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How Metformin Is Metabolized?

Long-term Effects Of Metformin On Metabolism And Microvascular And Macrovascular Disease In Patients With Type 2 Diabetes Mellitus

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 >>

Metformin: From Mechanisms Of Action To Therapies

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 >>

Metformin

Metformin

Metformin, marketed under the trade name Glucophage among others, is the first-line medication for the treatment of type 2 diabetes,[4][5] particularly in people who are overweight.[6] It is also used in the treatment of polycystic ovary syndrome.[4] Limited evidence suggests metformin may prevent the cardiovascular disease and cancer complications of diabetes.[7][8] It is not associated with weight gain.[8] It is taken by mouth.[4] Metformin is generally well tolerated.[9] Common side effects include diarrhea, nausea and abdominal pain.[4] It has a low risk of causing low blood sugar.[4] High blood lactic acid level is a concern if the medication is prescribed inappropriately and in overly large doses.[10] It should not be used in those with significant liver disease or kidney problems.[4] While no clear harm comes from use during pregnancy, insulin is generally preferred for gestational diabetes.[4][11] Metformin is in the biguanide class.[4] It works by decreasing glucose production by the liver and increasing the insulin sensitivity of body tissues.[4] Metformin was discovered in 1922.[12] French physician Jean Sterne began study in humans in the 1950s.[12] It was introduced as a medication in France in 1957 and the United States in 1995.[4][13] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[14] Metformin is believed to be the most widely used medication for diabetes which is taken by mouth.[12] It is available as a generic medication.[4] The wholesale price in the developed world is between 0.21 and 5.55 USD per month as of 2014.[15] In the United States, it costs 5 to 25 USD per month.[4] Medical uses[edit] Metformin is primarily used for type 2 diabetes, but is increasingly be Continue reading >>

Erc | Mobile

Erc | Mobile

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 >>

Mitochondrial Metabolism And Type-2 Diabetes: A Specific Target Of Metformin - Em|consulte

Mitochondrial Metabolism And Type-2 Diabetes: A Specific Target Of Metformin - Em|consulte

Mitochondrial metabolism and type-2 diabetes: a specific target of metformin XM Leverve[1], B Guigas[1], D Detaille[1], C Batandier[1], EA Koceir[1 et 2], C Chauvin[1], E Fontaine[1], NF Wiernsperger[3] [1]INSERM E-0221 Bionergtique Fondamentale et Applique, Universit Joseph-Fourier, Grenoble, France, [2]Laboratoire BPO-Nutrition et Mtabolismes, Facult des Sciences Biologiques, Universit des Sciences et de la Technologie Houari-Boumedienne, Alger, Algrie. [4]INSERM E-0221 Bionergtique Fondamentale et Applique, Universit Joseph-Fourier, BP 53X, 38041 Grenoble Cedex, France. Phone: 33 476 51 43 86 Fax: 33 476 51 43 05 E-mail: Several links relate mitochondrial metabolism and type 2 diabetes or chronic hyperglycaemia. Among them, ATP synthesis by oxidative phosphorylation and cellular energy metabolism (ATP/ADP ratio), redox status and reactive oxygen species (ROS) production, membrane potential and substrate transport across the mitochondrial membrane are involved at various steps of the very complex network of glucose metabolism. Recently, the following findings (1) mitochondrial ROS production is central in the signalling pathway of harmful effects of hyperglycaemia, (2) AMPK activation is a major regulator of both glucose and lipid metabolism connected with cellular energy status, (3) hyperglycaemia by inhibiting glucose-6-phosphate dehydrogenase (G6PDH) by a cAMP mechanism plays a crucial role in NADPH/NADP ratio and thus in the pro-oxidant/anti-oxidant cellular status, have deeply changed our view of diabetes and related complications. It has been reported that metformin has many different cellular effects according to the experimental models and/or conditions. However, recent important findings may explain its unique efficacy in the treatment of hyperglycaemia- or Continue reading >>

Lkb1- Ampk Pathway Regulation Of Glucose Metabolism And Metformin Action In Liver Shaw, Reuben James Salk Institute For Biological Studies, La Jolla, Ca, United States

Lkb1- Ampk Pathway Regulation Of Glucose Metabolism And Metformin Action In Liver Shaw, Reuben James Salk Institute For Biological Studies, La Jolla, Ca, United States

LKB1- AMPK pathway regulation of glucose metabolism and metformin action in liver Deregulation of glucose and lipid metabolism in peripheral tissues is a hallmark of type 2 diabetes. AMP- activated protein kinase (AMPK) is a master regulator of cellular and organismal metabolism which acts as sensor of cellular energy status and plays key roles in glucose and lipid homeostasis in metabolic tissues. AMPK is activated by low nutrients, exercise, adipokines such adiponectin, and by the widely used diabetes therapeutic metformin. Upon activation in liver, AMPK functions to reduce gluconeogenesis and lipogenesis through incompletely understood mechanisms. Previously, the serine/threonine kinase LKB1 was identified as the critical upstream kinase mediating AMPK activation in most mammalian tissues. Genetic deletion of LKB1 in the liver of adult mice resulted in complete loss of hepatic AMPK activity and significant increases in gluconeogenesis and hepatic lipid accumulation, while attenuating the ability of metformin to lower blood glucose. A major challenge in the field remained in decoding the molecular mechanisms through which LKB1-AMPK signaling controls metabolism. Over the past 4 years of this funding, my laboratory performed a multi-pronged screen for direct substrates of AMPK, which led to the identification and study of a number of novel AMPK substrates critical in metabolism, including Raptor, ULK1, Cry1, Srebp1, and HDACs4, 5, and 7. In this first renewal, it is proposed to further dissect the role of AMPK and related kinases in control of glucose metabolism and the therapeutic action of metformin. Given the recent advances in decoding the molecular effectors of the LKB1/AMPK signaling pathway, the relative contributions of different AMPK substrates to metabolic c Continue reading >>

