Metabolic Effects Of Metformin Research Articles

Data-dependent and -independent acquisition lipidomics analysis reveals the tissue-dependent effect of metformin on lipid metabolism.

Despite the well-recognized health benefits, the mechanisms and site of action of metformin remains elusive. Metformin-induced global lipidomic changes in plasma of animal models and human subjects have been reported. However, there is a lack of systemic evaluation of metformin-induced lipidomic changes in different tissues. Metformin uptake requires active transporters such as organic cation transporters (OCTs), and hence, it is anticipated that metformin actions are tissue-dependent. In this study, we aim to characterize metformin effects in non-diabetic male mice with a special focus on lipidomics analysis. The findings from this study will help us to better understand the cell-autonomous (direct actions in target cells) or non-cell-autonomous (indirect actions in target cells) mechanisms of metformin and provide insights into the development of more potent yet safe drugs targeting a particular organ instead of systemic metabolism for metabolic regulations without major side effects. To characterize metformin-induced lipidomic alterations in different tissues of non-diabetic male mice and further identify lipids affected by metformin through cell-autonomous or systemic mechanisms based on the correlation between lipid alterations in tissues and the corresponding in-tissue metformin concentrations. A dual extraction method involving 80% methanol followed by MTBE (methyl tert-butyl ether) extraction enables the analysis of free fatty acids, polar metabolites, and lipids. Extracts from tissues and plasma of male mice treated with or without metformin in drinking water for 12days were analyzed using HILIC chromatography coupled to Q Exactive Plus mass spectrometer or reversed-phase liquid chromatography coupled to MS/MS scan workflow (hybrid mode) on LC-Orbitrap Exploris 480 mass spectrometer using biologically relevant lipids-containing inclusion list for data-independent acquisition (DIA), named as BRI-DIA workflow followed by data-dependent acquisition (DDA), to maximum the coverage of lipids and minimize the negative effect of stochasticity of precursor selection on experimental consistency and reproducibility. Lipidomics analysis of 6 mouse tissues and plasma allowed a systemic evaluation of lipidomic changes induced by metformin in different tissues. We observed that (1) the degrees of lipidomic changes induced by metformin treatment overly correlated with tissue concentrations of metformin; (2) the impact on lysophosphatidylcholine (lysoPC) and cardiolipins was positively correlated with tissue concentrations of metformin, while neutral lipids such as triglycerides did not correlate with the corresponding tissue metformin concentrations; (3) increase of intestinal tricarboxylic acid (TCA) cycle intermediates after metformin treatment. The data collected in this study from non-diabetic mice with 12-day metformin treatment suggest that the overall metabolic effect of metformin is positively correlated with tissue concentrations and the effect on individual lipid subclass is via both cell-autonomous mechanisms (cardiolipins and lysoPC) and non-cell-autonomous mechanisms (triglycerides).

Metabolic effects of metformin in patients with type 2 diabetes mellitus and new coronavirus infection

Metabolic effects of metformin in patients with type 2 diabetes mellitus and new coronavirus infection

Anti-obesity and metabolic benefits of metformin: Comparison of different delivery routes

Obesity is a severe public health problem. Healthy lifestyle interventions are commonly recommended for fighting obesity. But they are hard to follow and have low efficacy. Pharmacotherapy and surgery are of high efficacy but are beset with side effects. Browning subcutaneous white adipose tissue (WAT) is a practical and efficient approach for combating obesity. Metformin, a commonly used FDA-approved antidiabetic drug, is potent to induce browning of WAT through phosphorylation and activation of AMP-activated protein kinase. However, oral administration of metformin has low oral bioavailability, fast renal clearance, and low target specificity that limit metformin's application in browning WAT. Local and transdermal delivery of metformin directly to subcutaneous WAT using injection or microneedle (MN) in combination with iontophoresis (INT) may solve these problems. In this paper, we administered metformin to C57BL/6J obese mice using the following three routes: transdermal delivery (MN and INT), local injection into inguinal WAT (IgWAT, a type of subcutaneous WAT in mice), and oral gavage. The anti-obesity and metabolic effects of metformin via these delivery routes were determined and compared. As compared to local IgWAT injection and oral gavage delivery, transdermal delivery of metformin using MN and INT resulted in 9 % lower body weight and 7 % decrease in body fat% accompanied by improved energy metabolism and decreased inflammation through browning IgWAT in obese C57BL/6J mice. Transdermal delivery of metformin using MN and INT is an effective approach in browning subcutaneous WAT for combating obesity and improving metabolic health.

