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Metformin AND Lactate

S Gibiino, A Trappoli, B Balzarro, A R Atti, D De Ronchi
A 71-year-old man developed coma with severe respiratory failure, hypotension, and tachycardia induced by the intentional ingestion of quetiapine fumarate extended release (XR) 20 g. At the time, he had been treated for bipolar depression with venlafaxine 75 mg/day, lamotrigine 100 mg/day, pregabalin 75 mg/day, and quetiapine XR 400 mg/day for approximately 1 year. Comorbidities were hypertension treated with metoprolol, diabetes mellitus type 2 treated with metformin, and benign prostatic hyperplasia treated with silodosin...
December 2015: Drug Saf Case Rep
Yu-Shen Huang, Yi-Chieh Li, Pei-Yun Tsai, Chia-En Lin, Chien-Ming Chen, Shih-Ming Chen, Jen-Ai Lee
Lead (Pb) is an environmental pollutant associated with several diseases, such as nephrotoxicity. Methylglyoxal (MG) is a reactive dicarbonyl compound formed during glycolysis and reported to increase in kidney damage. Metformin is used as a MG scavenger in the clinic. In this study, we investigated the mechanism of Pb-induced renal injury and the effect of metformin on Pb-induced nephrotoxicity. Eighteen Wistar rats were randomly divided into three groups: control, Pb, and Pb + metformin groups. Pb (250 ppm) was administered in drinking water, and 50 mg/Kg of metformin was co-administered orally...
October 14, 2016: Biomedical Chromatography: BMC
Gabriela Figueroa-González, Verónica García-Castillo, Jossimar Coronel-Hernández, Eduardo López-Urrutia, Sonia León-Cabrera, Luis E Arias-Romero, L I Terrazas, Miriam Rodríguez-Sosa, Alma Delia Campos-Parra, Eduardo Zúñiga-Calzada, Cesar Lopez-Camarillo, Fermín Morales-González, Nadia J Jacobo-Herrera, Carlos Pérez-Plasencia
Colorectal cancer (CRC) is an important health issue worldwide, accounting for the third place of cancer incidence. Chronic inflammation, as seen in Crohn's disease and ulcerative colitis, is the most important risk factor for developing CRC, as it favours neoplastic transformation by enhancing epithelial cell turnover in the colonic mucosa. Treatments for CRC need to be improved; currently they are not specific and have several secondary effects in patients. The main objective of this work was to evaluate a new therapeutic strategy against a colitis-related colorectal cancer in vivo and in vitro by targeting mTOR-signaling and lactate dehydrogenase A...
2016: Journal of Cancer
Xingwei Liang, Qiyuan Yang, Lupei Zhang, Joseph W Maricelli, Buel D Rodgers, Mei-Jun Zhu, Min Du
Maternal obesity and high-fat diet (HFD) predisposes offspring to obesity and metabolic diseases. Due to uncoupling, brown adipose tissue (BAT) dissipates energy via heat generation, mitigating obesity and diabetes. The lactation stage is a manageable period for improving the health of offspring of obese mothers, but the impact of maternal HFD during lactation on offspring BAT function is unknown. To determine, female mice were fed either a control or HFD during lactation. At weaning, HFD offspring gained more body weight and had greater body fat mass compared to the control, and these differences maintained into adulthood, which correlated with glucose intolerance and insulin resistance in HFD offspring...
September 30, 2016: Scientific Reports
Luca Visconti, Valeria Cernaro, Domenico Ferrara, Giuseppe Costantino, Carmela Aloisi, Luisa Amico, Valeria Chirico, Domenico Santoro, Alberto Noto, Antonio David, Michele Buemi, Antonio Lacquaniti
Metformin, belonging to a class of drugs called biguanides, is the recommended first-line treatment for overweight patients with type 2 diabetes mellitus. It has multiple mechanisms of action, such as reduction of gluconeogenesis, increases peripheral uptake of glucose, and decreases fatty acid oxidation. However, a potential serious complication, defined metformin-associated lactic acidosis (MALA), is related to increased plasma lactate levels, linked to an elevated plasma metformin concentrations and/or a coexistent condition altering lactate production or clearance...
