylation
PubMed: 25456737
DOI: 10.1016/j.cmet.2014.09.018 -
Metabolism: Clinical and Experimental Aug 2022Metformin was first used to treat type 2 diabetes in the late 1950s and in 2022 remains the first-choice drug used daily by approximately 150 million people. An... (Meta-Analysis)
Meta-Analysis Review
Metformin was first used to treat type 2 diabetes in the late 1950s and in 2022 remains the first-choice drug used daily by approximately 150 million people. An accumulation of positive pre-clinical and clinical data has stimulated interest in re-purposing metformin to treat a variety of diseases including COVID-19. In polycystic ovary syndrome metformin improves insulin sensitivity. In type 1 diabetes metformin may help reduce the insulin dose. Meta-analysis and data from pre-clinical and clinical studies link metformin to a reduction in the incidence of cancer. Clinical trials, including MILES (Metformin In Longevity Study), and TAME (Targeting Aging with Metformin), have been designed to determine if metformin can offset aging and extend lifespan. Pre-clinical and clinical data suggest that metformin, via suppression of pro-inflammatory pathways, protection of mitochondria and vascular function, and direct actions on neuronal stem cells, may protect against neurodegenerative diseases. Metformin has also been studied for its anti-bacterial, -viral, -malaria efficacy. Collectively, these data raise the question: Is metformin a drug for all diseases? It remains unclear as to whether all of these putative beneficial effects are secondary to its actions as an anti-hyperglycemic and insulin-sensitizing drug, or result from other cellular actions, including inhibition of mTOR (mammalian target for rapamycin), or direct anti-viral actions. Clarification is also sought as to whether data from ex vivo studies based on the use of high concentrations of metformin can be translated into clinical benefits, or whether they reflect a 'Paracelsus' effect. The environmental impact of metformin, a drug with no known metabolites, is another emerging issue that has been linked to endocrine disruption in fish, and extensive use in T2D has also raised concerns over effects on human reproduction. The objectives for this review are to: 1) evaluate the putative mechanism(s) of action of metformin; 2) analyze the controversial evidence for metformin's effectiveness in the treatment of diseases other than type 2 diabetes; 3) assess the reproducibility of the data, and finally 4) reach an informed conclusion as to whether metformin is a drug for all diseases and reasons. We conclude that the primary clinical benefits of metformin result from its insulin-sensitizing and antihyperglycaemic effects that secondarily contribute to a reduced risk of a number of diseases and thereby enhancing healthspan. However, benefits like improving vascular endothelial function that are independent of effects on glucose homeostasis add to metformin's therapeutic actions.
Topics: Animals; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin; Mammals; Metformin; Reproducibility of Results; COVID-19 Drug Treatment
PubMed: 35640743
DOI: 10.1016/j.metabol.2022.155223 -
Nature Reviews. Endocrinology Mar 2014Metformin has been the mainstay of therapy for diabetes mellitus for many years; however, the mechanistic aspects of metformin action remained ill-defined. Recent... (Review)
Review
Metformin has been the mainstay of therapy for diabetes mellitus for many years; however, the mechanistic aspects of metformin action remained ill-defined. Recent advances revealed that this drug, in addition to its glucose-lowering action, might be promising for specifically targeting metabolic differences between normal and abnormal metabolic signalling. The knowledge gained from dissecting the principal mechanisms by which metformin works can help us to develop novel treatments. The centre of metformin's mechanism of action is the alteration of the energy metabolism of the cell. Metformin exerts its prevailing, glucose-lowering effect by inhibiting hepatic gluconeogenesis and opposing the action of glucagon. The inhibition of mitochondrial complex I results in defective cAMP and protein kinase A signalling in response to glucagon. Stimulation of 5'-AMP-activated protein kinase, although dispensable for the glucose-lowering effect of metformin, confers insulin sensitivity, mainly by modulating lipid metabolism. Metformin might influence tumourigenesis, both indirectly, through the systemic reduction of insulin levels, and directly, via the induction of energetic stress; however, these effects require further investigation. Here, we discuss the updated understanding of the antigluconeogenic action of metformin in the liver and the implications of the discoveries of metformin targets for the treatment of diabetes mellitus and cancer.
Topics: AMP-Activated Protein Kinases; Diabetes Mellitus, Type 2; Energy Metabolism; Glucagon; Gluconeogenesis; Humans; Liver; Metformin; Signal Transduction
PubMed: 24393785
DOI: 10.1038/nrendo.2013.256 -
Cell Metabolism Jul 2020Biological aging involves an interplay of conserved and targetable molecular mechanisms, summarized as the hallmarks of aging. Metformin, a biguanide that combats... (Review)
Review
Biological aging involves an interplay of conserved and targetable molecular mechanisms, summarized as the hallmarks of aging. Metformin, a biguanide that combats age-related disorders and improves health span, is the first drug to be tested for its age-targeting effects in the large clinical trial-TAME (targeting aging by metformin). This review focuses on metformin's mechanisms in attenuating hallmarks of aging and their interconnectivity, by improving nutrient sensing, enhancing autophagy and intercellular communication, protecting against macromolecular damage, delaying stem cell aging, modulating mitochondrial function, regulating transcription, and lowering telomere attrition and senescence. These characteristics make metformin an attractive gerotherapeutic to translate to human trials.