Diabetes, Metformin and the Clinical Course of Covid-19: Outcomes, Mechanisms and Suggestions on the Therapeutic Use of Metformin.

Objectives: Pre-existing or new diabetes confers an adverse prognosis in people with Covid-19. We reviewed the clinical literature on clinical outcomes in metformin-treated subjects presenting with Covid-19. Methods: Structured PubMed search: metformin AND [covid (ti) OR covid-19 (ti) OR covid19 (ti) OR coronavirus (ti) OR SARS-Cov2 (ti)], supplemented with another PubMed search: “diabetes AND [covid OR covid-19 OR covid19 OR coronavirus (i) OR SARS-Cov2 (ti)]” (limited to “Clinical Study”, “Clinical Trial”, “Controlled Clinical Trial”, “Meta-Analysis”, “Observational Study”, “Randomized Controlled Trial”, “Systematic Review”). Results: The effects of metformin on the clinical course of Covid-19 were evaluated in retrospective analyses: most noted improved clinical outcomes amongst type 2 diabetes patients treated with metformin at the time of hospitalisation with Covid-19 infection. These outcomes include reduced admission into intensive care and reduced mortality in subgroups with versus without metformin treatment. Conclusion: The pleiotropic actions of metformin associated with lower background cardiovascular risk may mediate some of these effects, for example reductions of insulin resistance, systemic inflammation and hypercoagulability. Modulation by metformin of the cell-surface ACE2 protein (a key binding target for SARS-CoV 2 spike protein) via the AMP kinase pathway may be involved. While pre-existing metformin treatment offers potentially beneficial effects and can be continued when Covid-19 infection is not severe, reports of increased acidosis and lactic acidosis in patients with more severe Covid-19 disease remind that metformin should be withdrawn in patients with hypoxaemia or acute renal disease. Prospective study of the clinical and metabolic effects of metformin in Covid-19 is warranted.

Cholinergic and metabolic effects of metformin in mouse brain

Metformin is widely used as a first-line treatment for type 2 diabetes, but central effects of metformin have received little attention. When metformin (200 mg/kg i.p.) was administered to C57Bl6 mice, metformin concentration in cerebrospinal fluid peaked at 29 μM after 30 min but dropped quickly and was low at 90 min. In mouse hypothalamus sampled by microdialysis, systemically administered metformin caused minor and transient increases of acetylcholine, glucose and lactate while choline levels decreased. When metformin (0.2−10 mM) was locally infused via retrodialysis, there was a short-lasting increase of acetylcholine in the hypothalamus. Extracellular lactate levels in hypothalamus showed a massive increase upon metformin infusion while glucose levels decreased. In isolated mitochondria of mouse brain, metformin inhibited oxygen consumption and the activity of complex I. Inhibition of mitochondrial respiration likely explains lactate formation in the brain during metformin infusion which may cause lactic acidosis during metformin intoxication. The changes of cholinergic activity in the hypothalamus may be associated with appetite suppression observed during metformin treatment.

