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Diabetologia Mar 2016Metformin is an effective agent with a good safety profile that is widely used as a first-line treatment for type 2 diabetes, yet its mechanisms of action and... (Review)
Review
Metformin is an effective agent with a good safety profile that is widely used as a first-line treatment for type 2 diabetes, yet its mechanisms of action and variability in terms of efficacy and side effects remain poorly understood. Although the liver is recognised as a major site of metformin pharmacodynamics, recent evidence also implicates the gut as an important site of action. Metformin has a number of actions within the gut. It increases intestinal glucose uptake and lactate production, increases GLP-1 concentrations and the bile acid pool within the intestine, and alters the microbiome. A novel delayed-release preparation of metformin has recently been shown to improve glycaemic control to a similar extent to immediate-release metformin, but with less systemic exposure. We believe that metformin response and tolerance is intrinsically linked with the gut. This review examines the passage of metformin through the gut, and how this can affect the efficacy of metformin treatment in the individual, and contribute to the side effects associated with metformin intolerance.
Topics: Gastrointestinal Tract; Glucagon-Like Peptide 1; Humans; Metformin; Microbiota
PubMed: 26780750
DOI: 10.1007/s00125-015-3844-9 -
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 -
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 -
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 -
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 -
International Journal of Molecular... Jan 2022Metformin is the most commonly used treatment to increase insulin sensitivity in insulin-resistant (IR) conditions such as diabetes, prediabetes, polycystic ovary... (Review)
Review
Metformin is the most commonly used treatment to increase insulin sensitivity in insulin-resistant (IR) conditions such as diabetes, prediabetes, polycystic ovary syndrome, and obesity. There is a well-documented correlation between glucose transporter 4 (GLUT4) expression and the level of IR. Therefore, the observed increase in peripheral glucose utilization after metformin treatment most likely comes from the induction of GLUT4 expression and its increased translocation to the plasma membrane. However, the mechanisms behind this effect and the critical metformin targets are still largely undefined. The present review explores the evidence for the crucial role of changes in the expression and activation of insulin signaling pathway mediators, AMPK, several GLUT4 translocation mediators, and the effect of posttranscriptional modifications based on previously published preclinical and clinical models of metformin's mode of action in animal and human studies. Our aim is to provide a comprehensive review of the studies in this field in order to shed some light on the complex interactions between metformin action, GLUT4 expression, GLUT4 translocation, and the observed increase in peripheral insulin sensitivity.
Topics: Animals; Female; Gene Expression; Glucose; Glucose Transport Proteins, Facilitative; Glucose Transporter Type 4; Humans; Insulin; Insulin Resistance; Male; Metformin; Obesity; Polycystic Ovary Syndrome
PubMed: 35163187
DOI: 10.3390/ijms23031264 -
Cell Metabolism Feb 2024Here, we summarize the current knowledge on eight promising drugs and natural compounds that have been tested in the clinic: metformin, NAD precursors, glucagon-like... (Review)
Review
Here, we summarize the current knowledge on eight promising drugs and natural compounds that have been tested in the clinic: metformin, NAD precursors, glucagon-like peptide-1 receptor agonists, TORC1 inhibitors, spermidine, senolytics, probiotics, and anti-inflammatories. Multiple clinical trials have commenced to evaluate the efficacy of such agents against age-associated diseases including diabetes, cardiovascular disease, cancer, and neurodegenerative diseases. There are reasonable expectations that drugs able to decelerate or reverse aging processes will also exert broad disease-preventing or -attenuating effects. Hence, the outcome of past, ongoing, and future disease-specific trials may pave the way to the development of new anti-aging medicines. Drugs approved for specific disease indications may subsequently be repurposed for the treatment of organism-wide aging consequences.
Topics: Humans; NAD; Aging; Metformin; Cardiovascular Diseases; Neoplasms
PubMed: 38181790
DOI: 10.1016/j.cmet.2023.12.007 -
Drugs Jul 2015People with elevated, non-diabetic, levels of blood glucose are at risk of progressing to clinical type 2 diabetes and are commonly termed 'prediabetic'. The term... (Review)
Review
People with elevated, non-diabetic, levels of blood glucose are at risk of progressing to clinical type 2 diabetes and are commonly termed 'prediabetic'. The term prediabetes usually refers to high-normal fasting plasma glucose (impaired fasting glucose) and/or plasma glucose 2 h following a 75 g oral glucose tolerance test (impaired glucose tolerance). Current US guidelines consider high-normal HbA1c to also represent a prediabetic state. Individuals with prediabetic levels of dysglycaemia are already at elevated risk of damage to the microvasculature and macrovasculature, resembling the long-term complications of diabetes. Halting or reversing the progressive decline in insulin sensitivity and β-cell function holds the key to achieving prevention of type 2 diabetes in at-risk subjects. Lifestyle interventions aimed at inducing weight loss, pharmacologic treatments (metformin, thiazolidinediones, acarbose, basal insulin and drugs for weight loss) and bariatric surgery have all been shown to reduce the risk of progression to type 2 diabetes in prediabetic subjects. However, lifestyle interventions are difficult for patients to maintain and the weight loss achieved tends to be regained over time. Metformin enhances the action of insulin in liver and skeletal muscle, and its efficacy for delaying or preventing the onset of diabetes has been proven in large, well-designed, randomised trials, such as the Diabetes Prevention Program and other studies. Decades of clinical use have demonstrated that metformin is generally well-tolerated and safe. We have reviewed in detail the evidence base supporting the therapeutic use of metformin for diabetes prevention.
