Metformin Pathways: Pharmacokinetics And Pharmacodynamics
Metformin pathways: pharmacokinetics and pharmacodynamics aDepartment of Genetics, Stanford University Medical Center, Stanford University, Stanford bDepartment of Bioengineering, Stanford University Medical Center, Stanford University, Stanford aDepartment of Genetics, Stanford University Medical Center, Stanford University, Stanford bDepartment of Bioengineering, Stanford University Medical Center, Stanford University, Stanford cDepartment of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA Correspondence to Teri E. Klein, PhD, Department of Genetics, Stanford University Medical Center, Stanford University, 1501 California Ave, Palo Alto, CA 94304, USA Tel: + 1 650 725 0659; fax: + 1 650 725 3863; [email protected] The publisher's final edited version of this article is available at Pharmacogenet Genomics See other articles in PMC that cite the published article. Metformin is a first-line therapy for type 2 diabetes mellitus (T2DM, formerly non-insulin-dependent diabetes mellitus), and is one of the most commonly prescribed drugs worldwide. As a biguanide agent, metformin lowers both basal and postprandial plasma glucose (PPG) [ 1 , 2 ]. It can be used as a monotherapy or in combination with other antidiabetic agents including sulfonylureas, -glucosidase inhibitors, insulin, thiazolidinediones, DPP-4 inhibitors as well as GLP-1 agonists. Metformin works by inhibiting the production of hepatic glucose, reducing intestinal glucose absorption, and improving glucose uptake and utilization. Besides lowering the blood glucose level, metformin may have additional health benefits, including weight reduction, lowering plasma lipid levels, and prevention of some vascular complications [ 3 ]. As the prevalence o Continue reading >>
Metformin: The Sweet Link Between Tumor Genetics And Metabolism?
(1) Department of Radiation Oncology, Kimmel Cancer Center and Jefferson Medical College of Thomas Jefferson, Philadelphia PA (2) Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA Epidemiological studies have shown a correlation between insulin resistance, a marker of impaired glucose metabolism and metabolic syndrome, and malignancy development. Insulin resistance leads to a hyperinsulinemic state, which is thought to promote carcinogenesis via the direct effect of insulin on the insulin like growth factor 1 (IGF-1), an increase in IGF-1 synthesis, modulation of sex hormone availability, and finally through the resultant elevated glucose levels that promote inflammation and aid glycolysis in cancer cells. In addition to an increased incidence of cancer induction, insulin resistance has also been correlated with worse prognosis in cancer patients undergoing active treatment. Metformin is an oral agent that is widely used in the treatment of diabetes as it has been shown to sensitize cells to the effects of insulin. Several epidemiologic studies show a potential protective effect of metformin in diabetic patients. Preclinical studies have shown a direct inhibitory effect of metformin on cancer cell lines both in vitro and in vivo. This is thought to be mediated through multiple mechanisms, including effects on cellular metabolism via the AMP-activated protein kinase (AMPK) pathway, effects on cell cycle progression, and decreased cellular oxygen consumption. Though the data is conflicting, several retrospective studies suggest an antitumor benefit of metformin in cancer patients undergoing active treatment. Several prospective studies examining the role of metformin as an adjunctive antineoplastic agent are currently ongoing. Th Continue reading >>
Mechanism Of Metformin: A Tale Of Two Sites
Metformin (dimethylbiguanide) features as a current first-line pharmacological treatment for type 2 diabetes (T2D) in almost all guidelines and recommendations worldwide. It has been known that the antihyperglycemic effect of metformin is mainly due to the inhibition of hepatic glucose output, and therefore, the liver is presumably the primary site of metformin function. However, in this issue of Diabetes Care, Fineman and colleagues (1) demonstrate surprising results from their clinical trials that suggest the primary effect of metformin resides in the human gut. Metformin is an orally administered drug used for lowering blood glucose concentrations in patients with T2D, particularly in those overweight and obese as well as those with normal renal function. Pharmacologically, metformin belongs to the biguanide class of antidiabetes drugs. The history of biguanides can be traced from the use of Galega officinalis (commonly known as galega) for treating diabetes in medieval Europe (2). Guanidine, the active component of galega, is the parent compound used to synthesize the biguanides. Among three main biguanides introduced for diabetes therapy in late 1950s, metformin (Fig. 1A) has a superior safety profile and is well tolerated. The other two biguanides, phenformin and buformin, were withdrawn in the early 1970s due to the risk of lactic acidosis and increased cardiac mortality. The incidence of lactic acidosis with metformin at therapeutic doses is rare (less than three cases per 100,000 patient-years) and is not greater than with nonmetformin therapies (3). Major clinical advantages of metformin include specific reduction of hepatic glucose output, with subsequent improvement of peripheral insulin sensitivity, and remarkable cardiovascular safety, but without increasi Continue reading >>
Metabolic Holy Grail?
