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| Metformin, sold under the brand name Glucophage, among others, is the main 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, and is sometimes used as an off-label adjunct to lessen the risk of metabolic syndrome in people who take antipsychotic medication. It has been shown to inhibit inflammation, and is not associated with weight gain. Metformin is taken by mouth.
Metformin is generally well tolerated. Common adverse effects include diarrhea, nausea, and abdominal pain. It has a small risk of causing low blood sugar. High blood lactic acid level (acidosis) is a concern if the medication is used in overly large doses or prescribed in people with severe kidney problems.
Metformin is a biguanide anti-hyperglycemic agent. It works by decreasing glucose production in the liver, increasing the insulin sensitivity of body tissues, and increasing GDF15 secretion, which reduces appetite and caloric intake.
Metformin was first described in the scientific literature in 1922 by Emil Werner and James Bell. French physician Jean Sterne began the study in humans in the 1950s. It was introduced as a medication in France in 1957. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication. In 2022, it was the second most commonly prescribed medication in the United States, with more than 86 million prescriptions. In Australia, it was one of the top 10 most prescribed medications between 2017 and 2023. |
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Read full article at Wikipedia
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| InChI=1S/C4H11N5/c1-9(2)4(7)8-3(5)6/h1-2H3,(H5,5,6,7,8) |
| XZWYZXLIPXDOLR-UHFFFAOYSA-N |
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environmental contaminant
Any minor or unwanted substance introduced into the environment that can have undesired effects.
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xenobiotic
A xenobiotic (Greek, xenos "foreign"; bios "life") is a compound that is foreign to a living organism. Principal xenobiotics include: drugs, carcinogens and various compounds that have been introduced into the environment by artificial means.
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hypoglycemic agent
A drug which lowers the blood glucose level.
geroprotector
Any compound that supports healthy aging, slows the biological aging process, or extends lifespan.
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View more via ChEBI Ontology
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N,N-dimethyltriimidodicarbonic diamide
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metformin
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WHO MedNet
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metformina
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WHO MedNet
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metformine
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WHO MedNet
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metforminum
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WHO MedNet
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1,1-dimethylbiguanide
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ChemIDplus
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dimethylbiguanide
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ChemIDplus
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dimethyldiguanide
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ChemIDplus
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LA 6023
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DrugBank
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LA-6023
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ChemIDplus
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N,N-dimethylbiguanide
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ChemIDplus
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N,N-dimethyldiguanide
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ChemIDplus
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N,N-dimethylguanylguanidine
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DrugCentral
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N,N-dimethylimidodicarbonimidic diamide
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IUPAC
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N1,N1-dimethylbiguanide
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ChemIDplus
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1725
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DrugCentral
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C07151
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KEGG COMPOUND
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D04966
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KEGG DRUG
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DB00331
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DrugBank
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FDB022739
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FooDB
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HMDB0001921
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HMDB
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LSM-4730
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LINCS
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Metformin
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606492
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Reaxys
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657-24-9
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CAS Registry Number
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ChemIDplus
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Tądel K, Wiatrak B, Bodetko D, Barg E (2020)
Metformin and proliferation of cancer cell lines.
Pediatric endocrinology, diabetes, and metabolism 26, 159-166 [PubMed:33191721]
[show Abstract]
IntroductionMetformin is a widely used drug in treating type 2 diabetes and insulin resistance and nowadays scientists are searching for new poten-tial and multiple roles in prevention and treatment of carcinogenic processes.Aim of the studyThe aim of the study was to compare the impact of normoglycemia and hyperglycemia with doses of metformin on vivacity and prolifer-ation of cancer cell lines (MCF-7, MCF-7/DX, A549, CCRF/CEM, THP-1, NHDF).Material and methodsWe designed our experiment using raising glucose environment (40 mM, 100 mM, 150 mM, 300 mM) and we added increasing con-centrations of metformin (5 mM, 10 mM, 20 mM, 30 mM). We incubated cells for 24 h, 48 h, 72 h, 96 h. In order to measure of viabil-ity of cancer cells we use MTT assay - a typical test to mark cytotoxic effects of tested substances.ResultsAnalysis indicated that populations of cancer cells in our terms was lowering, the incubation of 24 h and 48 h showed favorable results than 72 h and 96 h. In normoglycemic environment (glucose level about 100 mM) and after added metformin in various concentrations we observed decreasing percentage of vivid cells for all cancer cell lines (MCF-7, MCF-7/DX, A549, CCRF/CEM, THP-1).ConclusionsThe results of our study showed beneficial effects of metformin on decreasing proliferation of cancer cells. Percentage of vivid popula-tions were lowering and we confirmed anti-cancer effect of this drug. | Rivero Viera Y, Auyanet Saavedra I, Guerra Rodríguez R, Esparza Martín N, Fernández Granados S, García Cantón C (2019)
Metformin and diuretics.
Nefrologia 39, 557-558 [PubMed:31208831] | Guo Z, Sevrioukova IF, Denisov IG, Zhang X, Chiu TL, Thomas DG, Hanse EA, Cuellar RAD, Grinkova YV, Langenfeld VW, Swedien DS, Stamschror JD, Alvarez J, Luna F, Galván A, Bae YK, Wulfkuhle JD, Gallagher RI, Petricoin EF, Norris B, Flory CM, Schumacher RJ, O'Sullivan MG, Cao Q, Chu H, Lipscomb JD, Atkins WM, Gupta K, Kelekar A, Blair IA, Capdevila JH, Falck JR, Sligar SG, Poulos TL, Georg GI, Ambrose E, Potter DA (2017)
Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria.
Cell chemical biology 24, 1259-1275.e6 [PubMed:28919040]
[show Abstract]
The mechanisms by which cancer cell-intrinsic CYP monooxygenases promote tumor progression are largely unknown. CYP3A4 was unexpectedly associated with breast cancer mitochondria and synthesized arachidonic acid (AA)-derived epoxyeicosatrienoic acids (EETs), which promoted the electron transport chain/respiration and inhibited AMPKα. CYP3A4 knockdown activated AMPKα, promoted autophagy, and prevented mammary tumor formation. The diabetes drug metformin inhibited CYP3A4-mediated EET biosynthesis and depleted cancer cell-intrinsic EETs. Metformin bound to the active-site heme of CYP3A4 in a co-crystal structure, establishing CYP3A4 as a biguanide target. Structure-based design led to discovery of N1-hexyl-N5-benzyl-biguanide (HBB), which bound to the CYP3A4 heme with higher affinity than metformin. HBB potently and specifically inhibited CYP3A4 AA epoxygenase activity. HBB also inhibited growth of established ER+ mammary tumors and suppressed intratumoral mTOR. CYP3A4 AA epoxygenase inhibition by biguanides thus demonstrates convergence between eicosanoid activity in mitochondria and biguanide action in cancer, opening a new avenue for cancer drug discovery. | Aatsinki SM, Buler M, Salomäki H, Koulu M, Pavek P, Hakkola J (2014)
Metformin induces PGC-1α expression and selectively affects hepatic PGC-1α functions.