Combination Therapy For Patients With Type 2 Diabetes: Repaglinide In Combination With Metformin

Combination Therapy For Patients With Type 2 Diabetes: Repaglinide In Combination With Metformin

Repaglinide is rapidly and almost completely absorbed after oral administration, with peak plasma concentrations achieved in about 1 h.[ 52 ] When taken 15 min before a meal, repaglinide produces a rapid insulin-releasing effect that lasts for 3 h, coinciding with the duration of meal digestion. Repaglinide is cleared rapidly from the circulation. Total body clearance of a 2-mg intravenous dose over 15 min was 33 l/h.[ 52 ] Repaglinide clearance depends predominantly on liver blood flow, but also on protein binding and liver enzyme activity. Following an oral dose, repaglinide concentrations fall rapidly, reaching predose concentrations within 45 h after oral administration. Repaglinide is mainly metabolized via oxidative biotransformation involving the hepatic microsomal cytochrome P450 (CYP450) system. In patients with reduced renal function, repaglinide may be advantageous considering that excretion of repaglinide is principally by the biliary route. The rapid elimination half-life of repaglinide and lack of accumulation upon repeated dosing reduce the risk of hypoglycemia.[ 53 ] Repaglinide has been safe and well tolerated in patients with varying degrees of renal impairment.[ 5456 ] Glycemic control was maintained in a similar manner in patients with and without renal impairment. Rates of minor hypoglycemic episodes were similar in patients with varying degrees of renal impairment, and no major hypoglycemic episodes were reported in these studies. In patients with severe renal impairment, a longer half-life was observed with repaglinide following multiple dosing[ 55 ] and the final repaglinide dose was lower in patients with severe renal impairment when compared with patients with mild-to-moderate impairment.[ 54 ] Metformin is a stable hydrophilic biguanide that Continue reading >>

Liver Disease Affects Metformin Metabolism

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 >>

Metformin Pathways: Pharmacokinetics And Pharmacodynamics

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?

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 >>

Metformin And Pancreatic Cancer Metabolism

Metformin And Pancreatic Cancer Metabolism

Metformin and Pancreatic Cancer Metabolism By Mary Jo Cantoria, Hitendra Patel, Laszlo G. Boros and Emmanuelle J.Meuillet 5. Chemotherapeutic properties of metformin Figure 3. Metformin impairs signaling molecules for cancer survival. Metformin and Pancreatic Cancer Metabolism Mary Jo Cantoria1, 2, Hitendra Patel2, 3, Laszlo G. Boros4, 5 and Emmanuelle J. Meuillet2, 6 [1] Department of Nutritional Sciences, The University of Arizona, Tucson, USA [2] The University of Arizona Cancer Center, Tucson, AZ, USA [3] College of Medicine, The University of Arizona, Tucson, USA [5] Department of Pediatrics, Los Angeles Biomedical Research, USA [6] Institute at the Harbor-UCLA Medical Center, Torrance, CA, USA [7] Department of Nutritional Sciences, The University of Arizona, Tucson, USA Numerous epidemiological studies have reported that metformin, a well-known and widely used anti-diabetic drug, may provide protective benefits in decreasing pancreatic cancer risk among the diabetic population. Following a brief introduction regarding metformins history and pharmacological properties, this book chapter presents epidemiological findings showing how metformin is associated with protection against pancreatic cancer. We also introduce the anti-cancer effects of metformin through AMPK-independent and AMPK-dependent manners [ 1 - 6 ]. These mechanisms include its inhibitory effects on the insulin growth factor-1 (IGF-1), G protein-coupled receptor (GPCR) and mTORC1 signaling pathways [ 3 - 10 ]. We then discuss the metabolic effects of metformin in cancer. For example, metformin has been shown to inhibit glycolysis in various cancer cell lines [ 11 - 13 ]. Metformin is a known inhibitor of complex I of the electron transport chain [ 14 - 18 ], potentially limiting the intact oxidative Continue reading >>

Metformin & Metabolism: Beyond Diabetes

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 >>

Metformin

Metformin

Postmarketing cases of Metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of Metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and Metformin plasma levels generally >5 mcg/mL (see PRECAUTIONS). Risk factors for Metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g. carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage Metformin-associated lactic acidosis in these high risk groups are provided (see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and PRECAUTIONS). If Metformin-associated lactic acidosis is suspected, immediately discontinue Metformin and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended (see PRECAUTIONS). Table 1: Select Mean (±S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin Hydrochloride Tablets Subject Groups: Metformin hydrochloride tablets dose* (number of subjects) Cmax† (mcg/mL) Tmax‡ (hrs) Renal Clearance (mL/min) * All doses given fasting except the first 18 doses of the multiple dose studies † Peak plasma concentration ‡ Time to peak plasma concentration § Co 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

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 >>

Effect Of Metformin On Metabolic Improvement And Gut Microbiota

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 >>

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