Metformin
Drugs

If_you_take_metformin_and_have_been_feeling_weaker

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Video

Sito farmaco

Association of B12 deficiency and clinical neuropathy with metformin use in type 2 diabetes patients, 2013

L’EMA estende l’uso della metformina per il trattamento del diabete di tipo 2

Use of metformin to treat diabetes now expanded to patients with moderately reduced kidney function

Mitochondrial dysfunction in breast cancer cells prevents tumor growth: understanding chemoprevention with metformin. 2013

• Metformin is a well-established diabetes drug that prevents the onset of most types of human cancers in diabetic patients, especially by targeting cancer stem cells. Metformin exerts its protective effects by functioning as a weak "mitochondrial poison," as it acts as a complex I inhibitor and prevents oxidative mitochondrial metabolism (OXPHOS). Thus, mitochondrial metabolism must play an essential role in promoting tumor growth. To determine the functional role of "mitochondrial health" in breast cancer pathogenesis, here we used mitochondrial uncoupling proteins (UCPs) to genetically induce mitochondrial dysfunction in either human breast cancer cells (MDA-MB-231) or cancer-associated fibroblasts (hTERT-BJ1 cells). Our results directly show that all three UCP family members (UCP-1/2/3) induce autophagy and mitochondrial dysfunction in human breast cancer cells, which results in significant reductions in tumor growth. Conversely, induction of mitochondrial dysfunction in cancer-associated fibroblasts has just the opposite effect. More specifically, overexpression of UCP-1 in stromal fibroblasts increases β-oxidation, ketone body production and the release of ATP-rich vesicles, which "fuels" tumor growth by providing high-energy nutrients in a paracrine fashion to epithelial cancer cells. Hence, the effects of mitochondrial dysfunction are truly compartment-specific. Thus, we conclude that the beneficial anticancer effects of mitochondrial inhibitors (such as metformin) may be attributed to the induction of mitochondrial dysfunction in the epithelial cancer cell compartment. Our studies identify cancer cell mitochondria as a clear target for drug discovery and for novel therapeutic interventions.

Effect of metformin on the urinary metabolites of diet-induced-obese mice studied by ultra performance liquid chromatography coupled to time-of-flight mass spectrometry (UPLC-TOF/MS). 2013

• Obesity is becoming a health concern worldwide and metformin, a first line anti-diabetic drug, was associated with weight loss under different backgrounds. However, most researches focused on the anti-diabetic mechanism and less attention has been paid on the mechanism of weight loss of metformin. Therefore, we established a metabonomic method to evaluate metformin action in preventing obesity in a high fat diet-induced-obesity (DIO) mice model. 36 male C57BL/6 mice (8-week old) were randomly divided into control group (n=12, normal chow), model group (n=12, high fat chow) and metformin group (n=12, high fat chow and dosed with metformin) over 16 weeks. A urinary metabonomic study using UPLC-TOF/MS was performed in combination with multivariate statistical analysis. In addition, indices of body weight and food intake as well as fasting blood glucose, fed blood glucose, oral glucose tolerance test (OGTT) and plasma insulin were collected. Significant weight loss in metformin-treated mice was achieved and 21 potential biomarkers were identified. Decreased glucose, myristic acid, stearidonic acid, lysoPC (16:0), lysoPC (18:0), L-glutamic acid, L-methionine, L-threonine, L-phenylalanine, L-histidine, L-carnitine, L-malic acid and pantothenic acid in urine indicated that metformin may have exerted effects on energy metabolism. Further, based on the biomarkers, we cautiously propose that tricarboxylic acid cycle (TCA) may have been compromised by metformin and might contribute to the activation of adenosine monophosphate kinase (AMPK), then AMPK activation led to more β-oxidation of certain fatty acids and augmented lipolysis and thus induced weight loss. Related cellular and molecular studies are being considered to further investigate the underlying mechanism.

Metformin as Anti-Tumor Agent

PRO

Metformin Shows Promise as Potential Anti-Tumor Agent.
Sunday August 2, 2009
A study from the University of Texas M.D. Anderson Cancer Center shows a possible link between the diabetes drug, metformin, and better outcomes for women with breast cancer.
(gonzaleg-Angulo JCO july 2009 see attachment below)
The study consisted of 2,529 women with breast cancer who had chemotherapy before surgery. 155 of the women were diabetic and 87 of those women were taking metformin at time of the study.
The group with the highest "cancer-free" rate after chemotherapy and before surgery, were the diabetic women who were taking metformin. 24% of that group were free from cancer compared to 8% of the diabetic women who were not taking metformin and 16% of the women who did not have diabetes.
"http://diabetes.about.com/b/2009/08/02/metformin-shows-promise-as-potential-anti-tumor-agent.htm"