British journal of pharmacology 171, 2351-2363 [PubMed:24428821]
[show Abstract]
Background and purposeThe objective of this study was to determine how the AMPK activating antidiabetic drug metformin affects the major activator of hepatic gluconeogenesis, PPARγ coactivator 1α (PGC-1α) and liver functions regulated by PGC-1α.Experimental approachMouse and human primary hepatocytes and mice in vivo were treated with metformin. Adenoviral overexpression, siRNA and reporter gene constructs were used for mechanistic studies.Key resultsMetformin increased PGC-1α mRNA and protein expression in mouse primary hepatocytes. 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) (another AMPK activator) had the opposite effect. Metformin also increased PGC-1α in human primary hepatocytes; this effect of metformin was abolished by AMPK inhibitor compound C and sirtuin 1 siRNA. AMPK overexpression by AMPK-Ad also increased PGC-1α. Whereas metformin increased PGC-1α, it down-regulated gluconeogenic genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). Furthermore, metformin attenuated the increase in PEPCK and G6Pase mRNAs induced by PGC-1α overexpression, but did not affect PGC-1α-mediated induction of mitochondrial genes. Metformin down-regulated several key transcription factors that mediate the effect of PGC-1α on gluconeogenic genes including Krüppel-like factor 15, forkhead box protein O1 and hepatocyte NF 4α, whereas it increased nuclear respiratory factor 1, which is involved in PGC-1α-mediated regulation of mitochondrial proteins.Conclusions and implicationsDown-regulation of PGC-1α is not necessary for suppression of gluconeogenic genes by metformin. Importantly, metformin selectively affects hepatic PGC-1α-mediated gene regulation and prevents activation of gluconeogenesis, but does not influence its regulation of mitochondrial genes. These results identify selective modulation of hepatic PGC-1α functions as a novel mechanism involved in the therapeutic action of metformin. | Cabreiro F, Au C, Leung KY, Vergara-Irigaray N, Cochemé HM, Noori T, Weinkove D, Schuster E, Greene ND, Gems D (2013)
Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism.
Cell 153, 228-239 [PubMed:23540700]
[show Abstract]
The biguanide drug metformin is widely prescribed to treat type 2 diabetes and metabolic syndrome, but its mode of action remains uncertain. Metformin also increases lifespan in Caenorhabditis elegans cocultured with Escherichia coli. This bacterium exerts complex nutritional and pathogenic effects on its nematode predator/host that impact health and aging. We report that metformin increases lifespan by altering microbial folate and methionine metabolism. Alterations in metformin-induced longevity by mutation of worm methionine synthase (metr-1) and S-adenosylmethionine synthase (sams-1) imply metformin-induced methionine restriction in the host, consistent with action of this drug as a dietary restriction mimetic. Metformin increases or decreases worm lifespan, depending on E. coli strain metformin sensitivity and glucose concentration. In mammals, the intestinal microbiome influences host metabolism, including development of metabolic disease. Thus, metformin-induced alteration of microbial metabolism could contribute to therapeutic efficacy-and also to its side effects, which include folate deficiency and gastrointestinal upset. | Slack C, Foley A, Partridge L (2012)
Activation of AMPK by the putative dietary restriction mimetic metformin is insufficient to extend lifespan in Drosophila.
PloS one 7, e47699 [PubMed:23077661]
[show Abstract]
The biguanide drug, metformin, commonly used to treat type-2 diabetes, has been shown to extend lifespan and reduce fecundity in C. elegans through a dietary restriction-like mechanism via the AMP-activated protein kinase (AMPK) and the AMPK-activating kinase, LKB1. We have investigated whether the longevity-promoting effects of metformin are evolutionarily conserved using the fruit fly, Drosophila melanogaster. We show here that while feeding metformin to adult Drosophila resulted in a robust activation of AMPK and reduced lipid stores, it did not increase lifespan in either male or female flies. In fact, we found that when administered at high concentrations, metformin is toxic to flies. Furthermore, no decreases in female fecundity were observed except at the most toxic dose. Analysis of intestinal physiology after metformin treatment suggests that these deleterious effects may result from disruptions to intestinal fluid homeostasis. Thus, metformin appears to have evolutionarily conserved effects on metabolism but not on fecundity or lifespan. | Wu J, Zhu Y, Jiang Y, Cao Y (2008)
Effects of metformin and ethinyl estradiol-cyproterone acetate on clinical, endocrine and metabolic factors in women with polycystic ovary syndrome.
Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 24, 392-398 [PubMed:18608522]
[show Abstract]
BackgroundPolycystic ovary syndrome (PCOS) is a major endocrine abnormality that affects women of reproductive age. Oral contraceptive pills are usually the first choice of treatment for PCOS when fertility is not desired. Metformin, an insulin-sensitizing drug, has been shown to improve such metabolic abnormality. Aim. To compare the effects of a contraceptive pill in combination with metformin on the clinical, endocrine and metabolic parameters in obese and non-obese patients with PCOS.MethodsSixty PCOS patients (25 obese, 35 non-obese) were enrolled in this prospective clinical study. PCOS was defined according to the Rotterdam criteria. Patients were randomized to oral treatment with Diane35 (35 microg ethinyl estradiol plus 2 mg cyproterone acetate), metformin or a combination of Diane35/metformin for 3 months. Body mass index (BMI), waist-to-hip ratio (WHR), Ferriman-Gallwey (FG) score, leuteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, fasting insulin and glucose/insulin ratio were measured at baseline and at the end of treatment.ResultsDiane35 resulted in a higher reduction of FG score in both obese and non-obese PCOS patients compared with metformin. Menstrual regularity was restored in all PCOS patients treated with Diane35 compared with only 28% of those receiving metformin. Metformin significantly decreased BMI and WHR in obese patients (p < 0.05). Testosterone levels decreased in all three groups. LH levels and LH/FSH ratio decreased with Diane35 and Diane35/metformin in both obese and non-obese patients. Metformin significantly decreased fasting insulin concentrations (p < 0.05 and p < 0.01) and increased the insulin sensitivity (p < 0.05) in both obese and non-obese PCOS patients, while no significant changes were observed in the Diane35 group. In addition, insulin levels also decreased (p < 0.05) in the Diane35/metformin group.ConclusionsOur data show that a combination of metformin and contraceptive pill may be more effective in suppressing the hyperandrogenemia of obese and non-obese PCOS patients than metformin alone and may reduce insulin levels more than contraceptive pill alone. Hence, combined treatment may become a more effective therapeutic option for PCOS. | Ben Sahra I, Laurent K, Loubat A, Giorgetti-Peraldi S, Colosetti P, Auberger P, Tanti JF, Le Marchand-Brustel Y, Bost F (2008)
The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level.
Oncogene 27, 3576-3586 [PubMed:18212742]
[show Abstract]
Metformin is a widely used antidiabetic agent, which regulates glucose homeostasis through inhibition of liver glucose production and an increase in muscle glucose uptake. Recent studies suggest that metformin may reduce the risk of cancer, but its mode of action in cancer remains not elucidated. We investigated the effect of metformin on human prostate cancer cell proliferation in vitro and in vivo. Metformin inhibited the proliferation of DU145, PC-3 and LNCaP cancer cells with a 50% decrease of cell viability and had a modest effect on normal prostate epithelial cell line P69. Metformin did not induce apoptosis but blocked cell cycle in G(0)/G(1). This blockade was accompanied by a strong decrease of cyclin D1 protein level, pRb phosphorylation and an increase in p27(kip) protein expression. Metformin activated the AMP kinase pathway, a fuel sensor signaling pathway. However, inhibition of the AMPK pathway using siRNA against the two catalytic subunits of AMPK did not prevent the antiproliferative effect of metformin in prostate cancer cells. Importantly, oral and intraperitoneal treatment with metformin led to a 50 and 35% reduction of tumor growth, respectively, in mice bearing xenografts of LNCaP. Similar, to the in vitro study, metformin led to a strong reduction of cyclin D1 protein level in tumors providing evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent epidemiological studies. | Bridger T, MacDonald S, Baltzer F, Rodd C (2006)
Randomized placebo-controlled trial of metformin for adolescents with polycystic ovary syndrome.