August 10, 2016: Renal Failure
Abdullah K Al-Hwiesh, Ibrahiem S Abdul-Rahman, Abdul-Salam Noor, Mohammed A Nasr-El-Deen, Abdalla Abdelrahman, Tamer S El-Salamony, Fahd A Al-Muhanna, Khalid M Al-Otaibi, Nehad Al-Audah
♦ Objective: Metformin continues to be the safest and most widely used antidiabetic drug. In spite of its well-known benefits; metformin use in end-stage renal disease (ESRD) patients is still restricted. Little has been reported about the effect of peritoneal dialysis (PD) on metformin clearance and the phantom of lactic acidosis deprives ESRD patients from metformin therapeutic advantages. Peritoneal dialysis is probably a safeguard against lactic acidosis, and it is likely that using this drug would be feasible in this group of patients...
September 28, 2016: Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis
Andrew Jm Lewis, Jack Jj Miller, Chloe McCallum, Oliver J Rider, Stefan Neubauer, Lisa C Heather, Damian J Tyler
Metformin improves cardiovascular outcomes in type 2 diabetes, but its exact mechanisms of action remain controversial. We used hyperpolarized [1-(13)C]pyruvate magnetic resonance spectroscopy to determine the effects of metformin treatment upon heart and liver pyruvate metabolism in rats in vivo Both oral treatment for four weeks and a single intravenous metformin infusion significantly increased the cardiac [1-(13)C]lactate:[1-(13)C]pyruvate ratio, but had no effect on the [1-(13)C]bicarbonate + (13)CO2:[1-(13)C]pyruvate ratio, an index of pyruvate dehydrogenase flux...
August 25, 2016: Diabetes
Luigi Ippolito, Alberto Marini, Lorenzo Cavallini, Andrea Morandi, Laura Pietrovito, Gianfranco Pintus, Elisa Giannoni, Thomas Schrader, Martin Puhr, Paola Chiarugi, Maria Letizia Taddei
Drug resistance of cancer cells is recognized as the primary cause of failure of chemotherapeutic treatment in most human cancers. Growing evidences support the idea that deregulated cellular metabolism is linked to such resistance. Indeed, both components of the glycolytic and mitochondrial pathways are involved in altered metabolism linked to chemoresistance of several cancers. Here we investigated the drug-induced metabolic adaptations able to confer advantages to docetaxel resistant prostate cancer (PCa) cells...
August 16, 2016: Oncotarget
Nicholas Carlson, Kristine Hommel, Jonas B Olesen, Thomas A Gerds, Anne-Merete Soja, Tina Vilsbøll, Anne-Lise Kamper, Christian Torp-Pedersen, Gunnar Gislason
Recent guidelines governing anti-diabetic medications increasingly advocate metformin as first-line therapy in all patients with type 2 diabetes. However, metformin could be associated with increased risk of acute kidney injury (AKI), acute dialysis and lactate acidosis in marginal patients. In a retrospective nationwide cohort study, a total of 168 443 drug-naïve patients with type 2 diabetes ≥50 years, initiating treatment with either metformin or sulphonyl in Denmark between 2000 and 2012 were included in this study (70...
August 18, 2016: Diabetes, Obesity & Metabolism
Muhammad Tayyab Akhtar, Mohamad Syakir Bin Mohd Sarib, Intan Safinar Ismail, Faridah Abas, Amin Ismail, Nordin Hj Lajis, Khozirah Shaari
Andrographis paniculata is an annual herb and widely cultivated in Southeast Asian countries for its medicinal use. In recent investigations, A. paniculata was found to be effective against Type 1 diabetes mellitus (Type 1 DM). Here, we used a non-genetic out-bred Sprague-Dawley rat model to test the antidiabetic activity of A. paniculata against Type 2 diabetes mellitus (Type 2 DM). Proton Nuclear Magnetic Resonance (¹H-NMR) spectroscopy in combination with multivariate data analyses was used to evaluate the A...
