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Redox Biology Jul 2020Type 2 diabetes (T2D) is a very prevalent, multisystemic, chronic metabolic disorder closely related to atherosclerosis and cardiovascular diseases. It is characterised... (Review)
Review
Type 2 diabetes (T2D) is a very prevalent, multisystemic, chronic metabolic disorder closely related to atherosclerosis and cardiovascular diseases. It is characterised by mitochondrial dysfunction and the presence of oxidative stress. Metformin is one of the safest and most effective anti-hyperglycaemic agents currently employed as first-line oral therapy for T2D. It has demonstrated additional beneficial effects, unrelated to its hypoglycaemic action, on weight loss and several diseases, such as cancer, cardiovascular disorders and metabolic diseases, including thyroid diseases. Despite the vast clinical experience gained over several decades of use, the mechanism of action of metformin is still not fully understood. This review provides an overview of the existing literature concerning the beneficial mitochondrial and vascular effects of metformin, which it exerts by diminishing oxidative stress and reducing leukocyte-endothelium interactions. Specifically, we describe the molecular mechanisms involved in metformin's effect on gluconeogenesis, its capacity to interfere with major metabolic pathways (AMPK and mTORC1), its action on mitochondria and its antioxidant effects. We also discuss potential targets for therapeutic intervention based on these molecular actions.
Topics: Diabetes Mellitus, Type 2; Endothelium; Humans; Leukocytes; Metformin; Mitochondria
PubMed: 32535544
DOI: 10.1016/j.redox.2020.101517 -
Journal For Immunotherapy of Cancer May 2023Despite their revolutionary success in cancer treatment over the last decades, immunotherapies encounter limitations in certain tumor types and patients. The efficacy of...
BACKGROUND
Despite their revolutionary success in cancer treatment over the last decades, immunotherapies encounter limitations in certain tumor types and patients. The efficacy of immunotherapies depends on tumor antigen-specific CD8 T-cell viability and functionality within the immunosuppressive tumor microenvironment, where oxygen levels are often low. Hypoxia can reduce CD8 T-cell fitness in several ways and CD8 T cells are mostly excluded from hypoxic tumor regions. Given the challenges to achieve durable reduction of hypoxia in the clinic, ameliorating CD8 T-cell survival and effector function in hypoxic condition could improve tumor response to immunotherapies.
METHODS
Activated CD8 T cells were exposed to hypoxia and metformin and analyzed by fluorescence-activated cell sorting for cell proliferation, apoptosis and phenotype. In vivo, metformin was administered to mice bearing hypoxic tumors and receiving either adoptive cell therapy with tumor-specific CD8 T cells, or immune checkpoint inhibitors; tumor growth was followed over time and CD8 T-cell infiltration, survival and localization in normoxic or hypoxic tumor regions were assessed by flow cytometry and immunofluorescence. Tumor oxygenation and hypoxia were measured by electron paramagnetic resonance and pimonidazole staining, respectively.
RESULTS
We found that the antidiabetic drug metformin directly improved CD8 T-cell fitness in hypoxia, both in vitro and in vivo. Metformin rescued murine and human CD8 T cells from hypoxia-induced apoptosis and increased their proliferation and cytokine production, while blunting the upregulation of programmed cell death protein 1 and lymphocyte-activation gene 3. This appeared to result from a reduced production of reactive oxygen species, due to the inhibition of mitochondrial complex I. Differently from what others reported, metformin did not reduce tumor hypoxia, but rather increased CD8 T-cell infiltration and survival in hypoxic tumor areas, and synergized with cyclophosphamide to enhance tumor response to adoptive cell therapy or immune checkpoint blockade in different tumor models.
CONCLUSIONS
This study describes a novel mechanism of action of metformin and presents a promising strategy to achieve immune rejection in hypoxic and immunosuppressive tumors, which would otherwise be resistant to immunotherapy.
Topics: Humans; Animals; Mice; Metformin; Neoplasms; CD8-Positive T-Lymphocytes; Immunotherapy; Immunosuppression Therapy; Immunosuppressive Agents; Hypoxia; Tumor Microenvironment
PubMed: 37147018
DOI: 10.1136/jitc-2022-005719 -
Diabetes Research and Clinical Practice Sep 2018Metformin is a lipophilic biguanide which inhibits hepatic gluconeogenesis and improves peripheral utilization of glucose. It is the first line pharmacotherapy for... (Review)
Review
Metformin is a lipophilic biguanide which inhibits hepatic gluconeogenesis and improves peripheral utilization of glucose. It is the first line pharmacotherapy for glucose control in patients with Type 2 diabetes due to its safety, efficacy and tolerability. Metformin exhibits pleotropic effects, which may have beneficial effects on a variety of tissues independent of glucose control. A potential anti-tumourigenic effect of metformin may be mediated by its role in activating AMP-kinase, which in turn inhibits mammalian target of rapamycin (mTOR). Non-AMPK dependent protective pathways may include reduction of insulin, insulin-like growth factor-1, leptin, inflammatory pathways and potentiation of adiponectin, all of which may have a role in tumourigenesis. A role in inhibiting cancer stem cells is also postulated. A number of large scale observational and cohort studies suggest metformin is associated with a reduced risk of a number of cancers, although the data is not conclusive. Recent randomised studies reporting use of metformin in treatment of cancer have revealed mixed results, and the results of much larger randomised trials of metformin as an adjuvant therapy in breast and colorectal cancers are awaited.