Archives of pediatrics & adolescent medicine 160, 241-246 [PubMed:16520442]
[show Abstract]
ObjectiveTo determine whether metformin or placebo could, in conjunction with healthy lifestyle counseling, decrease serum testosterone levels and related aberrations in adolescents with hyperandrogenism, hyperinsulinemia, and polycystic ovarian syndrome.DesignRandomized, placebo-controlled, double-blind trial.SettingPediatric university teaching hospital.ParticipantsTwenty-two adolescents aged 13 to 18 years with hyperinsulinemia and polycystic ovarian syndrome.InterventionParticipants were randomly assigned to take a 12-week course of either metformin or placebo.Main outcome measuresPretreatment and posttreatment oral glucose tolerance tests, fasting lipid profiles, and clinical measurements.ResultsThere was a significant decline in mean serum testosterone concentration with metformin (-38.3 ng/dL) compared with placebo (-0.86 ng/dL) (95% confidence interval, -infinity to -0.29 for the mean difference between groups). At completion, the relative risk of menses was 2.50 times higher in the metformin group compared with the placebo (95% confidence interval, 1.12 to 5.58). Measures of insulin sensitivity, including insulin area under the curve and HOMA (homeostasis model assessment), demonstrated improvement only with metformin, but these did not reach statistical significance. High-density lipoprotein cholesterol levels increased by 6.98 mg/dL with metformin vs a decrease of -2.33 mg/dL with placebo (95% confidence interval, 0.78 to 18.23 for the mean difference between groups). There were no significant changes in body mass index, hirsutism, triglyceride levels, or total and low-density lipoprotein cholesterol levels.ConclusionMetformin significantly lowered total testosterone concentrations, increased the likelihood of menses, and improved high-density lipoprotein cholesterol levels without affecting measures of insulin sensitivity or body weight. | Zakikhani M, Dowling R, Fantus IG, Sonenberg N, Pollak M (2006)
Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells.
Cancer research 66, 10269-10273 [PubMed:17062558]
[show Abstract]
Recent population studies provide clues that the use of metformin may be associated with reduced incidence and improved prognosis of certain cancers. This drug is widely used in the treatment of type 2 diabetes, where it is often referred to as an "insulin sensitizer" because it not only lowers blood glucose but also reduces the hyperinsulinemia associated with insulin resistance. As insulin and insulin-like growth factors stimulate proliferation of many normal and transformed cell types, agents that facilitate signaling through these receptors would be expected to enhance proliferation. We show here that metformin acts as a growth inhibitor rather than an insulin sensitizer for epithelial cells. Breast cancer cells can be protected against metformin-induced growth inhibition by small interfering RNA against AMP kinase. This shows that AMP kinase pathway activation by metformin, recently shown to be necessary for metformin inhibition of gluconeogenesis in hepatocytes, is also involved in metformin-induced growth inhibition of epithelial cells. The growth inhibition was associated with decreased mammalian target of rapamycin and S6 kinase activation and a general decrease in mRNA translation. These results provide evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent population studies and justify further work to explore potential roles for activators of AMP kinase in cancer prevention and treatment. | Magalhães FO, Gouveia LM, Torquato MT, Paccola GM, Piccinato CE, Foss MC (2006)
Metformin increases blood flow and forearm glucose uptake in a group of non-obese type 2 diabetes patients.
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 38, 513-517 [PubMed:16941277]
[show Abstract]
The present study was designed to determine the effects of metformin on the forearm glucose uptake and blood flow after an oral glucose challenge. Eleven normal subjects, and ten non-obese type 2 diabetes patients without medication of anti-hyperglycemic drug and with medication of metformin for four weeks, were studied after an overnight fast (12-14 h) and 3 hours after ingestion of 75 g of glucose. Peripheral glucose metabolism was analyzed by the forearm technique combined with indirect calorimetry. The forearm glucose uptake increased in diabetes patients taking metformin (63.5+/-9.1 VS. 39.1+/-5.3 mg/100 ml FA. 3 h). The increase of forearm glucose uptake was due to increase of blood flow. The glucose oxidation was greater in the group treated with metformin, compared to the same group without anti-hyperglycemic drug (19.3+/-2.6 VS. 7.7+/-2.6 mg/100 ml FA. 3 hrs). The free fatty acids were higher in diabetes patients, which normalized after taking metformin. In conclusion, it was found that in these participants metformin acts in insulin resistance; it increases glucose muscle uptake and blood flow. The enhancement of blood flow and lower free fatty acids, not described yet, could be direct effects of the drug or due to reduced glucose toxicity. These positive effects must be responsible for the improvement in vascular function. | Gore DC, Wolf SE, Sanford A, Herndon DN, Wolfe RR (2005)
Influence of metformin on glucose intolerance and muscle catabolism following severe burn injury.
Annals of surgery 241, 334-342 [PubMed:15650645]
[show Abstract]
Summary background dataHyperglycemia and accelerated muscle catabolism have been shown to adversely affect immune response and survival. The purpose of this study was to determine the effect of metformin on glucose kinetics and muscle protein metabolism in severely burned patients and assess any potential benefit of metformin in this clinical setting.MethodsIn a double-blind, randomized manner, 8 adult burn patients received metformin (850 mg every 8 hours x 7 days), while 5 burn patients received placebo. Infusions of 6,6d2 glucose, d5 phenylalanine, sequential muscle biopsies, and femoral arterial, venous blood sampling allowed determination of glucose and muscle protein kinetics. Measurements were obtained immediately prior and at the conclusion of 7 days of treatment (metformin versus placebo). All patients received enteral feeds of comparable amounts during study.ResultsPatients receiving metformin had a significant decrease in their plasma glucose concentration, the rate of glucose production, and an increase in glucose clearance. Metformin administration was also associated with a significant increase in the fractional synthetic rate of muscle protein and improvement in net muscle protein balance. Glucose kinetics and muscle protein metabolism were not significantly altered in the patients receiving placebo.ConclusionsMetformin attenuates hyperglycemia and increases muscle protein synthesis in severely burned patients, thereby indicating a metabolic link between hyperglycemia and muscle loss following severe injury. Therefore, therapies that improve glucose tolerance such as metformin may be of clinical value in ameliorating muscle catabolism in critically injured patients. | Kouki T, Takasu N, Nakachi A, Tamanaha T, Komiya I, Tawata M (2005)
Low-dose metformin improves hyperglycaemia related to myotonic dystrophy.