2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Bo Li, Xinzhe Li, Zhenhong Ni, Yan Zhang, Yijun Zeng, Xiaohuan Yan, Yan Huang, Jintao He, Xilin Lyu, Yaran Wu, Yuting Wang, Yingru Zheng, Fengtian He
Both dichloroacetate (DCA) and metformin (Met) have shown promising antitumor efficacy by regulating cancer cell metabolism. However, the DCA-mediated protective autophagy and Met-induced lactate accumulation limit their tumor-killing potential respectively. So overcoming the corresponding shortages will improve their therapeutic effects. In the present study, we found that DCA and Met synergistically inhibited the growth and enhanced the apoptosis of ovarian cancer cells. Interestingly, we for the first time revealed that Met sensitized DCA via dramatically attenuating DCA-induced Mcl-1 protein and protective autophagy, while DCA sensitized Met through markedly alleviating Met-induced excessive lactate accumulation and glucose consumption...
July 19, 2016: Oncotarget
Damien Sémely, Emily Bennett, Christine Vallejo, Franck Saint-Marcoux, Louis Merle, Yves Nouaille, Gérard Lachâtre, Marie-Laure Laroche
OBJECTIVE: Metformin-associated lactic acidosis (MALA) is a rare but serious adverse reaction with a mortality rate of up to 50%. Unfortunately, diagnosis and care management are often delayed. The objective was to assess the impact on the mortality rate and length of hospital stay of a MALA early diagnosis procedure in diabetic patients with metformin at emergency department (ED) admission. METHOD: From 1/7/2012, a new MALA diagnosis procedure (pH, lactate, metformin) was implemented in all diabetic patients with metformin just after their admission to the ED...
June 16, 2016: Thérapie
Suneel Kumar Garg, Omender Singh, Desh Deepak, Akhilesh Singh, Rohit Yadav, Kirti Vashist
We present a case of a 49-year-old female with an alleged history of ingestion of approximately 100 tablets of metformin (850 mg each). Investigations revealed severe lactic acidosis with lactate levels of 13.5 mmol/L and pH of 7.17. This indicates severe toxicity and is associated with a high mortality. Charcoal-based sorbent hemoperfusion was done as a desperate effort, as patient continued to deteriorate despite supportive care and high-volume continuous venovenous hemodiafiltration. The patient survived despite metformin-associated lactic acidosis related to severe metformin toxicity...
May 2016: Indian Journal of Critical Care Medicine
Silvia Peppicelli, Alessandra Toti, Elisa Giannoni, Francesca Bianchini, Francesca Margheri, Mario Del Rosso, Lido Calorini
Low extracellular pH promotes in melanoma cells a malignant phenotype characterized by an epithelial-to-mesenchymal transition (EMT) program, endowed with mesenchymal markers, high invasiveness and pro-metastatic property. Here, we demonstrate that melanoma cells exposed to an acidic extracellular microenvironment, 6.7±0.1, shift to an oxidative phosphorylation (Oxphos) metabolism. Metformin, a biguanide commonly used for type 2 diabetes, inhibited the most relevant features of acid-induced phenotype, including EMT and Oxphos...
July 17, 2016: Cell Cycle
A V Alexandrova, N V Pul'kova, D A Sakharov
We analyzed hepatotoxicity of three drugs: acetaminophen, metformin, and isoniazid. Spheroids of differentiated HepaRG cells cultured under microfluidic conditions were used as the model. Acute toxicity of substances was assessed by analyzing cell viability, while lactate concentration in the culture medium was used as the potential marker for evaluation of chronic exposure and non-lethal side effects of xenobiotics. The results were compared with mitochondrial activity and DNA fragmentation data. The efficiency and possibility of applying the integrated approach for assessment of drug hepatotoxicity are discussed...