Top scientists agree that metformin is an antiaging drug … Is Metformin the Treatment with metformin mimics some of the benefits of calorie restriction By Will Block M etformin is an oral antidiabetic drug used for the treatment of type-2 diabetes, a metabolic disorder characterized by high blood glucose, insulin resistance, and relative insulin deficiency (even though insulin levels are higher than normal). It is also used for metabolic syndrome and glucose intolerance, prediabetic conditions. Metformin was introduced in Europe in 1958, and Canada in 1972. However, it was not until 1995 that the FDA got around to approving it in the United States. Falsely conflating it with the drug phenformin,* the FDA deemed that metformin research and clinical experience performed and gathered outside the US was substandard. In truth, metformin is much safer than phenformin, as the data show.1 “If the same criteria were used for older people as are used for younger people, nearly every senior citizen would be diagnosed as diabetic.” Plus, then as now, the FDA moaned that it had been “hobbled” by budgetary considerations. Compared to the National Institutes of Health’s budget ($31.3 billion requested for this fiscal year vs. $4.9 billion for the FDA), the FDA claims it doesn’t have enough to afford the regulatory work required for speedy approval.† Despite the retardation of its acceptance, metformin is now believed to be the most widely prescribed antidiabetic drug in the world and in the United States alone, more than 48 million prescriptions were filled in 2010 for its generic formulations. * Phenformin had been withdrawn in 1976 due to the stupidity of certain doctors who continued to prescribe it in the face of abnormal liver or kidney function. See ref. #2. † Continue reading >>
Metformin & Metabolism: Beyond Diabetes
You dont want to get diabetes; you really dont. Despite the fact that this disease is generally manageable, the consequences of losing the ability to regulate your blood sugar are potentially debilitating and even fatal. Complications of type 2 diabetes are many, and they can be extreme. Obesity and diabetes, without attempting hyperbole, are almost at plague proportions in some countries such as the US and the UK. There are estimated to be approximately 4.5 million people in the UK living with diabetes, of which approximately 1.1 million are undiagnosed. As of 2012, 29.1 million Americans were living with diabetes (of which 8.1 million were undiagnosed and therefore untreated), and 86 million people older than age 20 had prediabetes. Diabetes is the 7th leading cause of death in the US, although it is likely that the contribution of diabetes is underestimated. These huge numbers primarily relate to type 2 diabetes and have been increasing year on year. Type 1 diabetes is treated with insulin. However, treatment for type 2 diabetes is quite different. While there are a number of drugs, metformin is the front-line drug for diabetes treatment if a healthy diet and physical activity alone are insufficient to control blood sugar (glucose) levels. Metformin works in two basic ways to lower blood sugar levels. Primarily, it reduces the amount of sugar produced by cells in the liver. Secondly, it increases the sensitivity of muscle cells to insulin so that glucose can be absorbed. Metformin reduces insulin resistance and improves the uptake of glucose in muscle. You might be surprised to learn that it also reduces the risk of cancer and lowers the values of LDL cholesterol (Adam et al, 20161). Quite a busy and useful drug. However, the mode of action of metformin in type 2 di Continue reading >>
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Metformin is a biguanide, whose chemical scaffold was discovered by the extraction of the galegine, a guanidine analogue, from French lilac (Galega officinalis) plants. Metformin is the first-line therapy for type 2 diabetes ( Alexander et al. 2008 ). In 2005, a 23% reduction in the incidence of any cancer in type 2 diabetic patients treated with metformin was reported ( Evans et al. 2005 ). In recent years, results from retrospective epidemiological and in vitro studies have supported the rationale of designing clinical trials using metformin as an adjuvant in chemotherapy for cancer patients ( Zhang et al. 2013 ). Conversely, the recently raised criticisms about the role of metformin in cancer have underlined the clinical heterogeneity between trials and the presence of time-related biases ( Stevens et al. 2012 , Suissa & Azoulay 2012 , Badrick & Renehan 2014 ). Indeed, recent experimental results have shed new light on the mechanisms of action of metformin as a key regulator of cellular metabolism. It has been reported that metformin inhibits proliferation and induces apoptosis in cancer cells as a result of decreased energy disposition due to an increased AMP:ATP ratio and AMP-activated protein kinase (AMPK) activation ( Viollet et al. 2011 ). The ability of metformin to mimic a condition of caloric restriction is currently of great interest in the field of oncology ( Omar et al. 2010 ). In fact, to compensate the rapid cell growth and proliferation, cancer cells exploit all possible mechanisms, including increased metabolism, demand for nutrients and consumption of glucose, which is known as the Warburg effect ( Koppenol et al. 2011 ). Results of recent studies have indicated that metformin treatment might inhibit glucose uptake in tumours. In this review, we desc Continue reading >>
Beneficial Effects Of Metformin On Energy Metabolism And Visceral Fat Volume Through A Possible Mechanism Of Fatty Acid Oxidation In Human Subjects And Rats
Click through the PLOS taxonomy to find articles in your field. For more information about PLOS Subject Areas, click here . Beneficial effects of metformin on energy metabolism and visceral fat volume through a possible mechanism of fatty acid oxidation in human subjects and rats Affiliation Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan Affiliation Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan Affiliation Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan Affiliation Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan Affiliation Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan Affiliation Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan Affiliation Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan Affiliation Institute of Animal Experimentation, Kurume University School of Medicine, Kurume, Japan Continue reading >>
Is Metformin Associated With Lactic Acidosis?