Diabetic medicine : a journal of the British Diabetic Association 22, 346-347 [PubMed:15717887]
[show Abstract]
BackgroundOne of the clinical features of myotonic dystrophy is insulin resistance with non-obese diabetes mellitus (DM). Recently, the mechanism of insulin resistance in patients with myotonic dystrophy was revealed. The optimal treatment of DM with myotonic dystrophy has not been established. We report the effect of metformin in a patient with myotonic dystrophy without obesity.Case reportA 58-year-old woman (BMI = 22.1 kg/m2) with myotonic dystrophy and DM was followed at our clinic. She had been treated with glimepiride for DM for the last 6 months, without achieving good control (HbA(1c) 9.3%). She was admitted with congestive heart failure and cholecystitis. She was treated with diuretics, antibiotics and insulin. As her blood glucose fell, we discontinued insulin and started glimepiride, but her glycaemic control had worsened. We started metformin instead of glimepiride. After 4 weeks of metformin, HbA(1c) was decreased to 7.4%, while HOMA-IR during glimepiride treatment was 4.9, and 3.7 with metformin. Three months later, HbA(1c) was maintained (7.5%).ConclusionIt is important to choose the optimal treatment for DM in myotonic dystrophy, because the patients have hyperinsulinemia caused by specific mechanism and could not reduce the insulin resistance. Metformin improved hyperglycemia through increased insulin-independent glucose uptake in peripheral muscle. We believe metformin is the optimal agent for these patients. | De Jager J, Kooy A, Lehert P, Bets D, Wulffelé MG, Teerlink T, Scheffer PG, Schalkwijk CG, Donker AJ, Stehouwer CD (2005)
Effects of short-term treatment with metformin on markers of endothelial function and inflammatory activity in type 2 diabetes mellitus: a randomized, placebo-controlled trial.
Journal of internal medicine 257, 100-109 [PubMed:15606381]
[show Abstract]
ObjectivesThe UK Prospective Diabetes Study (UKPDS) showed that treatment with metformin decreases macrovascular morbidity and mortality independent of glycaemic control. We hypothesized that metformin may achieve this by improving endothelial function and chronic, low-grade inflammation. Data on this issue are scarce and we therefore tested, in the setting of a randomized, placebo-controlled trial, whether metformin can affect endothelial function and low-grade inflammation.DesignThe Hyperinsulinaemia the Outcome of its Metabolic Effects (HOME) trial is a double-blind trial, in which all patients were randomized to receive either metformin or placebo in addition to insulin therapy. At the beginning and the end of a 16-week treatment period fasting blood samples were drawn and a physical examination was carried out.SettingThe trial was conducted in the outpatient clinics of three nonacademic hospitals (Hoogeveen, Meppel and Coevorden; the Netherlands).SubjectsPatients were included if they were between 30 and 80 years of age; had received a diagnosis of diabetes after the age of 25; had never had an episode of ketoacidosis; and their blood glucose-lowering treatment previously consisted of oral agents but now only consisted of either insulin (n = 345) or insulin and metformin (n = 45). We excluded pregnant women and women trying to become pregnant, patients with a Cockroft-Gault-estimated creatinine clearance <50 mL min(-1), or low plasma cholinesterase (reference value <3.5 units L(-1)), patients with congestive heart failure (New York Heart Association class III/IV), or patients with other serious medical or psychiatric disease. A total of 745 eligible patients were approached; 390 gave informed consent and were randomized (196 metformin, 194 placebo). About 353 patients completed 16 weeks of treatment (171 metformin, 182 placebo).Main outcome measuresThe HOME trial was designed to study the metabolic and cardiovascular effects of metformin during a follow-up of 4 years. Presented here are the results of an interim analysis after 16 weeks of treatment.ResultsWhen compared with placebo, metformin treatment was associated with an increase in urinary albumin excretion of 21% (-1 to +48; P = 0.06); a decrease in plasma von Willebrand factor of 6% (-10 to -2; P = 0.0007); a decrease in soluble vascular cell adhesion molecule-1 of 4% (-7 to -2; P = 0.0002); a decrease in soluble E-selectin of 6% (-10 to -2; P = 0.008); a decrease in tissue-type plasminogen activator of 16% (-20 to -12; P < 0.0001); and a decrease in plasminogen activator inhibitor-1 of 20% (-27 to -10; P = 0.0001). These changes could not be explained by metformin-associated changes in glycaemic control, body weight or insulin dose. Markers of inflammation, i.e. C-reactive protein and soluble intercellular adhesion molecule-1, did not change with metformin treatment.ConclusionsIn patients with type 2 diabetes treated with insulin, metformin treatment was associated with improvement of endothelial function, which was largely unrelated to changes in glycaemic control, but not with improvement of chronic, low-grade inflammation. | Briggs GG, Ambrose PJ, Nageotte MP, Padilla G, Wan S (2005)
Excretion of metformin into breast milk and the effect on nursing infants.
Obstetrics and gynecology 105, 1437-1441 [PubMed:15932841]
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ObjectiveTo determine whether metformin is excreted into breast milk and whether this exposure adversely affects the blood glucose of nursing infants.MethodsSeven women were started on metformin 500 mg twice daily on the first day after cesarean delivery. Breastfeeding was started at the same time. Two women were excluded. Two other women stopped breastfeeding for personal reasons unrelated to the drug therapy, but did provide serum and milk samples, because they regularly pumped their breasts to maintain lactation. Peak and trough serum and milk samples were drawn between postoperative days 4 and 17. In 3 infants, blood was drawn for glucose determination at the same time as the maternal samples.ResultsThe trough milk concentration in 1 subject was below the assay detection limit. Excluding this subject, the mean peak and trough serum metformin concentrations were 1.06 mug/mL (range 0.68-1.90 mug/mL) and 0.42 mug/mL (range 0.26-0.51 mug/mL), respectively, whereas the mean peak and trough metformin concentrations in breast milk were 0.42 mug/mL (range 0.38-0.46 mug/mL) and 0.39 mug/mL (range 0.31-0.52 mug/mL), respectively. The mean milk:serum ratio was 0.63 (range 0.36-1.00) and the mean estimated infant dose as a percentage of the mother's weight-adjusted dose was 0.65% (range 0.43-1.08%). In 3 infants, the blood glucose concentrations 4 hours after a feeding were within the normal limit, ranging from 47-77 mg/dL.ConclusionMetformin is excreted into breast milk, but the amounts seem to be clinically insignificant. No adverse effects on the blood glucose of the 3 nursing infants were measured. | Gore DC, Herndon DN, Wolfe RR (2005)
Comparison of peripheral metabolic effects of insulin and metformin following severe burn injury.