Topics: Animals; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Metformin; Neoplasms
PubMed: 29807101
DOI: 10.1016/j.diabres.2018.05.023 -
EBioMedicine Oct 2023Metformin shows beneficial effects on cardiometabolic health in diabetic individuals. However, the beneficial effects in the general population, especially in...
BACKGROUND
Metformin shows beneficial effects on cardiometabolic health in diabetic individuals. However, the beneficial effects in the general population, especially in non-diabetic individuals are unclear. We aim to estimate the effects of perturbation of seven metformin targets on cardiometabolic health using Mendelian randomization (MR).
METHODS
Genetic variants close to metformin-targeted genes associated with expression of the corresponding genes and glycated haemoglobin (HbA) level were used to proxy therapeutic effects of seven metformin-related drug targets. Eight cardiometabolic phenotypes under metformin trials were selected as outcomes (average N = 466,947). MR estimates representing the weighted average effects of the seven effects of metformin targets on the eight outcomes were generated. One-sample MR was applied to estimate the averaged and target-specific effects in 338,425 non-diabetic individuals in UK Biobank.
FINDINGS
Genetically proxied averaged effects of five metformin targets, equivalent to a 0.62% reduction of HbA level, was associated with 37.8% lower risk of coronary artery disease (CAD) (odds ratio [OR] = 0.62, 95% confidence interval [CI] = 0.46-0.84), lower levels of body mass index (BMI) (β = -0.22, 95% CI = -0.35 to -0.09), systolic blood pressure (SBP) (β = -0.19, 95% CI = -0.28 to -0.09) and diastolic blood pressure (DBP) levels (β = -0.29, 95% CI = -0.39 to -0.19). One-sample MR suggested that the seven metformin targets showed averaged and target-specific beneficial effects on BMI, SBP and DBP in non-diabetic individuals.
INTERPRETATION
This study showed that perturbation of seven metformin targets has beneficial effects on BMI and blood pressure in non-diabetic individuals. Clinical trials are needed to investigate whether similar effects can be achieved with metformin medications.
FUNDING
Funding information is provided in the Acknowledgements.
Topics: Humans; Metformin; Mendelian Randomization Analysis; Risk; Coronary Artery Disease; Genome-Wide Association Study; Diabetes Mellitus; Polymorphism, Single Nucleotide
PubMed: 37734206
DOI: 10.1016/j.ebiom.2023.104803 -
Aging Cell Feb 2021Metformin, a drug widely used for treating diabetes, can prolong the lifespan in several species. Metformin also has the promise to slow down age-related cognitive...
Metformin, a drug widely used for treating diabetes, can prolong the lifespan in several species. Metformin also has the promise to slow down age-related cognitive impairment. However, metformin's therapeutic use as an anti-aging drug is yet to be accepted because of conflicting animal and human studies results. We examined the effects of metformin treatment in late middle age on cognitive function in old age. Eighteen-month-old male C57BL6/J mice received metformin or no treatment for 10 weeks. A series of behavioral tests revealed improved cognitive function in animals that received metformin. Such findings were evident from a better ability for pattern separation, object location, and recognition memory function. Quantification of microglia revealed that metformin treatment reduced the incidence of pathological microglial clusters with alternative activation of microglia into an M2 phenotype, displaying highly ramified processes in the hippocampus. Metformin treatment also seemed to reduce astrocyte hypertrophy. Additional analysis demonstrated that metformin treatment in late middle age increased adenosine monophosphate-activated protein kinase activation, reduced proinflammatory cytokine levels, and the mammalian target of rapamycin signaling, and enhanced autophagy in the hippocampus. However, metformin treatment did not alter neurogenesis or synapses in the hippocampus, implying that improved cognitive function with metformin did not involve enhanced neurogenesis or neosynaptogenesis. The results provide new evidence that metformin treatment commencing in late middle age has promise for improving cognitive function in old age. Modulation of microglia, proinflammatory cytokines, and autophagy appear to be the mechanisms by which metformin facilitated functional benefits in the aged brain.
Topics: Aging; Animals; Autophagy; Cognition; Hippocampus; Male; Metformin; Mice; Mice, Inbred C57BL; Microglia
PubMed: 33443781
DOI: 10.1111/acel.13277 -
Aging Cell Nov 2023Muscle inflammation and fibrosis underlie disuse-related complications and may contribute to impaired muscle recovery in aging. Cellular senescence is an emerging link... (Randomized Controlled Trial)
Randomized Controlled Trial
Disuse-induced muscle fibrosis, cellular senescence, and senescence-associated secretory phenotype in older adults are alleviated during re-ambulation with metformin pre-treatment.