Is Metformin Associated With Lactic Acidosis? The use of metformin in patients with renal impairment is associated with an increased risk for lactic acidosis. Why is this and what is the mechanism? Are sulfonylureas associated with lactic acidosis? Adjunct Faculty, Albany College of Pharmacy, Albany, New York; Clinical Pharmacy Specialist, VA Medical Center, Bath, New York Metformin is one of most commonly prescribed medications for the treatment of type 2 diabetes mellitus. Metformin exerts its activity by increasing peripheral glucose uptake and utilization, and decreasing hepatic gluconeogenesis. By decreasing pyruvate dehydrogenase activity and mitochondrial reducing agent transport, metformin enhances anaerobic metabolism and increased production of tricarboxylic acid cycle precursors. Inhibition of pyruvate dehydrogenase subsequently decreases the channeling of these precursors into aerobic metabolism and causes increased metabolism of pyruvate to lactate and ultimately lactic acid production.[ 1 ] In a patient with normal renal function, the excess lactic acid is simply cleared through the kidneys. However, in a patient with renal impairment, both metformin and lactic acid are cleared less effectively and may result in further accumulation of both.[ 1 ] The complication of lactic acidosis is serious and potentially fatal. Increased risk for lactic acidosis associated with metformin is controversial. A Cochrane Systematic Review of over 200 trials evaluated the incidence of lactic acidosis among patients prescribed metformin vs non-metformin antidiabetes medications. Of 100,000 people, the incidence of lactic acidosis was 5.1 cases in the metformin group and 5.8 cases in the non-metformin group. The authors concluded that metformin is not associated with an incre Continue reading >>
Liver Disease Affects Metformin Metabolism
Increased diabetes drug exposure may increase risk of adverse reactions in type 2 patients with NASH… Obesity increases the risk of nonalcoholic steatohepatitis (NASH), which occurs when there is too much fat in the liver. NASH is often asymptomatic and because testing for it requires a liver biopsy, many cases go undiagnosed. It is estimated that between 6 and 17 percent of Americans currently have NASH. With obesity on the rise, that number will continue to grow. While it is known that NASH can affect hepatic clearance of drugs, researchers at the University of Arizona College of Pharmacy decided to study how NASH affects kidney transporters such as Oct1, Oct2, and Mate1, which are primarily responsible for the elimination of metformin. Using mouse models of obesity, diabetes, NASH, and a choline and methionine deficient diet, the researchers found that this caused decreases in Oct2 and Mate1 expression in the kidneys, leading to a 4.8-fold increase in serum metformin levels. “This study, in addition to several of our other recent studies shows that NASH, either alone or in combination with genetic differences in drug transporters, can have a profound effect on drug exposure,” said research associate John Clarke. Nathan Cherrington, professor at the university’s Department of Pharmacology and Toxicology, adds that the next step is to continue the research to demonstrate that NASH can lead to metformin retention in humans. While metformin is considered a relatively safe and effective drug, increased exposure may increase the risk of adverse reactions. “If any clinician is going to provide precision medicine, they’ll need to know the ability of the liver and kidneys to metabolize and eliminate drugs,” says Cherrington. He believes this study will lead to b Continue reading >>
Effect Of Metformin On Metabolic Improvement And Gut Microbiota
Effect of Metformin on Metabolic Improvement and Gut Microbiota aCenter for Human and Environmental Microbiome, School of Public Health, Seoul National University, Seoul, South Korea bN-Bio, Seoul National University, Seoul, South Korea Metformin is commonly used as the first line of medication for the treatment of metabolic syndromes, such as obesity and type 2 diabetes (T2D). Recently, metformin-induced changes in the gut microbiota have been reported; however, the relationship between metformin treatment and the gut microbiota remains unclear. In this study, the composition of the gut microbiota was investigated using a mouse model of high-fat-diet (HFD)-induced obesity with and without metformin treatment. As expected, metformin treatment improved markers of metabolic disorders, including serum glucose levels, body weight, and total cholesterol levels. Moreover, Akkermansia muciniphila (12.44% 5.26%) and Clostridium cocleatum (0.10% 