The Journal of trauma 59, 316-22; discussion 322-3 [PubMed:16294070]
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ObjectiveBoth insulin and metformin have been shown to attenuate hyperglycemia and reduce net muscle protein catabolism following burn injury. The purpose of this study was to compare the peripheral metabolic effects of insulin and metformin in severe burn patients.MethodsSix adult patients with burns greater than 40% of their body surface underwent metabolic evaluation utilizing isotopic dilution of phenylalanine, femoral arterial and venous blood sampling, and sequential biopsies of leg muscle. Following baseline measurements, insulin was infused into the femoral artery at 0.45 mIU/min 100 mL leg volume. Patients were then given metformin (850 mg every 8 hours) for seven days with repeat metabolic evaluation before and during intra-arterial infusion of insulin.ResultsIntra-arterial administration of insulin significantly increased insulin concentrations within the femoral vein, creating hyperinsulinemia localized to the extremity. Metformin had no significant effect on either peripheral glucose clearance or the rate of glucose oxidation. Furthermore, the availability of ATP and energy charge within muscle was not overtly affected by either insulin or metformin. Metformin did significantly increase the fractional synthetic rate of muscle protein which increased even further with insulin administration. Both metformin and insulin separately increased the rate of muscle protein synthesis as calculated using three compartment modeling.ConclusionThis study demonstrates a significant anabolic effect on muscle protein with metformin and a modest response with insulin. Findings also suggest that metformin and insulin may work synergistically to further improve muscle protein kinetics. | Wang Y, Tang Y, Gu J, Fawcett JP, Bai X (2004)
Rapid and sensitive liquid chromatography-tandem mass spectrometric method for the quantitation of metformin in human plasma.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 808, 215-219 [PubMed:15261814]
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A rapid and sensitive liquid chromatography-tandem mass spectrometric (LC-MS-MS) method for the determination of metformin in human plasma using phenformin as internal standard has been developed and validated. Sample preparation of plasma involved acidification with acetic acid, deproteination with acetonitrile and washing with dichloromethane. Samples were then analyzed by HPLC on a short Nucleosil C18 column (5 microm, 50 mm x 4.6 mm i.d.) using a mobile phase consisting of acetonitrile:methanol:10mM ammonium acetate pH 7.0 (20:20:60, v/v/v) delivered at 0.65 ml/min. Detection was performed using an Applied Biosystems Sciex API 4000 mass spectrometer set at unit resolution in the multiple reaction monitoring (MRM) mode. Atmospheric pressure chemical ionization (APCI) was used for ion production. The assay was linear over the range 1-2000 ng/ml with intra- and inter-day precision of <8.6% and accuracy in the range 91-110%. The limit of detection was 250 pg/ml in plasma. The method was successfully applied to a clinical pharmacokinetic study of an extended-release tablet of metformin hydrochloride (500 mg) administered as a single oral dose. | Robert F, Fendri S, Hary L, Lacroix C, Andréjak M, Lalau JD (2003)
Kinetics of plasma and erythrocyte metformin after acute administration in healthy subjects.
Diabetes & metabolism 29, 279-283 [PubMed:12909816]
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ObjectivesAlthough the existence of a deep compartment for metformin has long been hypothesized, there is still little direct information concerning metformin distribution in individual tissues in man. The only available study involves chronic metformin therapy. In that study, the measurement of metformin in erythrocytes provided a reliable indicator of metformin distribution and of potential accumulation. To determine the kinetics of metformin in plasma and in erythrocytes after acute oral administration, we performed the present study in healthy subjects after a single oral dose of metformin and compared the pharmacokinetics parameters in erythrocytes to those in plasma.MethodsSix nondiabetic participants took the study dose of 850 mg metformin at 8: 00 AM after a non-standardized breakfast (i.e., as recommended in clinical practice). Blood samples were collected for metformin measurement in plasma and in erythrocytes at 0, 1, 2, 3, 4, 6, 9, 24, 33, 48, 57, and 72 h.ResultsMaximum metformin concentration was attained at 3.0 +/- 0.3 h in plasma and 4.7 +/- 0.5 h in erythrocytes. This difference was not significant. Metformin concentrations peaked at a maximum almost 6 times higher in plasma than in erythrocytes (1.7 +/- 0.1 and 0.3 +/- 0.0 mg/l, respectively). However, because the elimination half-life of metformin was much longer in erythrocytes (23.4 +/- 1.9 h vs. 2.7 +/- 1.2 h), there was no difference in area under the curve between plasma and erythrocytes. The distribution volume (plasma) was calculated to be 146 +/- 11 l. Plasma and erythrocytes concentration-time curves showed that metformin was not detectable in plasma 24 hours after the oral administration, while it remained detectable in erythrocytes up to 48 hours. Metformin concentrations crossed approximately 13 hours after having reached their maximum values in plasma, approximately 16 h after metformin intake.ConclusionHaving demonstrated the rapid elimination of metformin from plasma and its slow disappearance from erythrocytes, the presents results should contribute to adjustment of metformin dosage to renal function, assessment of drug compliance, and retrospective analysis (when blood samples are drawn with delay) of the link between metformin and development of lactic acidosis. Most importantly, the present findings should help to ascertain the optimal dosage of metformin, particularly in elderly patients. | Lalau JD, Lacroix C (2003)
Measurement of metformin concentration in erythrocytes: clinical implications.
Diabetes, obesity & metabolism 5, 93-98 [PubMed:12630933]
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AimsAlthough pharmacokinetics studies have long suggested a deep compartment for the antidiabetic drug metformin, there is still little information concerning metformin accumulation by individual tissues in man. In the present study, the erythrocyte was chosen to represent this putative deep compartment and metformin concentration in erythrocytes (EM) was compared with that in plasma (PM) to delineate clinical implications.MethodsA reference group of 58 patients with well-tolerated metformin treatment was studied to provide standard mean metformin concentrations in the fasting state. Secondly, to provide transverse data reflecting clinical practice, the authors reviewed an investigation group of 93 metformin-treated patients with available PM and EM, which had been requested either to adjust metformin dosage to renal function, or to screen for potential metformin accumulation following renal failure, metformin overdose or lactic acidosis. Thirdly, the case of an individual with major metformin accumulation was studied to provide information about metformin elimination.ResultsFrom the bulk of data, we performed three types of analyses: (1) PM and EM were compared. In the investigation group, this comparison was extended to subgroups separated according to low-to-normal, moderately increased or highly increased metformin concentration. (2) Correlative analyses of PM, EM and serum creatinine were performed. (3) A kinetic study of the spontaneous decline of PM and EM was conducted. PM and EM were, respectively, 0.5 +/- 0.4 mg/l and 0.8 +/- 0.4 mg/l in the reference group, and 11.7 +/- 17.8 mg/l (mean +/- SD, range 0.0-71.9 mg/l) and 7.5 +/- 9.4 mg/l (0.0-34 mg/l) in the investigation group, mean serum creatinine of which was 290 +/- 258 micro mol/l. In the low-to-normal PM subgroup (n = 28), PM and EM were, respectively, 0.39 +/- 0.38 mg/l and 0.84 +/- 0.68 mg/l (p < 0.001). In the moderately increased PM subgroup (from therapeutic concentrations +2 SD to 5 mg/l, n = 24), PM and EM were 2.82 +/- 1.13 mg/l and 2.72 +/- 2.03 mg/l (NS). In the sharply increased PM subgroup (> 5 mg/l, n = 41), PM and EM were 27.6 +/- 23.2 mg/l and 17.0 +/- 11.4 mg/l (p = < 0.001). PM and EM were tightly correlated (r = 0.72 in the reference group and r = 0.90 in the investigation group, p < 0.001 for both). Metformin concentrations were also correlated with those of serum creatinine, but more so in the investigation group; in subgroups, a positive correlation was found only at high metformin concentrations and in erythrocytes. The kinetic study performed in the patient with major metformin accumulation showed that PM and EM dropped within less than 3 days from a maximum concentration of 80.0 mg/l and 20.4 mg/l, respectively, to 0.67 mg/l and 6.52 mg/l.ConclusionsIn conclusion, metformin appears to accumulate in erythrocytes and, consequently, may be part of a deep compartment for the drug. This evidence of slow decline in erythrocyte metformin concentration may contribute to retrospective diagnosis of metformin accumulation and to refinements in adjusting metformin dosage to renal function. | Musi N, Hirshman MF, Nygren J, Svanfeldt M, Bavenholm P, Rooyackers O, Zhou G, Williamson JM, Ljunqvist O, Efendic S, Moller DE, Thorell A, Goodyear LJ (2002)
Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes.