May 2016: Bulletin of Experimental Biology and Medicine
Jing Jin, Hao Gu, Nicole M Anders, Tianhua Ren, Mali Jiang, Michael Tao, Qi Peng, Michelle A Rudek, Wenzhen Duan
Huntington's disease (HD) is a devastating neurodegenerative disease caused by the pathological elongation of the CAG repeats in the huntingtin gene. Caloric restriction (CR) has been the most reproducible environmental intervention to improve health and prolong life span. We have demonstrated that CR delayed onset and slowed disease progression in a mouse model of HD. Metformin, an antidiabetic drug, mimics CR by acting on cell metabolism at multiple levels. Long-term administration of metformin improved health and life span in mice...
May 25, 2016: Neuromolecular Medicine
Koji Harada, Tarannum Ferdous, Toyoko Harada, Yoshiya Ueyama
Cancer cells show enhanced glucose consumption and lactate production even in the presence of abundant oxygen, a phenomenon known as the Warburg effect, which is related to tumor proliferation, progression and drug-resistance in cancers. Hypoxia-inducible factor-1 (HIF-1) and several members of Phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway positively contribute to the Warburg effect, whereas AMP activated protein Kinase (AMPK) acts as a negative regulator...
July 2016: International Journal of Oncology
Ahmed Omar, Ruth Ellen, Alexander Sorisky
We report a case of metformin-associated lactic acidosis (MALA) in the setting of normal renal function and review the relevant medical literature. A 77-year-old female diagnosed with type 2 diabetes mellitus previously treated with insulin and gliclazide MR was started on metformin. A few weeks later, she was found to have lactic acidosis. Renal function was normal, and no severe underlying illness was identified. Metformin was discontinued, and lactate levels normalized within 4 days, suggesting metformin was a reversible precipitant of the lactic acidosis...
August 2016: Canadian Journal of Diabetes
Alessandro Protti, Paolo Properzi, Sandra Magnoni, Alessandro Santini, Thomas Langer, Silvia Guenzani, Stefano Ferrero, Giulia Bassani, Nino Stocchetti, Luciano Gattinoni
Lactic acidosis during metformin intoxication is classically mainly attributed to diminished lactate clearance through liver gluconeogenesis. Here we studied 6 healthy, sedated and mechanically ventilated pigs to clarify whether high dose of metformin also increases skeletal muscle lactate production. Each animal had two microdialysis catheters inserted in gluteus muscles, one per side. One catheter was infused with saline (control) while the other one was infused with metformin diluted in saline (1M), both at a rate of 0...
July 25, 2016: Toxicology Letters
Corinna Seliger, Anne-Louise Meyer, Kathrin Renner, Verena Leidgens, Sylvia Moeckel, Birgit Jachnik, Katja Dettmer, Ulrike Tischler, Valeria Gerthofer, Lisa Rauer, Martin Uhl, Martin Proescholdt, Ulrich Bogdahn, Markus J Riemenschneider, Peter J Oefner, Marina Kreutz, Arabel Vollmann-Zwerenz, Peter Hau
To this day, glioblastoma (GBM) remains an incurable brain tumor. Previous research has shown that metformin, an oral anti-diabetic drug, may decrease GBM cell proliferation and migration especially in brain tumor initiating cells (BTICs). As transforming growth factor β 2 (TGF-β2) has been reported to promote high-grade glioma and is inhibited by metformin in other tumors, we explored whether metformin directly interferes with TGF-β2-signaling. Functional investigation of proliferation and migration of primary BTICs after treatment with metformin+/-TGF-β2 revealed that metformin doses as low as 0...
July 2, 2016: Cell Cycle
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