Efficacy of metformin and fermentable fiber combination therapy in adolescents with severe obesity and insulin resistance: study protocol for a double-blind randomized controlled trial

BackgroundAccumulating evidence suggests that the metabolic effects of metformin and fermentable fibers are mediated, in part, through diverging or overlapping effects on the composition and metabolic functions of the gut microbiome. Pre-clinical animal models have established that the addition of fiber to metformin monotherapy improves glucose tolerance. However, possible synergistic effects of combination therapy (metformin plus fiber) have not been investigated in humans. Moreover, the underlying mechanisms of synergy have yet to be elucidated. The aim of this study is to compare in adolescents with obesity the metabolic effects of metformin and fermentable fibers in combination with those of metformin or fiber alone. We will also determine if therapeutic responses correlate with compositional and functional features of the gut microbiome.MethodsThis is a parallel three-armed, double-blinded, randomized controlled trial. Adolescents (aged 12–18 years) with obesity, insulin resistance (IR), and a family history of type 2 diabetes mellitus (T2DM) will receive either metformin (850 mg p.o. twice/day), fermentable fibers (35 g/day), or a combination of metformin plus fiber for 12 months. Participants will be seen at baseline, 3, 6, and 12 months, with a phone follow-up at 1 and 9 months. Primary and secondary outcomes will be assessed at baseline, 6, and 12 months. The primary outcome is change in IR estimated by homeostatic model assessment of IR; key secondary outcomes include changes in the Matsuda index, oral disposition index, body mass index z-score, and fat mass to fat-free mass ratio. To gain mechanistic insight, endpoints that reflect host-microbiota interactions will also be assessed: obesity-related immune, metabolic, and satiety markers; humoral metabolites; and fecal microbiota composition, short-chain fatty acids, and bile acids.DiscussionThis study will compare the potential metabolic benefits of fiber with those of metformin in adolescents with obesity, determine if metformin and fiber act synergistically to improve IR, and elucidate whether the metabolic benefits of metformin and fiber associate with changes in fecal microbiota composition and the output of health-related metabolites. This study will provide insight into the potential role of the gut microbiome as a target for enhancing the therapeutic efficacy of emerging treatments for T2DM prevention.Trial registrationClinicalTrials.gov NCT04578652. Registered on 8 October 2020.

Efficacy and Safety of Metformin in Gestational Diabetes Mellitus

Background: Gestational Diabetes Mellitus (GDM) is a sequence of serious unfavorable maternal and perinatal outcomes specially if uncontrolled. Although insulin is a standard therapy, Metformin can be used as an alternative medication to insulin. This study aimed to establish the efficacy, safety, and other metabolic effects of metformin in GDM due to limited studies in the local population. Methods: This quasi experimental trial was conducted on pregnant female at 24 weeks of gestation and above, presenting to Ziauddin Hospital. A total of 361 patients who were diagnosed with GDM were enrolled. Patients were divided into three groups: diet control, metformin, and metformin with insulin. The Chi Square and ANOVA were used to compare the maternal and neonatal outcomes. Further post hoc analysis of significant parameters was done using Tukey HSD test. Results: Weight gain in pregnancy and gestational age at delivery gives significant mean differences across three study groups (p=<0.01). In diet control group, weight was significantly gained as compare to metformin group. Similarly, the gestational age in diet control group was significantly higher as compare to metformin and metformin with insulin group (p=<0.01). The higher gestational age was found in patients treated with metformin as compared to metformin with insulin group (37.25±1.41). Conclusion: Metformin alone as well as in combination with insulin, is a safe, effective treatment option and more acceptable to women with GDM. Metformin has shown to cause less weight gain during pregnancy with minimal risk of maternal and neonatal hypoglycemia. Keywords: Gestational Diabetes Mellitus; Metformin; Insulin

Characterising cell intrinsic and whole body metabolic effects of metformin in prostate cancer

Characterising cell intrinsic and whole body metabolic effects of metformin in prostate cancer

Effect of Metformin For Decreasing Proliferative Marker in Women with Endometrial Cancer: A Randomized Double-blind Placebo-Controlled Trial.