Topics: Aging; Animals; Autophagy; Cell Communication; Cellular Senescence; Humans; Hypoglycemic Agents; Metformin; Mitochondria
PubMed: 32333835
DOI: 10.1016/j.cmet.2020.04.001 -
Diabetologia Sep 2017Metformin is one of the most popular oral glucose-lowering medications, widely considered to be the optimal initial therapy for patients with type 2 diabetes mellitus.... (Review)
Review
Metformin is one of the most popular oral glucose-lowering medications, widely considered to be the optimal initial therapy for patients with type 2 diabetes mellitus. Interestingly, there still remains controversy regarding the drug's precise mechanism of action, which is thought to involve a reduction in hepatic glucose production. It is now recommended as first-line treatment in various guidelines, including that of the EASD and ADA. Its favoured status lies in its efficacy, low cost, weight neutrality and good safety profile. Other benefits have also been described, including improvements in certain lipids, inflammatory markers, and a reduction in cardiovascular events, apparently independent from the drug's glucose-lowering effect. Data have emerged questioning the previous reluctance to use this agent in those with mild to moderate chronic kidney disease. Regulations guiding its use in patients with stable, modest renal dysfunction have, as a result, become more lenient in recent years. With no long-term studies comparing it against newer glucose-lowering drugs, some of which have more robust evidence for cardioprotection, metformin's established role as 'foundation therapy' in type 2 diabetes may justifiably be challenged.
Topics: Animals; Biguanides; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin
PubMed: 28770321
DOI: 10.1007/s00125-017-4336-x -
Postepy Higieny I Medycyny... Mar 2017The generally accepted mechanism of metformin's effect is stimulation of adenosine monophosphate (AMP)-activated protein kinase (AMPK). AMPK is directly activated by an... (Review)
Review
The generally accepted mechanism of metformin's effect is stimulation of adenosine monophosphate (AMP)-activated protein kinase (AMPK). AMPK is directly activated by an increase in AMP:ATP ratio in metabolic stress conditions including hypoxia and glucose deprivation. Lately, many novel pathways, besides AMPK induction, have been revealed, which can explain some of metformin's beneficial effects. It may help to identify new targets for treatment of diabetes and metabolic syndrome. Moreover, metformin is now attracting the attention of researchers in fields other than diabetes, as it has been shown to have anti-cancer, immunoregulatory and anti-aging effects. The aim of this review is to describe the potential anti-cancer and anti-aging properties of metformin and discuss the possible underlying mechanisms.
Topics: Animals; Antineoplastic Agents; Cell Death; Glucose; Humans; Hypoglycemic Agents; Metformin; Neoplasms; Signal Transduction
PubMed: 28258677
DOI: 10.5604/01.3001.0010.3801 -
Diabetologia Sep 2017Metformin (dimethylbiguanide) has become the preferred first-line oral blood glucose-lowering agent to manage type 2 diabetes. Its history is linked to Galega...
Metformin (dimethylbiguanide) has become the preferred first-line oral blood glucose-lowering agent to manage type 2 diabetes. Its history is linked to Galega officinalis (also known as goat's rue), a traditional herbal medicine in Europe, found to be rich in guanidine, which, in 1918, was shown to lower blood glucose. Guanidine derivatives, including metformin, were synthesised and some (not metformin) were used to treat diabetes in the 1920s and 1930s but were discontinued due to toxicity and the increased availability of insulin. Metformin was rediscovered in the search for antimalarial agents in the 1940s and, during clinical tests, proved useful to treat influenza when it sometimes lowered blood glucose. This property was pursued by the French physician Jean Sterne, who first reported the use of metformin to treat diabetes in 1957. However, metformin received limited attention as it was less potent than other glucose-lowering biguanides (phenformin and buformin), which were generally discontinued in the late 1970s due to high risk of lactic acidosis. Metformin's future was precarious, its reputation tarnished by association with other biguanides despite evident differences. The ability of metformin to counter insulin resistance and address adult-onset hyperglycaemia without weight gain or increased risk of hypoglycaemia gradually gathered credence in Europe, and after intensive scrutiny metformin was introduced into the USA in 1995. Long-term cardiovascular benefits of metformin were identified by the UK Prospective Diabetes Study (UKPDS) in 1998, providing a new rationale to adopt metformin as initial therapy to manage hyperglycaemia in type 2 diabetes. Sixty years after its introduction in diabetes treatment, metformin has become the most prescribed glucose-lowering medicine worldwide with the potential for further therapeutic applications.
Topics: Biguanides; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin
PubMed: 28776081
DOI: 10.1007/s00125-017-4318-z -
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 -
Theranostics 2022Aging is a natural process, which plays a critical role in the pathogenesis of a variety of diseases, i.e., aging-related diseases, such as diabetes, osteoarthritis,... (Review)
Review
Aging is a natural process, which plays a critical role in the pathogenesis of a variety of diseases, i.e., aging-related diseases, such as diabetes, osteoarthritis, Alzheimer disease, cardiovascular diseases, cancers, obesity and other metabolic abnormalities. Metformin, the most widely used antidiabetic drug, has been reported to delay aging and display protective effect on attenuating progression of various aging-related diseases by impacting key hallmark events of aging, including dysregulated nutrient sensing, loss of proteostasis, mitochondrial dysfunction, altered intercellular communication, telomere attrition, genomic instability, epigenetic alterations, stem cell exhaustion and cellular senescence. In this review, we provide updated information and knowledge on applications of metformin in prevention and treatment of aging and aging-related diseases. We focus our discussions on the roles and underlying mechanisms of metformin in modulating aging and treating aging-related diseases.
Topics: Aging; Cellular Senescence; Genomic Instability; Humans; Metformin; Telomere
PubMed: 35401820
DOI: 10.7150/thno.71360