0.09%) abundances increased significantly after metformin treatment of mice on the HFD. The relative abundance of A. muciniphila in the fecal microbiota was also found to increase in brain heart infusion (BHI) medium supplemented with metformin in vitro. In addition to the changes in the microbiota associated with metformin treatment, when other influences were controlled for, a total of 18 KEGG metabolic pathways (including those for sphingolipid and fatty acid metabolism) were significantly upregulated in the gut microbiota during metformin treatment of mice on an HFD. Our results demonstrate that the gut microbiota and their metabolic pathways are influenced by metformin treatment. Metformin is a common antidiabetic agent in the biguanide class and is known to suppress glucose production in the liver, increase insulin sensitivity, an Continue reading >>
Metformin Influences Nitrogen And Urea Metabolism
Follow all of ScienceDaily's latest research news and top science headlines ! Metformin influences nitrogen and urea metabolism Helmholtz Zentrum Muenchen - German Research Centre for Environmental Health The most frequently prescribed oral antidiabetic drug metformin significantly affects metabolic pathways, report scientists. Metformin is a widespread oral medication to increase insulin sensitivity in patients with type 2 diabetes (T2D). According to a number of studies, it additionally reduces the risk of cardiovascular complications. The most frequently prescribed oral antidiabetic drug metformin significantly affects metabolic pathways. This was reported by scientists from the Helmholtz Zentrum Mnchen together with colleagues from the German Diabetes Center (DDZ) in Dsseldorf. The underlying study was conducted with further scientists of the German Center for Diabetes Research (DZD). These results have now been published in the journal 'Diabetes'. Metformin is a widespread oral medication to increase insulin sensitivity in patients with type 2 diabetes (T2D). According to a number of studies, it additionally reduces the risk of cardiovascular complications. Last year, a team led by Dr. Rui Wang-Sattler discovered that metformin intake lowers the levels of the harmful LDL cholesterol by activating the AMPK protein complex. Dr. Wang-Sattler is head of the "Metabolism" research group in the Research Unit of Molecular Epidemiology at the Institute of Epidemiology II at the Helmholtz Zentrum Mnchen. Her group aims to understand the molecular mechanisms that underlie the activity of metformin. Metformin intake changes metabolite profiles in population-based KORA* study In the present work, the interdisciplinary team of scientists was able to explain a further feature of Continue reading >>
Metformin, marketed under the trade name Glucophage among others, is the first-line medication for the treatment of type 2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome. Limited evidence suggests metformin may prevent the cardiovascular disease and cancer complications of diabetes. It is not associated with weight gain. It is taken by mouth. Metformin is generally well tolerated. Common side effects include diarrhea, nausea and abdominal pain. It has a low risk of causing low blood sugar. High blood lactic acid level is a concern if the medication is prescribed inappropriately and in overly large doses. It should not be used in those with significant liver disease or kidney problems. While no clear harm comes from use during pregnancy, insulin is generally preferred for gestational diabetes. Metformin is in the biguanide class. It works by decreasing glucose production by the liver and increasing the insulin sensitivity of body tissues. Metformin was discovered in 1922. French physician Jean Sterne began study in humans in the 1950s. It was introduced as a medication in France in 1957 and the United States in 1995. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. Metformin is believed to be the most widely used medication for diabetes which is taken by mouth. It is available as a generic medication. The wholesale price in the developed world is between 0.21 and 5.55 USD per month as of 2014. In the United States, it costs 5 to 25 USD per month. Medical uses Metformin is primarily used for type 2 diabetes, but is increasingly be Continue reading >>
Long-term Effects Of Metformin On Metabolism And Microvascular And Macrovascular Disease In Patients With Type 2 Diabetes Mellitus