Objective:To compare the Ki-67 index of endometrial cancer cells before and after treatment between the metformin and placebo group in women with endometrial cancer (EC). Methods:This study was a randomized, double-blind, placebo-controlled trial conducting in non-diabetic women who diagnosed with endometrioid EC and had a schedule for elective surgical staging at Rajavithi Hospital between August 2018 and June 2019. Tissue specimens were obtained via endometrial curettage at the time of initial diagnosis (pre-treatment) and hysterectomy (post-treatment) to assess the value of the Ki-67 index by immunochemistry. Patients were randomly assigned into 2 groups: metformin and placebo group. Metformin 850 mg or placebo 1 tab were administered once daily for at least 7 days, starting on the first morning after recruitment until one day before surgery. Baseline characteristics (e.g., age, body mass index, co-morbidities) including surgical and pathological characteristics were recorded. The metabolic effect of metformin was also evaluated by a recording of fasting blood sugar, HbA1C and potential adverse events including nausea, vomiting, dizziness, and hypoglycemic symptom. Results:A total of 49 EC patients were included in this study. Twenty-five patients were assigned to the metformin group and 24 patients were assigned to the placebo group. Baseline demographic, surgical, and pathological characteristics between the 2 groups were similar. Metformin significantly changed the Ki-67 index relative to placebo, with a mean decrease of 23.3% (p=0.001) and a mean proportional decrease of 39.1% (p=0.006) before and after treatment. Additionally, no significant differences were detected in metabolic effects and adverse events between the metformin and the placebo groups. Conclusion:Short-term treatment with an oral metformin significantly reduced a proliferative marker Ki-67 index in women with endometrioid EC awaiting surgical staging. This study supports the biological effect of metformin in EC and potential applications in the adjuvant treatment in EC patients.

The metabolic effects of metformin, cyproterone-acetate and their combination in women with polycystic ovary syndrome

The metabolic effects of metformin, cyproterone-acetate and their combination in women with polycystic ovary syndrome

Metabolic Effects of Metformin in the Failing Heart.

Accumulating evidence shows that metformin is an insulin-sensitizing antidiabetic drug widely used in the treatment of type 2 diabetes mellitus (T2DM), which can exert favorable effects on cardiovascular risk and may be safely used in patients with heart failure (HF), and even able to reduce the incidence of HF and to reduce HF mortality. In failing hearts, metformin improves myocardial energy metabolic status through the activation of AMP (adenosine monophosphate)-activated protein kinase (AMPK) and the regulation of lipid and glucose metabolism. By increasing nitric oxide (NO) bioavailability, limiting interstitial fibrosis, reducing the deposition of advanced glycation end-products (AGEs), and inhibiting myocardial cell apoptosis metformin reduces cardiac remodeling and hypertrophy, and thereby preserves left ventricular systolic and diastolic functions. While a lot of preclinical and clinical studies showed the cardiovascular safety of metformin therapy in diabetic patients and HF, to confirm observed benefits, the specific large-scale trials configured for HF development in diabetic patients as a primary endpoints are necessary.

Gut Incretin Release as a Mediator of Metabolic Effects of Metformin in Type 2 Diabetic Patients with Chronic Heart Failure