Topics: Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin; Prediabetic State
PubMed: 26059289
DOI: 10.1007/s40265-015-0416-8 -
Biomedicine & Pharmacotherapy =... May 2021Metformin is the first-line option for treating newly diagnosed diabetic patients and also involved in other pharmacological actions, including antitumor effect,... (Review)
Review
Metformin is the first-line option for treating newly diagnosed diabetic patients and also involved in other pharmacological actions, including antitumor effect, anti-aging effect, polycystic ovarian syndrome prevention, cardiovascular action, and neuroprotective effect, etc. However, the mechanisms of metformin actions were not fully illuminated. Recently, increasing researches showed that autophagy is a vital medium of metformin playing pharmacological actions. Nevertheless, results on the effects of metformin on autophagy were inconsistent. Apart from few clinical evidences, more data focused on kinds of no-clinical models. First, many studies showed that metformin could induce autophagy via a number of signaling pathways, including AMPK-related signaling pathways (e.g. AMPK/mTOR, AMPK/CEBPD, MiTF/TFE, AMPK/ULK1, and AMPK/miR-221), Redd1/mTOR, STAT, SIRT, Na/H exchangers, MAPK/ERK, PK2/PKR/AKT/ GSK3β, and TRIB3. Secondly, some signaling pathways were involved in the process of metformin inhibiting autophagy, such as AMPK-related signaling pathways (AMPK/NF-κB and other undetermined AMPK-related signaling pathways), Hedgehog, miR-570-3p, miR-142-3p, and MiR-3127-5p. Thirdly, two types of signaling pathways including PI3K/AKT/mTOR and endoplasmic reticulum (ER) stress could bidirectionally impact the effectiveness of metformin on autophagy. Finally, multiple signal pathways were reviewed collectively in terms of affecting the effectiveness of metformin on autophagy. The pharmacological effects of metformin combining its actions on autophagy were also discussed. It would help better apply metformin to treat diseases in term of mediating autophagy.
Topics: Animals; Autophagy; Autophagy-Related Proteins; Humans; Hypoglycemic Agents; Metformin; Signal Transduction
PubMed: 33524789
DOI: 10.1016/j.biopha.2021.111286 -
Journal of Advanced Research Nov 2022Vascular smooth muscle cell (VSMC) senescence in the vasculature results in vascular aging as well as age-related diseases, while metformin improves the inflamm-aging...
INTRODUCTION
Vascular smooth muscle cell (VSMC) senescence in the vasculature results in vascular aging as well as age-related diseases, while metformin improves the inflamm-aging profile by enhancing autophagy. However, metformin's impact on VSMC senescence is largely undefined.
OBJECTIVES
To test the hypothesis that metformin exerts an anti-senescence role by restoring autophagic activity in VSMCs and vascular tissues.
METHODS
Animal models established by angiotensin II (Ang II) induction and physiological aging and senescent primary VSMCs from the aortas of elderly patients were treated with metformin. Cellular and vascular senescence were assessed by measuring the amounts of senescence-associated β-galactosidase and senescence markers, including p21 and p53. Autophagy levels were assessed by autophagy-related protein expression, transmission electron microscope, and autolysosome staining. In order to explore the underlying mechanism of the anti-senescence effects of metformin, 4D label-free quantitative proteomics and bioinformatic analyses were conducted, with subsequent experiments validating these findings.
RESULTS
Ang II-dependent senescence was suppressed by metformin in VSMCs and vascular tissues. Metformin also significantly improved arterial stiffness and alleviated structural changes in aged arteries, reduced senescence-associated secretory phenotype (SASP), and improved proliferation and migration of senescent VSMCs. Mechanistically, the proteomic analysis indicated that autophagy might contribute to metformin's anti-senescence effects. Reduced autophagic flux was observed in Ang II-induced cellular and vascular senescence; this reduction was reversed by metformin. Specifically, metformin enhanced the autophagic flux at the autophagosome-lysosome fusion level, whereas blockade of autophagosome-lysosome fusion inhibited the anti-senescence effects of metformin.
CONCLUSIONS
Metformin prevents VSMC and vascular senescence by promoting autolysosome formation.
Topics: Animals; Muscle, Smooth, Vascular; Cellular Senescence; Metformin; Proteomics; Tumor Suppressor Protein p53; Oxidative Stress; Angiotensin II; Autophagy
PubMed: 36328749
DOI: 10.1016/j.jare.2021.12.009