Diabetes 51, 2074-2081 [PubMed:12086935]
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Metformin is an effective hypoglycemic drug that lowers blood glucose concentrations by decreasing hepatic glucose production and increasing glucose disposal in skeletal muscle; however, the molecular site of metformin action is not well understood. AMP-activated protein kinase (AMPK) activity increases in response to depletion of cellular energy stores, and this enzyme has been implicated in the stimulation of glucose uptake into skeletal muscle and the inhibition of liver gluconeogenesis. We recently reported that AMPK is activated by metformin in cultured rat hepatocytes, mediating the inhibitory effects of the drug on hepatic glucose production. In the present study, we evaluated whether therapeutic doses of metformin increase AMPK activity in vivo in subjects with type 2 diabetes. Metformin treatment for 10 weeks significantly increased AMPK alpha2 activity in the skeletal muscle, and this was associated with increased phosphorylation of AMPK on Thr172 and decreased acetyl-CoA carboxylase-2 activity. The increase in AMPK alpha2 activity was likely due to a change in muscle energy status because ATP and phosphocreatine concentrations were lower after metformin treatment. Metformin-induced increases in AMPK activity were associated with higher rates of glucose disposal and muscle glycogen concentrations. These findings suggest that the metabolic effects of metformin in subjects with type 2 diabetes may be mediated by the activation of AMPK alpha2. | Jones KL, Arslanian S, Peterokova VA, Park JS, Tomlinson MJ (2002)
Effect of metformin in pediatric patients with type 2 diabetes: a randomized controlled trial.
Diabetes care 25, 89-94 [PubMed:11772907]
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ObjectiveMetformin is the most commonly prescribed oral antidiabetic agent in the U.S. for adults with type 2 diabetes. The incidence of type 2 diabetes in children has increased dramatically over the past 10 years, and yet, metformin has never been formally studied in children with type 2 diabetes.Research design and methodsThis study evaluated the safety and efficacy of metformin at doses up to 1,000 mg twice daily in 82 subjects aged 10-16 years for up to 16 weeks in a randomized double-blind placebo-controlled trial from September 1998 to November 1999. Subjects with type 2 diabetes were enrolled if they had a fasting plasma glucose (FPG) levels > or =7.0 and < or =13.3 mmol/l (> or =126 and < or =240 mg/dl), HbA(1c) > or =7.0%, stimulated C-peptide > or =0.5 nmol/l (> or =1.5 ng/ml), and a BMI > 50th percentile for age.ResultsMetformin significantly improved glycemic control. At the last double-blind visit, the adjusted mean change from baseline in FPG was -2.4 mmol/l (-42.9 mg/dl) for metformin compared with +1.2 mmol/l (+21.4 mg/dl) for placebo (P < 0.001). Mean HbA(1c) values, adjusted for baseline levels, were also significantly lower for metformin compared with placebo (7.5 vs. 8.6%, respectively; P < 0.001). Improvement in FPG was seen in both sexes and in all race subgroups. Metformin did not have a negative impact on body weight or lipid profile. Adverse events were similar to those reported in adults treated with metformin.ConclusionMetformin was shown to be safe and effective for treatment of type 2 diabetes in pediatric patients. | Carter D, Howlett HC, Wiernsperger NF, Bailey C (2002)
Effects of metformin on bile salt transport by monolayers of human intestinal Caco-2 cells.
Diabetes, obesity & metabolism 4, 424-427 [PubMed:12406042]
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The antidiabetic biguanide metformin has been shown to increase faecal excretion of bile salts in type 2 diabetes. Cultured human intestinal Caco-2 cell monolayers provide a model of human enterocytes. These monolayers are used here to determine the effect of metformin on the secondary-active, sodium-linked transfer of 14C-glycocholate from the apical (brush border) to the basolateral (serosal) surface. During 24-h incubations, 10-2 mol/l metformin significantly reduced 14C-glycocholate transfer. This could not be attributed to alterations of monolayer integrity or Na+-K+ ATPase pump activity. For example, the secondary-active transport of glucose and proline was not interrupted, and the inhibitory effect of metformin on bile salt transport was additive to the inhibitory effect of ouabain. The results suggest that metformin can act directly on intestinal enterocytes to reduce the active transfer of bile salts by a mechanism that is independent of Na+-K+ ATPase activity. | Hale TW, Kristensen JH, Hackett LP, Kohan R, Ilett KF (2002)
Transfer of metformin into human milk.
Diabetologia 45, 1509-1514 [PubMed:12436333]
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Aims/hypothesisThe aim of this study was to characterize the milk-to-plasma ratio and infant dose for metformin in breastfeeding women, and to measure plasma concentrations and assess any effects in their infants. We hypothesized that metformin used by mothers is safe for their breastfed infants.MethodsSeven women taking metformin (median dose 1500 mg orally daily) and their infants were studied. Metformin concentrations in plasma and milk were measured by high performance liquid chromatography. Infant exposure was estimated as the product of estimated milk production rate and the average concentration of the drug in milk and also expressed as a percentage of the weight-normalized maternal dose.ResultsThe mean milk-to-plasma ratio for metformin was 0.35 (95%CI 0.2-0.5). The mean of its average concentrations in milk over the dose interval was 0.27 mg/l (0.15-0.39 mg/l). The absolute infant dose averaged 0.04 mg x kg(-1) x day(-1) (0.02-0.06 mg x kg(-1) x day(-1)) and the mean relative infant dose was 0.28% (0.16-0.4%). Metformin was present in very low or undetectable concentrations in the plasma of four of the infants who were studied. No health problems were found in the six infants who were evaluated.Conclusions/interpretationThe concentrations of metformin in breast milk were generally low and the mean infant exposure to the drug was only 0.28% of the weight-normalized maternal dose. As this is well below the 10% level of concern for breastfeeding, and because the infants were healthy, we conclude that metformin use by breastfeeding mothers is safe. Nevertheless, each decision to breastfeed should be made after conducting a risk:benefit analysis for each mother and her infant. | Radziuk J, Pye S (2001)
Hepatic glucose uptake, gluconeogenesis and the regulation of glycogen synthesis.
Diabetes/metabolism research and reviews 17, 250-272 [PubMed:11544610]
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Hepatic glycogen is replenished during the absorptive period postprandially. This repletion is prompted partly by an increased hepatic uptake of glucose by the liver, partly by metabolite and hormonal signals in the portal vein, and partly by an increased gluconeogenic flux to glycogen (glyconeogenesis). There is some evidence that the direct formation of glycogen from glucose and that formed by gluconeogenic pathways is linked. This includes: (i) the inhibition of all glycogen synthesis, in vivo, when gluconeogenic flux is blocked by inhibitors; (ii) a dual relationship between glucose concentrations, lactate uptake by the liver and glycogen synthesis (by both pathways) which indicates that glucose sets the maximal rates of glycogen synthesis while lactate uptake determines the actual flux rate to glycogen; (iii) the decrease of both gluconeogenesis and glycogen synthesis by the biguanide, metformin; and (iv) correlations between increased gluconeogenesis and liver glycogen in obese patients and animal models. The degree to which the liver extracts portal glucose is not entirely agreed upon although a preponderance of evidence points to about a 5% extraction rate, following meals, which is dependent on a stimulation of glucokinase. This enzyme may be linked to the expression of other enzymes in the gluconeogenic pathway. Perivenous cells in the liver may induce additional gluconeogenesis in the periportal cells by increasing glycolytically produced lactate. A number of potential mechanisms therefore exist which could link glycogen synthesis from glucose and gluconeogenic substrate. | Amador-Licona N, Guízar-Mendoza J, Vargas E, Sánchez-Camargo G, Zamora-Mata L (2000)
The short-term effect of a switch from glibenclamide to metformin on blood pressure and microalbuminuria in patients with type 2 diabetes mellitus.