Introduction: Metformin (MET) is a 1st choice drug used in patients with type 2 diabetes (DM). Treatment with MET in patient with DM and heart failure (HF) is associated with better cardiovascular outcomes, but mechanisms of MET-mediated effects are unexplained. Our aim was to evaluate the effects of MET on substrate metabolism, cardiac function and structure in patient with DM and HF. Methods: 40 patients with DM and stable chronic HF (age: 59 ± 9 years) were studied in a random sequence cross-over clinical study testing the effect of 3-month usage of MET vs. placebo. The subjects were randomized to MET (2 g/day) or to placebo group. After the three months of treatment the medication was changed and the treatment continued for next 3 months. At the beginning and the end of each intervention period (3 times in total) the panel of various metabolic and cardiovascular tests was done: echocardiography, spiroergometry and meal test with evaluation of several variables like incretins (GLP-1 and peptide YY) and parameters of oxidative stress (MCP-1, TNFα). Results: Compared to placebo, MET was accompanied with significantly higher increase of selected gut-related hormones. GLP-1 area-under-curve increased during the meal test (MET vs. PL: 8571.39±6899.57 vs. 5665.82±4580.57pmol.hour.l-1; p<0.01). Also the peptide YY area-under-curve increased during the meal test (MET vs. PL: 29809.67±13442.43 vs. 23636.21±8183.08pmol.hour.l-1; p<0.05). MCP-1 showed inconsistent trend to increase during meal test. Fasted levels of TNFα were higher after MET, but there was no change during the meal test compared to placebo. MET therapy led to reduction of HbA1C (p<0.001) and reduced glucose area-under-curve (p<0.001) during glucose tolerance test. MET had neutral effect on cardiac structure and function. Conclusions: Our results suggest that metabolic effects of MET might be mediated by improvement of gut endocrine function. MET had neutral effect on cardiac function or structure. Disclosure E. Stolarikova: None. J. Kopecky: None. J. Veleba: None. K. Velebova: None. L. Belinova: None. V. Melenovsky: None. J. Kopecky: None. T. Pelikanova: None.

Concentration-dependent metabolic effects of metformin in healthy and Fanconi anemia lymphoblast cells.

Metformin (MET) is the drug of choice for patients with type 2 diabetes and has been proposed for use in cancer therapy and for treating other metabolic diseases. More than 14,000 studies have been published addressing the cellular mechanisms affected by MET. However, several in vitro studies have used concentrations of the drug 10-100-fold higher than the plasmatic concentration measured in patients. Here, we evaluated the biochemical, metabolic, and morphologic effects of various concentrations of MET. Moreover, we tested the effect of MET on Fanconi Anemia (FA) cells, a DNA repair genetic disease with defects in energetic and glucose metabolism, as well as on human promyelocytic leukemia (HL60) cell lines. We found that the response of wild-type cells to MET is concentration dependent. Low concentrations (15 and 150 µM) increase both oxidative phosphorylation and the oxidative stress response, acting on the AMPK/Sirt1 pathway, while the high concentration (1.5 mM) inhibits the respiratory chain, alters cell morphology, becoming toxic to the cells. In FA cells, MET was unable to correct the energetic/respiratory defect and did not improve the response to oxidative stress and DNA damage. By contrast, HL60 cells appear sensitive also at 150 μM. Our findings underline the importance of the MET concentration in evaluating the effect of this drug on cell metabolism and demonstrate that data obtained from in vitro experiments, that have used high concentrations of MET, cannot be readily translated into improving our understanding of the cellular effects of metformin when used in the clinical setting.

Immediate reduction of serum citrulline but no change of steroid profile after initiation of metformin in individuals with type 2 diabetes

Metformin is the most important first-line treatment for type 2 diabetes mellitus (T2DM) but its exact mode of action remains unknown. In this study, we used targeted metabolomics to gain new insights into the metabolic effects of metformin in humans with T2DM. We also examined changes in the serum steroid hormone profile. We quantified 167 serum metabolites and 19 steroid hormones using liquid chromatography-tandem mass spectrometry at three time points in individuals with previously untreated T2DM: before the start of metformin therapy (time point A), after the first dose (B) and after short-term therapy for 4–6 weeks (C). For metabolite analysis, we split the study cohort into a discovery and a replication study of 88 and 45 subjects, respectively. The statistical analysis was done using linear mixed-effects models. Among the metabolites quantified, citrulline showed the most pronounced changes. Compared to its baseline serum concentration, citrulline was reduced by 17% after the first dose of metformin (p=1.34E-07) and by 24% after short-term therapy (p=2.84E-08) in the discovery study. These results were confirmed in the replication study. The only other metabolite significantly changed after correction for multiple testing was PC ae C36:4 between baseline and 4–6 weeks. The serum steroid hormone profile showed no significant changes after metformin intake. In summary, we observed an immediate and sustained reduction of serum citrulline by metformin in humans. This may be relevant for some of the wanted or unwanted effects of the drug.