Muscle inflammation and fibrosis underlie disuse-related complications and may contribute to impaired muscle recovery in aging. Cellular senescence is an emerging link between inflammation, extracellular matrix (ECM) remodeling and poor muscle recovery after disuse. In rodents, metformin has been shown to prevent cellular senescence/senescent associated secretory phenotype (SASP), inflammation, and fibrosis making it a potentially practical therapeutic solution. Thus, the purpose of this study was to determine in older adults if metformin monotherapy during bed rest could reduce muscle fibrosis and cellular senescence/SASP during the re-ambulation period. A two-arm controlled trial was utilized in healthy male and female older adults (n = 20; BMI: <30, age: 60 years+) randomized into either placebo or metformin treatment during a two-week run-in and 5 days of bedrest followed by metformin withdrawal during 7 days of recovery. We found that metformin-treated individuals had less type-I myofiber atrophy during disuse, reduced pro-inflammatory transcriptional profiles, and lower muscle collagen deposition during recovery. Collagen content and myofiber size corresponded to reduced whole muscle cellular senescence and SASP markers. Moreover, metformin treatment reduced primary muscle resident fibro-adipogenic progenitors (FAPs) senescent markers and promoted a shift in fibroblast fate to be less myofibroblast-like. Together, these results suggest that metformin pre-treatment improved ECM remodeling after disuse in older adults by possibly altering cellular senescence and SASP in skeletal muscle and in FAPs.
Topics: Male; Female; Humans; Metformin; Senescence-Associated Secretory Phenotype; Cellular Senescence; Muscle, Skeletal; Inflammation; Walking; Collagen; Fibrosis
PubMed: 37486024
DOI: 10.1111/acel.13936 -
Molecular Biology Reports Jan 2023Metformin has good anti-hyperglycemic effectiveness, but does not induce hypoglycemia,is very safe, and has become the preferred drug for the treatment of type 2... (Review)
Review
BACKGROUND
Metformin has good anti-hyperglycemic effectiveness, but does not induce hypoglycemia,is very safe, and has become the preferred drug for the treatment of type 2 diabetes. Recently, the other effects of metformin, such as being anti-inflammatory and delaying aging, have also attracted increased attention.
METHODS AND RESULTS
The relevant literatures on pubmed and other websites for reading, classification and sorting, and did not involve any animal experiments.
CONCLUSION
Metformin has anti-inflammatory effects through multiple routes, which provides potential therapeutic targets for certain inflammatory diseases, such as neuroinflammation and rheumatoid arthritis. In addition, inflammation is a key component of tumor occurrence and development ; thus, targeted inflammatory intervention is a significant benefit for both cancer prevention and treatment. Therefore, metformin may have further potential for inflammation-related disease prevention and treatmen. However, the inflammatory mechanism is complex; various molecules are connected and influence each other. For example, metformin significantly inhibits p65 nuclear translocation, but pretreatment with compound C, an AMPK inhibitor, abolishes this effect, and silencing of HMGB1 inhibits NF-κB activation . SIRT1 deacetylates FoxO, increasing its transcriptional activity . mTOR in dendritic cells regulates FoxO1 via AKT. The interactions among various molecules should be further explored to clarify their specific mechanisms and provide more direction for the treatment of inflammatory diseases, as well as cancer.
Topics: Animals; Metformin; Diabetes Mellitus, Type 2; NF-kappa B; Inflammation; Anti-Inflammatory Agents; Neoplasms; AMP-Activated Protein Kinases
PubMed: 36319785
DOI: 10.1007/s11033-022-07954-5 -
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 -
Current Opinion in Lipidology Aug 2018We provide an overview of recent publications that extend clinically relevant knowledge relating to metformin's effects on lipids and atherosclerotic vascular disease... (Review)
Review
PURPOSE OF REVIEW
We provide an overview of recent publications that extend clinically relevant knowledge relating to metformin's effects on lipids and atherosclerotic vascular disease and/or provide insights into the drug's mechanisms of action on the heart and vasculature.
RECENT FINDINGS
We focus on original research in humans or in human tissues. Several recently completed randomized clinical trials have reported effects of metformin on surrogate measures of atherosclerotic vascular disease, including carotid-intima media thickness, vascular reactivity and calcification in people with Type 1 (T1D) and Type 2 (T2D) diabetes as well as nondiabetic dysglycaemia. In addition, observational studies have provided novel insights into the mechanisms of metformin's effects on carotid plaque, monocytes/macrophages, vascular smooth muscle and endothelial cells, including via 5'-adenosine monophosphate-activated protein kinase (AMPK) activation.
SUMMARY
Recent trials based on surrogate outcome measures have provided further data suggesting protective effects of metformin against vascular disease in youth and adults with Type 1 diabetes, as well as in adults with prediabetes and Type 2 diabetes. In parallel, human tissue and cell studies have provided new insights into pleiotropic effects of metformin and suggest novel drug targets. As metformin is an inexpensive agent with an established safety profile, larger scale clinical trials based on hard clinical outcomes [cardiovascular disease (CVD) events] are now indicated.
Topics: Atherosclerosis; Blood Vessels; Humans; Lipid Metabolism; Metformin
PubMed: 29878903
DOI: 10.1097/MOL.0000000000000532 -
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