Archives of medical research 31, 571-575 [PubMed:11257323]
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BackgroundRenal hyperfiltration and albuminuria have a deleterious effect on kidney function. Therefore, we studied the effect of metformin on blood pressure, renal hemodynamics, and microalbuminuria in type 2 diabetic patients.MethodsA clinical trial was designed in type 2 diabetic patients with incipient nephropathy. All patients were below the age of 65, normotensive, and without evidence of malignant, hepatic, or cardiovascular disorders. They were randomly allocated to receive glibenclamide or metformin. At baseline and 12 weeks thereafter we measured body mass index (BMI), serum insulin, blood glucose, lipid profile, glycosylated hemoglobin, blood pressure, glomerular filtration rate, renal plasma flow, and urine albumin.ResultsWe studied 23 patients in the glibenclamide group and 28 in the metformin group. There was no difference in baseline variables between the groups. Metabolic control was obtained in both groups. In the metformin group, all the following variables decreased: microalbuminuria was reduced by a mean of 24.2 mg/day (p = 0.008); systolic and diastolic blood pressure by a mean of 5.3 mmHg (p = 0.002) and 3.93 mmHg (p = 0.009), respectively; insulin levels by an average of 11.8 microIU/mL (p = 0.001), and total cholesterol levels and triglycerides by an average of 0.45 and 0.18 mmol/L, respectively. Insulin resistance measured by the homeostasis model decreased more in the metformin group than in the glibenclamide group. Patients treated with glibenclamide had an increase in HDL cholesterol of 0.082 mmol/L (p = 0.01).ConclusionsMetformin significantly decreased the urine albumin excretion rate with none of the expected changes in renal hemodynamics, probably due to its favorable effects on blood pressure, lipid profile, metabolic control, and insulin resistance. | Marathe PH, Wen Y, Norton J, Greene DS, Barbhaiya RH, Wilding IR (2000)
Effect of altered gastric emptying and gastrointestinal motility on metformin absorption.
British journal of clinical pharmacology 50, 325-332 [PubMed:11012555]
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AimsThe purpose of this in vivo human study was to assess the effect of altered gastric emptying and gastrointestinal motility on the absorption of metformin in healthy subjects.MethodsAn open-label, three treatment, three period crossover study was conducted in 11 healthy volunteers. Each subject received 550 mg metformin hydrochloride in solution alone; 5 min after a 10 mg i.v. dose of metoclopramide; and 30 min after a 30 mg oral dose of propantheline. Metformin solution was radiolabeled by the addition of 99mTc-DTPA. The gastrointestinal transit of the solution was monitored by gamma scintigraphy and the pharmacokinetic data were correlated with the scintigraphic findings.ResultsScintigraphic data indicated that pretreatment with metoclopramide decreased gastric emptying time and increased gastrointestinal motility while pretreatment with propantheline had the opposite effect. The systemic disposition of metformin was not altered by pretreatment with metoclopramide and propantheline, as judged by unchanged renal clearance and elimination half-life of metformin. Extent of metformin absorption was essentially unchanged after pretreatment with metoclopramide. However, AUC(0,infinity) and % UR (percent dose excreted unchanged in urine) generally increased with increase in gastric emptying time and small intestinal transit times. GI overlay plots showed that the absorption phase of metformin plasma profile always coincided with gastric emptying and the beginning of decline of metformin plasma concentrations was usually associated with the colon arrival. Only in cases where the intestinal transit was drastically prolonged by propantheline pretreatment, was a decline in plasma levels observed prior to colon arrival.ConclusionsMetformin is primarily absorbed from the small intestine. The extent of metformin absorption is improved when the gastrointestinal motility is slowed. These findings have significant implications in the design of a metformin modified release dosage form. | Einhorn D, Rendell M, Rosenzweig J, Egan JW, Mathisen AL, Schneider RL (2000)
Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus: a randomized, placebo-controlled study. The Pioglitazone 027 Study Group.
Clinical therapeutics 22, 1395-1409 [PubMed:11192132]
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BackgroundTheir complimentary mechanisms of action suggest that a combination of pioglitazone hydrochloride and metformin may have clinically beneficial effects in the treatment of patients with type 2 diabetes.ObjectiveThis study was undertaken to assess the efficacy and tolerability of pioglitazone in combination with metformin in patients with type 2 diabetes mellitus.MethodsThis was a 16-week, double-blind study with the option of enrollment in a separate open-ended, open-label study. It included patients with poorly controlled diabetes mellitus (glycated hemoglobin [HbA1c] > or =8.0%, fasting C-peptide >1.0 ng/mL) who had been receiving a stable regimen of metformin for > or =30 days. Patients with diabetic retinopathy, nephropathy, or neuropathy; impaired liver or kidney function; or unstable cardiovascular or cerebrovascular conditions were excluded. Patients were randomized to receive once-daily pioglitazone 30 mg + metformin or placebo + metformin. Patients in the open-label extension received pioglitazone 30 mg (with optional titration to 45 mg) + metformin.ResultsThree hundred twenty-eight patients were randomized to treatment (168 pioglitazone + metformin, 160 placebo + metformin), and 249 completed the study. Of these, 154 elected to enter the open-label extension study. Patients' mean age was 56 years; most (84%) were white and slightly more than half (57%) were male. Patients receiving piogli- tazone 30 mg + metformin had statistically significant mean decreases in HbA1c (-0.83%) and fasting plasma glucose (FPG) levels (-37.7 mg/dL) compared with placebo + metformin (P < or = 0.05). Decreases in FPG levels occurred as early as the fourth week of therapy, the first time point at which FPG was measured. The pioglitazone + metformin group had significant mean percentage changes in levels of triglycerides (-18.2%) and high-density lipoprotein cholesterol (+8.7%) compared with placebo + metformin (P < or = 0.05). Mean percentage increases were noted in low-density lipoprotein cholesterol levels (7.7%, pioglitazone + metformin; 11.9%, placebo + metformin) and total cholesterol (4.1%, pioglitazone + metformin; 1.1%, placebo + metformin), with no significant differences between groups. In the extension study, patients treated with open-label pioglitazone + metformin for 72 weeks had mean changes from baseline of -1.36% in HbA1c and -63.0 mg/dL in FPG. The incidence of adverse events was similar in both groups. Throughout the study, no patient in either treatment group had an alanine aminotransferase (ALT) value > or =3 times the upper limit of normal, a commonly used marker of potential liver damage. Thus, no evidence of drug-induced hepatotoxicity or drug-induced elevations in serum ALT was observed.ConclusionsIn this study in patients with type 2 diabetes mellitus, pioglitazone + metformin significantly improved HbA1c and FPG levels, with positive effects on serum lipid levels and no evidence of drug-induced hepatotoxicity. These effects were maintained for >1.5 years, including the open-label extension. | Gillies PS, Dunn CJ (2000)
Pioglitazone.