Metformin in type 1 diabetes

In The Lancet Diabetes & Endocrinology, John Petrie and colleagues report the main outcome results of the REducing with MetfOrmin Vascular Adverse Lesions (REMOVAL) study, 1 Petrie JR Chaturvedi N Ford I et al. REMOVAL Study GroupCardiovascular and metabolic effects of metformin in patients with type 1 diabetes (REMOVAL): a double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2017; (published online June 11)http://dx.doi.org/10.1016/S2213-8587(17)30194-8 PubMed Google Scholar a well designed, double-blind, randomised, placebo-controlled trial in 428 adult patients (40 years and older) with type 1 diabetes and multiple cardiovascular risk factors. The aim of REMOVAL was to investigate the effects of metformin (1000 mg twice daily) on intima-media thickening of the common carotid artery (cIMT)—a surrogate measure of atherosclerosis—as well as on metabolic and other outcomes over 3 years. Cardiovascular and metabolic effects of metformin in patients with type 1 diabetes (REMOVAL): a double-blind, randomised, placebo-controlled trialThese data do not support use of metformin to improve glycaemic control in adults with long-standing type 1 diabetes as suggested by current guidelines, but suggest that it might have a wider role in cardiovascular risk management. Full-Text PDF

Cardiovascular and metabolic effects of metformin in patients with type 1 diabetes (REMOVAL): a double-blind, randomised, placebo-controlled trial

Metformin might reduce insulin requirement and improve glycaemia in patients with type 1 diabetes, but whether it has cardiovascular benefits is unknown. We aimed to investigate whether metformin treatment (added to titrated insulin therapy) reduced atherosclerosis, as measured by progression of common carotid artery intima-media thickness (cIMT), in adults with type 1 diabetes at increased risk for cardiovascular disease. REMOVAL was a double-blind, placebo-controlled trial undertaken at 23 hospital diabetes clinics in five countries (Australia, Canada, Denmark, the Netherlands, and the UK). Adults aged 40 years and older with type 1 diabetes of at least 5 years' duration and at least three of ten specific cardiovascular risk factors were randomly assigned (via an interactive voice response system) to oral metformin 1000 mg twice daily or placebo. Participants and site staff were masked to treatment allocation. The primary outcome was averaged mean far-wall cIMT, quantified annually for 3 years, analysed in a modified intention-to-treat population (all randomly assigned participants with post-randomisation data available for the outcome of interest at any given timepoint, irrespective of subsequent adherence or study participation), using repeated measures regression. Secondary outcomes were HbA1c, LDL cholesterol, estimated glomerular filtration rate (eGFR), incident microalbuminuria (not reported), incident retinopathy, bodyweight, insulin dose, and endothelial function, also analysed in all participants with post-randomisation data available for the outcome of interest at any given timepoint. This trial is registered with ClinicalTrials.gov, number NCT01483560. Between Dec 14, 2011, and June 24, 2014, 493 participants entered a 3 month run-in to optimise risk factor and glycaemic control (single-blind placebo in the final month). Of 428 randomly assigned patients, 219 were allocated to metformin and 209 to placebo. Progression of mean cIMT was not significantly reduced with metformin (-0·005 mm per year, 95% CI -0·012 to 0·002; p=0·1664), although maximal cIMT (a prespecified tertiary outcome) was significantly reduced (-0·013 mm per year, -0·024 to -0·003; p=0·0093). HbA1c (mean 8·1% [SD 0·9] for metformin and 8·0% [0·8] for placebo at baseline) was reduced on average over 3 years by metformin (-0·13%, 95% CI -0·22 to -0·037; p=0·0060), but this was accounted for by a reduction at the 3-month timepoint (-0·24%, -0·34 to -0·13; p<0·0001) that was not sustained thereafter (p=0·0163 for visit-by-treatment interaction). Bodyweight (-1·17 kg, 95% CI -1·66 to -0·69; p<0·0001) and LDL cholesterol (-0·13 mmol/L, -0·24 to -0·03; p=0·0117) were reduced with metformin over 3 years of treatment, and eGFR was increased (4·0 mL/min per 1·73m2, 2·19 to 5·82; p<0·0001). Insulin requirement was not reduced on average over 3 years (-0·005 units per kg, 95% CI -0·022 to 0·012; p=0·545), but there was a significant visit-by-treatment interaction (p=0·0018). There was no effect on endothelial function as measured by reactive hyperaemia index, or on retinopathy. Discontinuation of treatment in 59 (27%) participants on metformin versus 26 (12%) on placebo (p=0·0002) was mainly due to an excess of gastrointestinal adverse effects, and there was no increase in hypoglycaemia with metformin. Five deaths occurred among patients allocated to metformin and two occurred among those allocated to placebo; none were judged by site principal investigators to be related to study medication. These data do not support use of metformin to improve glycaemic control in adults with long-standing type 1 diabetes as suggested by current guidelines, but suggest that it might have a wider role in cardiovascular risk management. JDRF.