Background We investigated whether metformin hydrochloride has sustained beneficial metabolic and (cardio) vascular effects in patients with type 2 diabetes mellitus (DM2). Methods We studied 390 patients treated with insulin in the outpatient clinics of 3 hospitals in a randomized, placebo-controlled trial with a follow-up period of 4.3 years. Either metformin hydrochloride, 850 mg, or placebo (1-3 times daily) was added to insulin therapy. The primary end point was an aggregate of microvascular and macrovascular morbidity and mortality. The secondary end points were microvascular and macrovascular morbidity and mortality, as separate aggregate scores. In addition, effects on hemoglobin A1c (HbA1c), insulin requirement, lipid levels, blood pressure, body weight, and body mass index were analyzed. Results Metformin treatment prevented weight gain (mean weight gain, −3.07 kg [range, −3.85 to −2.28 kg]; P < .001), improved glycemic control (mean reduction in HbA1c level, 0.4% percentage point [95% CI, 0.55-0.25]; P < .001) (where CI indicates confidence interval), despite the aim of similar glycemic control in both groups, and reduced insulin requirements (mean reduction, 19.63 IU/d [95% CI, 24.91-14.36 IU/d]; P < .001). Metformin was not associated with an improvement in the primary end point. It was, however, associated with an improvement in the secondary, macrovascular end point (hazard ratio, 0.61 (95% CI, 0.40-0.94; P = .02), which was partly explained by the difference in weight. The number needed to treat to prevent 1 macrovascular end point was 16.1 (95% CI, 9.2-66.6). Conclusions Metformin, added to insulin in patients with DM2, improved body weight, glycemic control, and insulin requirements but did not improve the primary end point. Metformin did, howeve Continue reading >>
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What Is Metformin?
MORE Metformin is a prescription drug used primarily in the treatment of Type II diabetes. It can be used on its own or combined with other medications. In the United States, it is sold under the brand names Fortamet, Glucophage, Glumetza and Riomet. "Metformin is very often prescribed as the first step in a diabetic's regime," said Ken Sternfeld, a New York-based pharmacist. How it works "When you're diabetic you lose the ability to use the insulin you need to offset the food," Sternfeld explained. "If you eat a carb or sugar that can't be metabolized or offset by the insulin you produce, your sugar levels will be higher. Metformin and drugs in that category will help your body better metabolize that food so that insulin levels will be able to stay more in line." Metformin aims to decrease glucose production in the liver, consequently lowering the levels of glucose in the bloodstream. It also changes the way that your blood cells react to insulin. "It makes them more sensitive to insulin," said Dr. Stephen Neabore, a primary care doctor at the Barnard Medical Center in Washington, D.C. "It makes the same amount of insulin work better. It transports the insulin to the cells in a more effective way." Metformin may have a preventive health role, as well. New research presented at the American Diabetes Association 2017 Scientific Sessions showed that long-term use of metformin is particularly useful in preventing the onset of type II diabetes in women who have suffered from gestational diabetes. Because metformin changes the way the body uses insulin, it is not used to treat Type I diabetes, a condition in which the body does not produce insulin at all. Metformin & PCOS Metformin is sometimes prescribed to treat polycystic ovarian syndrome (PCOS), according to Neabore. "I Continue reading >>
Metformin: From Mechanisms Of Action To Therapies
View all Images/DataFigure 1 Metformin is transported into hepatocytes mainly through OCT1 and partially inhibits mitochondrial respiratory-chain complex 1, resulting in reduced ATP levels and accumulation of AMP. Gluconeogenesis is reduced as a result of ATP deficit limiting glucose synthesis, increased AMP levels leading to reduced activity of the key gluconeogenic enzyme FBPase, inhibition of adenylate cyclase and cAMP-PKA signaling, and inhibition of mGPD contributing to altered redox state and reduced conversion of glycerol to glucose. Metformin-induced change in AMP/ATP ratio also activates AMPK, which suppresses lipid synthesis and exerts insulin sensitizing effects. Abbreviations: ACC, acetyl CoA carboxylase; AMPK, AMP-activated protein kinase; cAMP, cyclic AMP; complex 1, respiratory-chain complex 1; DHAP, dihydroxyacetone phosphate; FBPase, fructose-1,6-bisphosphatase; G3P, glycerol-3-phosphate; cGPD, cytosolic glycerophosphate dehydrogenase; mGPD, mitochondrial glycerophosphate dehydrogenase; OCT1, organic transporter 1; PKA, protein kinase A. 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. Main Text Introduction Me Continue reading >>