Low doses of the commonly used diabetes drug metformin may be an effective treatment for breast cancer, primarily because the drug appears to target breast cancer stem cells, Harvard Medical School researchers reported online September 14 in Cancer Research. Cancer stem cells, also called tumor-initiating cells, are thought to be relatively rare cells that can give rise to new tumors and are resistant to standard cancer treatments.
In the study, the combination of metformin and the chemotherapy agent doxorubicin was more effective than either drug alone at eliminating cancer cells and cancer stem cells in cultured cell lines of four genetically distinct breast cancer types, including HER2-positive and triple-negative breast cancers. In a breast cancer mouse model, the drug combination eliminated tumors and prevented regrowth, whereas doxorubicin alone only reduced tumor size and did not prevent regrowth, and metformin alone had little effect.
With both drugs, regression was quicker and, more importantly, there was no relapse.
When the researchers analyzed cell populations taken from the tumors of mice after three cycles of treatment, they found almost no cancer stem cells in the animals that received the drug combination but found the stem cells easily in tumors from mice given only doxorubicin. The highly beneficial effect of the combination treatment and the limited effect of either drug alone support the cancer stem cell hypothesis.
"http://www.cancer.gov/ncicancerbulletin/092209/page3"

CONTRO

Am J Cardiovasc Drugs. 2007;7(3):219-24.
Effects of simvastatin and metformin on inflammation and insulin resistance in individuals with mild metabolic syndrome. 2007

Bulcão C, Ribeiro-Filho FF, Sañudo A, Roberta Ferreira SG.

Division of Endocrinology, Department of Internal Medicine, Federal University of São Paulo, São Paulo, Brazil. cbulcao@uol.com.br
Abstract

BACKGROUND: In addition to lipid-lowering and insulin-sensitizing actions, statins (HMG-CoA reductase inhibitors) and metformin may have pleiotropic effects. OBJECTIVE: To study the effect of simvastatin and metformin on insulin sensitivity and inflammatory markers. METHODS: Forty-one subjects with body mass index (BMI) 25-39.9 kg/m(2) and impaired glucose tolerance were randomized to receive simvastatin or metformin for 16 weeks. Blood samples were obtained for measurement of metabolic and inflammatory parameters before and after each treatment. RESULTS: As expected, when compared with simvastatin, metformin therapy resulted in significant reductions in mean BMI, fasting plasma glucose, and homeostasis model assessment-insulin resistance (HOMA-IR), whereas simvastatin treatment resulted in significantly reduced total cholesterol, low-density lipoprotein-cholesterol (LDL-C), and apolipoprotein B levels. Independently of the medication used, significant decreases in C-reactive protein (CRP) and interleukin (IL)-6 were detected from baseline to treatment end. CRP showed a mean reduction of 0.12 +/- 0.04 mg/dL (p = 0.002) over the 16-week intervention period and IL-6 a mean reduction was 0.35 +/- 0.17 pg/mL (p = 0.046). No change was observed in the tumor necrosis factor-alpha levels. Baseline values of CRP and IL-6 and their percentage declines were correlated (r = 0.71 and r = 0.67, respectively; p < 0.001). In simvastatin recipients, no correlation was detected between reductions in CRP or IL-6 and lipids, whereas in metformin recipients, reductions in inflammatory markers were not correlated to BMI and HOMA-IR. CONCLUSION: Our findings suggest that both metformin and simvastatin have similar beneficial effects on low-grade inflammation, in addition to their classical effects on glucose and lipid metabolism. Moreover, they confirm the importance of treating at-risk individuals even before the precipitation of overt diabetes mellitus or full-blown metabolic syndrome.

Metformina riduce Tsh in diabetici ipotiroidei
In pazienti diabetici con ipotiroidismo, l'impiego di metformina riduce in maniera significativa i livelli serici dell'ormone Tsh (thyroid stimulating hormone), senza incidere su quelli della tetra-iodotironina (T4). A stabilirlo è uno studio condotto da un gruppo italiano presso l'Università di Brescia. In particolare, il gruppo di ricerca coordinato da Carlo Cappelli ha valutato le variazioni a breve e lungo termine dei livelli di ormoni tiroidei sia in pazienti diabetici con ipotiroidismo, sottoposti o meno a terapie con levotiroxina (L-T4), sia in individui con diabete di tipo 2 e normali funzioni tiroidee. Dopo un anno di trattamento con metformina, è stato registrato un decremento di Tsh soltanto nei diabetici ipotiroidei trattati (da 2,37 a 1,41) o non trattati (da 4,5 a 2,93) con L-T4. Nessun cambiamento significativo è stato, invece, rilevato nei livelli circolanti di T4. "Il nostro suggerimento è quello di andare a rivalutare in maniera scrupolosa la funzionalità tiroidea in questi pazienti dopo 6-12 mesi di trattamento con metformina" ha commentato Cappelli (L.A.).

Diabetes Care 2009, 32, 1589-1590