Synergistic cell death in FLT3-ITD positive acute myeloid leukemia by combined treatment with metformin and 6-benzylthioinosine

Current therapy for acute myeloid leukemia (AML) primarily includes high-dose cytotoxic chemotherapy with or without allogeneic stem cell transplantation. Targeting unique cellular metabolism of cancer cells is a potentially less toxic approach. Monotherapy with mitochondrial inhibitors like metformin have met with limited success since escape mechanisms such as increased glycolytic ATP production, especially in hyperglycemia, can overcome the metabolic blockade. As an alternative strategy for metformin therapy, we hypothesized that the combination of 6-benzylthioinosine (6-BT), a broad-spectrum metabolic inhibitor, and metformin could block this drug resistance mechanism. Metformin treatment alone resulted in significant suppression of ROS and mitochondrial respiration with increased glycolysis accompanied by modest cytotoxicity (10–25%). In contrast, 6-BT monotherapy resulted in inhibition of glucose uptake, decreased glycolysis, and decreased ATP with minimal changes in ROS and mitochondrial respiration. The combination of 6-BT with metformin resulted in significant cytotoxicity (60–70%) in monocytic AML cell lines and was associated with inhibition of FLT3-ITD activated STAT5 and reduced c-Myc and GLUT-1 expression. Therefore, although the anti-tumor and metabolic effects of metformin have been limited by the metabolic reprogramming within cells, the novel combination of 6-BT and metformin targets this bypass mechanism resulting in reduced glycolysis, STAT5 inhibition, and increased cell death.

Comparison clinical and metabolic effects of metformin and pioglitazone in polycystic ovary syndrome.

Introduction:Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women. PCOS comprises a broad spectrum of anomalies, including hyperandrogenism, chronic anovulation, obesity, and infertility. Insulin resistance and its compensatory hyperinsulinemia play a key role in the pathogenicity of PCOS. This study compares the effects of 2 types of insulin sensitizer drugs, metformin and pioglitazone, on clinical, metabolic, and endocrine characteristics of women with PCOS.Methods:In this randomized clinical trial, 56 women with PCOS (ages 20–49 years) were treated orally with either metformin (500 mg 3 times daily) or pioglitazone (30 mg daily) for 3 months. Clinical (body weight, blood pressure [BP], and body mass index) and laboratory indices (fasting blood sugar [FBS], serum triglyceride [TG], cholesterol, low-density lipoprotein, high-density lipoprotein, insulin, testosterone, and dehydroepiandrosterone [DHEA]) were measured before and after therapy. Data were analyzed by Chi-square and McNemar's tests.Results:Significant decreases were seen after treatment with metformin in extent of hair loss (P = 0.008), wrist circle (P = 0.011), weight (P = 0.047), diastolic BP (P = 0.023), and DHEA (P = 0.035). A significant decrease in TG was seen with pioglitazone treatment (P = 0.047). In both groups, significant decreases in acne, menstrual disturbance, FBS, and serum insulin were seen.Conclusion:There is a significant amelioration of endocrine and metabolic indices with pioglitazone in PCOS patients. Although we were not able to recommend one treatment regime over the other, pioglitazone offers a useful, alternate treatment in women with PCOS who are not able to tolerate metformin.