Drugs 60, 333-43; discussion 344-5 [PubMed:10983737]
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Pioglitazone is an orally administered insulin sensitising thiazolidinedione agent that has been developed for the treatment of type 2 diabetes mellitus. Pioglitazone activates the nuclear peroxisome proliferator activated receptor-gamma (PPAR-gamma), which leads to the increased transcription of various proteins regulating glucose and lipid metabolism. These proteins amplify the post-receptor actions of insulin in the liver and peripheral tissues, which leads to improved glycaemic control with no increase in the endogenous secretion of insulin. In placebo-controlled clinical trials, monotherapy with pioglitazone 15 to 45 mg/day has been shown to decrease blood glycosylated haemoglobin (HbA1c) levels in patients with type 2 diabetes mellitus. The addition of pioglitazone 30 mg/day to preexisting therapy with metformin, or of pioglitazone 15 or 30 mg/day to sulphonylurea, insulin or voglibose therapy, has been shown to decrease HbA1c and fasting blood glucose levels significantly in patients with poorly controlled type 2 diabetes mellitus. Pioglitazone has also been associated with improvements in serum lipid profiles in randomised placebo-controlled clinical studies. The drug has been well tolerated by adult patients of all ages in clinical studies. Oedema has been reported with monotherapy, and pooled data have shown hypoglycaemia in 2 to 15% of patients after the addition of pioglitazone to sulphonylurea or insulin treatment. There have been no reports of hepatotoxicity. | Mughal MA, Jan M, Maheri WM, Memon MY, Ali M (2000)
The effect of metformin on glycemic control, serum lipids and lipoproteins in diet alone and sulfonylurea-treated type 2 diabetic patients with sub-optimal metabolic control.
JPMA. The Journal of the Pakistan Medical Association 50, 381-386 [PubMed:11126815]
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ObjectiveTo see if Metformin Monotherapy affects glycemic control, serum lipid or lipoprotein levels in the treatment of type 2 diabetes who were poorly controlled with diet alone or despite maximal doses of (sulfonylurea) oral glucose lowering agents.DesignA prospective, clinical intervention trial conducted between 1996-1997.SettingTwo out patient diabetic clinics of Karachi.Patients and methodsA 12-week prospective clinical intervention trial. A total of 30 type 2 diabetic subjects were enrolled, of Whom 21 (12 men and 9 women) completed the study period. Their ages ranged between 35 and 70 years, (mean +/- SD 53.3 +/- 9.31) years, with a mean duration since diagnosis of diabetes was 4.5 +/- 2.3 years, body mass index (mean +/- SD) 26.8 +/- 3.53 kg/m2. They were previously treated with diet alone or had already been taking maximum doses of sulfonylurea monotherapy with suboptimal glycemic control, i.e., raised fasting blood glucose concentrations of 6-15 mmol/L or (108-270 mg/dL) on two occasions, with significant hyperglycemic symptoms. The patients were treated with metformin monotherapy with a follow up of 12 weeks. The initial dosage was 500 mg twice daily, and the dosage was increased to two or three tablets depending on the patient's metabolic changes. By comparing before and after 12 weeks therapy with metformin we assessed the importance of baseline parameters (glycemic control, serum lipid and lipoprotein concentrations, and measures of change in body weight and body mass index).ResultsMetformin therapy significantly decreased fasting blood glucose levels in all patients [(mean +/- SD) 227.2 +/- 37.5 to 168.6 +/- 20.5 mg/dl, p < 0.001)]. Serum total cholesterol decreased marginally [(mean +/- SD) 200.3 +/- 18.7 to 181.4 +/- 19.4 mg/dl, p < 0.01)]. Serum total triglycerides concentration also decreased [(mean +/- SD) 195.9 +/- 31.9 to 174.2 +/- 26.6 mg/dl, P < 0.01)]. Low-density lipoproteins declined [(mean +/- SD) 123.5 +/- 16.9 to 105.5 +/- 19.1 mg/dl, P < 0.01)], and very-low density lipoprotein cholesterol also decreased [(mean +/- SD) 39.2 +/- 6.4 to 34.8 +/- to 5.3 mg/dl, P < 0.01)]. Whereas, high-density lipoprotein cholesterol tended to increase [(mean +/- SD) 37.7 +/- 5.1 to 39.5 +/- 4.9 mg/dl, P < 0.01)], while no significant changes occurred in body weight and body mass index.ConclusionMetformin treatment was effective, safe, and generally well tolerated. | Morin-Papunen LC, Vauhkonen I, Koivunen RM, Ruokonen A, Martikainen HK, Tapanainen JS (2000)
Endocrine and metabolic effects of metformin versus ethinyl estradiol-cyproterone acetate in obese women with polycystic ovary syndrome: a randomized study.
The Journal of clinical endocrinology and metabolism 85, 3161-3168 [PubMed:10999803]
[show Abstract]
Metformin, a biguanide antihyperglycemic drug, has been shown to improve ovarian function and glucose metabolism in women with polycystic ovary syndrome (PCOS), but results concerning its effects on insulin sensitivity are controversial. Oral contraceptive pills are commonly used in the treatment of PCOS; but, like metformin, their influence on insulin sensitivity is not well known. We randomized 32 obese (body mass index > 27 kg/m2) women with PCOS, either to metformin (500 mg x 2 daily for 3 months, then 1,000 mg x 2 daily for 3 months) or to ethinyl estradiol (35 microg)-cyproterone acetate (2 mg) oral contraceptive pills (Diane Nova) for 6 months. Metformin significantly decreased the waist-to-hip ratio, serum testosterone, fasting free fatty acid, and insulin concentrations and improved oxidative glucose utilization and menstrual cyclicity, with slight (but nonsignificant) improvements in insulin hepatic extraction and insulin sensitivity. Diane Nova significantly decreased serum testosterone and increased serum sex hormone-binding globulin concentrations and glucose area under the curve during oral glucose tolerance test. It is concluded that metformin, probably by way of its effect on adipose tissue, leads to reduction of hyperinsulinemia and concomitant improvement in the menstrual pattern; and therefore, it offers a useful alternative treatment for obese, anovulatory women with PCOS. Despite slight worsening of glucose tolerance, Diane Nova is an efficient treatment for women with hyperandrogenism and hirsutism. | Seale FG, Robinson RD, Neal GS (2000)
Association of metformin and pregnancy in the polycystic ovary syndrome. A report of three cases.
The Journal of reproductive medicine 45, 507-510 [PubMed:10900588]
[show Abstract]
BackgroundInfertility is a common manifestation of the polycystic ovary syndrome (PCOS), a condition characterized by chronic anovulation, hyperinsulinemia and hyperandrogenism. Hyperinsulinemia leads to increased ovarian androgen production, resulting in follicular atresia and anovulation. Metformin, a medication that improves insulin sensitivity and decreases serum insulin levels, restores menstrual cyclicity and ovulatory function and may improve fertility rates in women with PCOS. We present three consecutive cases from our clinic that support this premise.CasesThree patients were seen in the reproductive endocrinology clinic with documented PCOS, long-standing infertility and clinically diagnosed insulin resistance. The first patient had hyperandrogenic, insulin-resistant acanthosis nigricans syndrome and had been resistant to multiple courses of clomiphene citrate; the second exhibited hypertension, hyperlipidemia and glucose intolerance along with anovulation; and the third presented with poorly controlled type 2 diabetes and a desire to conceive. Each patient received metformin, which led to restoration of menstrual cyclicity and conception in all three cases.ConclusionThese three patients reflect the heterogeneous nature of PCOS, and treating their underlying insulin resistance with metformin resulted in pregnancy. These findings suggest that metformin may be a useful adjunct for treatment of infertility in patients with PCOS. |
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2014-10-29