Abstract A24: Integration of tumor metabolomics, cancer genome sequencing and dynamic functional imaging to assess the metabolic effects of metformin in breast cancer

Abstract There is great interest in the effects on cancer metabolism of the diabetes drug, metformin and its potential as a cancer treatment. Despite intense investigation it is still not clear as to its metabolic effects on primary human cancer in vivo. 41 patients with primary breast cancer were recruited to a ‘window of opportunity study’ prior to neoadjuvant chemotherapy. Before and after 2 weeks of metformin, dynamic 18F-FDG PET-CT scans were carried out, breast core biopsies of the primary tumour taken for RNASeq, metabolomics and immunohistochemistry analysis and host serum metabolic markers assessed. Metabolomic mass spectrometry analysis revealed an increase in the ADP/ATP and AMP/ATP ratio (fold change 8.6 and 24.9, respectively, p = 0.07 and p = 0.14) after metformin treatment. RNA sequencing of the first 21 paired samples showed upregulation of many genes encoding components of complex 1, and the TCA cycle, glutaminolysis, and glycolysis pathways. Several genes encoding for glucose and glutamine transport were amongst those most consistently upregulated, including GLUT1, SLC38A1 and SLC7A5 (all p&amp;lt;0.0001). Dynamic PET-CT analysis of the first 17 paired scans demonstrated a trend toward a decrease in the variable K2 post-metformin (an estimate of 18F-FDG efflux from tumour intracellular pool back to blood), but with much variability between paired scans (0.70±0.11 vs 0.51±0.05 (p=0.14)). There was a decrease in serum C-peptide (0.56±0.04nmol/L vs 0.48±0.02nmol/L, pre- and post-metformin, p=0.003) consistent with reduced host insulin secretion. This is the first study in the clinical setting to show that metformin can cause an energy stress in cancer cells. The effect on mRNA expression was compatible with direct mitochondrial effects on the cancer cell leading to upregulation of the glutaminolysis and glycolysis pathways. The decrease in efflux of radiolabelled glucose may indicate retention of glucose possibly secondary to changes in blood glucose availability. We expect this study will help define biomarker development and future treatment strategies for metformin, in particular potential combination therapy. Note: This abstract was not presented at the conference. Citation Format: Simon R. Lord, Nilay Patel, D. Liu, J. Fenwick, C. Frezza, S. Henriques da Costa, E. Gaude, Q. Zhang, M. Wakelam, F. Gleeson, S. Haider, F. Buffa, A. L. Harris. Integration of tumor metabolomics, cancer genome sequencing and dynamic functional imaging to assess the metabolic effects of metformin in breast cancer [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A24.

Potential and real 'antineoplastic' and metabolic effect of metformin in diabetic and nondiabetic postmenopausal females.

The goal of this study was to determine if the single nucleotide polymorphisms marking potential sensitivity to metformin (MF) correlate with hormone-metabolic status as well as with actual response to MF in postmenopausal cancer patients with or without Type 2 diabetes mellitus and in diabetics without cancer. The carriage of ten different SNPs was evaluated in all patients by PCR, and hormone-metabolic status was estimated by anthropometry, ELISA and enzyme colorimetric assays. The response to daily 1-1.7 g of MF was studied based on hormone-metabolic parameters and indirect end points (endometrium thickness, mammographic breast density). The changes in evaluated 'antineoplastic' and metabolic response marker values were seen in 33.3 and 61.8% of the cases, respectively. Several genetic markers were found that showed an inclination to less frequent 'antineoplastic' or more frequent metabolic response to MF which may be helpful in further studies of this drug in cancer patients.